GARN26 • Georgia RNs and APRNs 2025-2026

Table of Contents

GARN26 • Georgia RNs and APRNs 2025-2026

How to Receive Credit

NetCE 5 Hour Course #98190 • Supplements for Aging

98190 • Supplements for Aging

1. INTRODUCTION

2. SUPPLEMENT USE IN OLDER ADULTS

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

5. NUTRITIONAL SUPPLEMENTS

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #90484 • Asthma: Diagnosis and Management

90484 • Asthma: Diagnosis and Management

1. INTRODUCTION

2. HISTORY OF ASTHMA

3. DEFINITION

4. EPIDEMIOLOGY

5. RISK FACTORS

6. PATHOPHYSIOLOGY

7. DIAGNOSIS

8. MEDICAL TREATMENT AND MANAGEMENT

9. SPECIAL POPULATIONS

10. PSYCHOSOCIAL MANAGEMENT

11. PATIENT EDUCATION

12. CONCLUSION

13. RESOURCES

14. APPENDIX

Works Cited

NetCE 15 Hour Course #94280 • Pharmacologic and Medical Advances in Obesity Management

94280 • Pharmacologic and Medical Advances in Obesity Management

1. INTRODUCTION

2. DEFINITIONS OF OBESITY

3. EPIDEMIOLOGY

4. ETIOLOGY OF THE OBESITY EPIDEMIC

5. THE REGULATION OF BODY WEIGHT

6. OVERVIEW OF CLINICAL MANAGEMENT

7. ANTIOBESITY MEDICATIONS

8. BARIATRIC SURGICAL PROCEDURES AND DEVICES

9. CONCLUSION

10. APPENDIX: PHYSIOLOGY AND PATHOPHYSIOLOGY

Works Cited

Evidence-Based Practice Recommendations Citations

GARN26 • Georgia RNs and APRNs 2025-2026

Chelsey McIntyre, PharmD

Sharon M. Griffin, RN, PhD

Patricia Walters-Fischer, RN, BS

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

GARN26 • Georgia RNs and APRNs 2025-2026

Expiration Date: 10/31/2026

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

98190 • Supplements for Aging

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

Table of Contents

98190 • Supplements for Aging

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. SUPPLEMENT USE IN OLDER ADULTS

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

BEERS CRITERIA

DRUG INTERACTIONS

CONDITION INTERACTIONS

PRODUCT QUALITY

5. NUTRITIONAL SUPPLEMENTS

MULTIVITAMINS

INDIVIDUAL MICRONUTRIENTS

OTHER NUTRITIONAL SUPPLEMENTS

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

MUSCULOSKELETAL HEALTH

EYE HEALTH

CARDIOVASCULAR HEALTH

JOINT HEALTH

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

LIFESTYLE INTERVENTIONS

NUTRIENT SUPPLEMENTS

HERBAL SUPPLEMENTS

ENDOGENOUS SUBSTANCES

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98190 • Supplements for Aging

Education Category. Alternative Medicine

Release Date. 06/01/2024

Expiration Date. 05/31/2027

Course Overview

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

Audience

This course is designed for healthcare professionals whose older patients are taking or are interested in supplements.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 5 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 5 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 5 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 6 hours for Alabama nurses. NetCE designates this activity for 5 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-017-H04-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 5 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.5 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide healthcare professionals in all practice settings the knowledge necessary to increase their understanding of the supplements that may be used by their older adult patients.

Learning Objectives

Upon completion of this course, you should be able to:

1. List the dietary supplements most commonly used for age-related changes.

2. Explain the safety concerns associated with the use of natural products in older adults.

3. Discuss the risks and benefits of common vitamins and minerals in older adults.

4. Review the evidence for the use of dietary supplements for age-related changes in physical health.

5. Describe the proposed and actual effects of dietary supplements for dementia.

Faculty

Chelsey McIntyre, PharmD, is a clinical pharmacist who specializes in drug information, literature analysis, and medical writing. She earned her Bachelor of Science degree in Genetics from the University of California, Davis. She then went on to complete her PharmD at Creighton University, followed by a clinical residency at the Children’s Hospital of Philadelphia (CHOP). Dr. McIntyre held the position of Drug Information and Policy Development Pharmacist at CHOP until her move to Washington state in 2017, after which she spent the next six years as a clinical editor for Natural Medicines, a clinical reference database focused on natural products and alternative therapies. She continues to create rigorous professional analysis and patient education materials for various publications while also practicing as a hospital pharmacist. Her professional interests include provider and patient education, as well as the application of evidence-based research to patient care.

Faculty Disclosure

Contributing faculty, Chelsey McIntyre, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

As the population ages, maintaining both physical and cognitive health becomes increasingly important. In recent years, the use of dietary supplements, including vitamins, minerals, fibers, and proteins, has gained significant attention for their potential to improve various aspects of health. Older adults may turn to these supplements to address age-related deficiencies, enhancing physical vitality, and supporting cognitive function. This course is designed to provide a comprehensive review of the role of supplements in promoting well-being among older adults.

2. SUPPLEMENT USE IN OLDER ADULTS

Older adults, defined as those at least 65 years of age, are a rapidly growing portion of the United States population that is expected to make up 20% of the country's total population by 2030 [1]. As life expectancy and overall quality of life continues to improve for this age group, many older adults have shown an increased interest in taking an active role in their health, often seeking out alternative and complementary options for both prevention and treatment.

The term "complementary therapy" covers a wide range of modalities, from breathing exercises and yoga, to healing touch and massage, to herbs and vitamins. For many Americans, the most commonly utilized complementary therapy is dietary supplements, a category that includes herbal products, vitamins, minerals, fibers, probiotics, fish oil, and many more.

In fact, as of 2017, 70% of older adults reported using at least one dietary supplement. A full 54% reported taking two supplements and 29% reported taking four or more supplements. The most frequently used supplements were multivitamins, Vitamin D, calcium, and omega-3s. At least 9% also reported using an herbal/botanical product, a number that is likely to have increased since the time of this survey [2].

Most older adults reported using these products to improve overall health. Other commonly cited reasons included bone health, nutritional supplementation, heart health and cholesterol, and eye health. Women, who reported using supplements more often than men, were more likely to use supplements for musculoskeletal health. Not surprisingly, most of this use was not related to recommendations from healthcare professionals, although the use of calcium, vitamin D, iron, and fiber products, specifically, was more likely to be associated with a recommendation from a healthcare professional [2].

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

There are many physiological changes that occur as the body ages. These changes affect almost every organ system and can alter the way that the body responds to activity, food, and medications.

Some of the most striking changes occur in the musculoskeletal system. These changes often manifest as a reduced tolerance for physical activity, changes in overall mobility, and an increase in various forms of pain. As the body ages, it naturally loses muscle and water content and increases fat stores. It also loses bone mass and experiences a reduction in joint lubrication [3].

Most older adults are also aware of changes to their cardiovascular system. As the body ages, cardiac output decreases, along with resting and maximal heart rate. Conversely, systemic vascular resistance increases, which leads to increased blood pressure. The cardiovascular system in general has a reduced response to stress and a reduction in baroreceptor activity. Many older adults also have high levels of cholesterol. These changes increase the risk for various adverse cardiovascular outcomes, as well as an increased likelihood for cardiovascular adverse effects from medications and natural products [3].

Another commonly recognized change occurs in the nervous system. As the central nervous system ages, portions of the brain, such as the hippocampus and the frontal and temporal lobes, shrink in size, which reduces the capacity for short-term memory and executive function. Sleep patterns also change, commonly resulting in insomnia. Older adults also undergo a reduction in neuroreceptors and an increase in receptor sensitivity. This can increase sensitivity to medications and natural products that affect the nervous system, such as those with anticholinergic or sedating activity [3].

Reduced production of hormones, specifically estrogen in women and testosterone in men, can cause a myriad of changes to the body. Older adults also often experience a reduction in taste perception [3].

Many of the other changes that occur with aging are more likely to alter the body's response to foods and medications, without necessarily causing noticeable changes in physical function [3,4,5]:

- The liver undergoes a reduction in volume and blood flow, reducing the functional capacity to metabolize chemicals.

- The large intestine becomes less motile, which may impact the absorption of various nutrients and chemicals.

- The kidneys undergo a gradual reduction in overall mass and blood flow, which reduces the glomerular filtration rate (GFR). These changes can reduce the clearance of medications and other chemicals that are normally eliminated by the kidneys.

- Thinning skin can increase the absorption of chemicals that are applied topically, whether absorption is intended or not.

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

As mentioned, various physiologic changes place older adults at an increased risk for adverse reactions to medications and natural products. The most predictable effects occur in relation to reduced kidney and/or liver function. However, reduced body water and increased body fat can also significantly alter the distribution and storage of chemicals in the body, which can increase sensitivity to the chemical and alter the likelihood for adverse effects.

In fact, medication-related adverse effects occur up to seven times more frequently in older adults when compared with younger adults. As many natural products are physiologically active and are cleared by the kidney and/or liver, this increased risk applies to natural products as well [6].

BEERS CRITERIA

Many healthcare professionals are familiar with the Beers Criteria, a list of drugs and drug classes that an expert panel, led by the American Geriatrics Society (AGS), considers to be potentially inappropriate for use in older adults. These include medications that are potentially harmful in all older adults, as well as those considered to be of concern in older adults with specific conditions or who are taking specific medications. In essence, this list identifies medications and medication classes for which potential harm is thought to outweigh expected benefit [7].

Although this list does not specifically include natural products, healthcare professionals should keep in mind that many supplements have pharmacological effects, some of which fall into classes listed on the Beers Criteria.

For example, sedative medications are a concern in older adults and should be used with caution. Many natural products are known to have clinically significant sedative effects and should thus be used with caution. Some common examples include kava, hops, passionflower, and valerian [8]. Anticholinergic medications are also considered to be of high concern in older adults. Some natural products, including bitter yam, European barberry, muira puama, and scopolia, have potent anticholinergic effects [9].

Various supplements also have anti-inflammatory activity, which may introduce many of the risks associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Similarly, many supplements can increase the risk of bleeding and should be used with caution in this population.

DRUG INTERACTIONS

Older adults are often prescribed multiple medications, which increases their risk of drug-drug and drug-supplement interactions. In fact, in the 2017 survey discussed earlier, older adults that reported taking at least three prescription drugs were more likely to also take dietary supplements, further increasing the risk for interactions [2].

Many of the same principles apply to drug-drug interactions and drug-supplement interactions:

- Many supplements are metabolized by the same enzymes that metabolize drugs, including the cytochrome P450 (CYP) enzyme family. Drugs that inhibit or induce these enzymes can alter the effects of natural products.

- Some supplements can cause significant inhibition of drug metabolizing enzymes, which can increase or decrease the effects and adverse effects of prescribed medications.

- Drug transporters, such as P-glycoprotein and the organic anion transporter (OAT) family, also transport the chemicals contained in supplements.

- Because supplements can have significant physiological effects, taking a supplement and drug with similar activity can cause additive effects. Examples of this type of interaction include additive reductions in blood glucose or blood pressure, additive antiplatelet activity, and additive photo-sensitization.

However, it is important to understand that there is much greater uncertainty and risk associated with drug-supplement interactions. This is due to two major factors. The first is the low quantity and quality of evidence available for drug-supplement interactions. Because there are no regulations requiring the evaluation of possible interactions with supplements, very few human studies are available. Thus, most of the proposed interactions are based on extrapolation from case reports, proposed physiological effects, and laboratory research. And more importantly, many possible interactions remain completely unknown.

The second factor is the variability of contents in natural products. Natural products do not necessarily contain reliable quantities of each ingredient, as is expected with medications. Some of this variability is due to inaccurate labelling and poor quality assurance by manufacturers. But in the case of herbs and botanicals, this variability is completely natural. Growing conditions, seasonal weather variations, harvesting practices, and extraction methods can all alter the chemical composition of herbal products. This makes it difficult to predict the likelihood for effects and interactions.

CONDITION INTERACTIONS

As with medications, natural products also carry a risk for condition interactions, particularly conditions that are more prevalent in older adults. Many of the physiological changes discussed previously can alter the effects of medications and natural products in the body.

Liver Disease

As mentioned, natural products are metabolized by many of the same enzymes involved in drug metabolism. Patients with liver disease may require lower doses, and natural products that have been associated with hepatoxicity should be avoided completely. These include some relatively well-known supplements, such as green tea extract, kava, garcinia, ephedra, turmeric, red yeast rice, and black cohosh [10].

Kidney Disease

Similarly, many natural products are excreted by the kidneys and should thus be used with caution in patients with kidney disease. Natural products that have been associated with nephrotoxicity should be avoided completely, including cannabis, colloidal silver, horse chestnut, saffron, and yohimbine [11].

Anticoagulation

Certain natural products have demonstrated clinically relevant antiplatelet or anticoagulant effects. In patients requiring the use of antiplatelet or anticoagulant medications, these products should be avoided. Some examples include garlic, ginseng, ginkgo, high doses of vitamin E or fish oil, and many others [12].

PRODUCT QUALITY

Variable Quality

As mentioned, the actual contents of supplements can vary, either due to inaccurate labelling or poor quality assurance by the manufacturer. To ensure the selection of a high-quality product, look for third-party quality certification stamps, such as those from United States Pharmacopeia (USP) or NSF.

USP

The USP is typically considered the standard for verifying the quality of dietary supplements. In addition to inspecting manufacturing facilities for compliance with Good Manufacturing Practices (GMP) at least two times in a three-year period, USP will also conduct random off-the-shelf analyses of verified products to ensure that the contents of the product match those listed on the label. This random testing holds manufacturers to a high standard. The USP verification stamp can be found on a product's label.

NSF

NSF is also a strong source of dietary supplement quality verification. However, general NSF certification does not always imply the same quality standards as USP verification. For a manufacturer to list NSF certification on their website, they must pass an NSF inspection of GMP compliance every six months. However, NSF does not conduct off-the-shelf analyses of products unless the manufacturer is enrolled in the "Contents Tested and Certified" or "Certified for Sport" programs. Under these programs, products are subject to random off-the-shelf testing. These products can carry the NSF seal of approval on the label. The seal will typically state "NSF: Contents Certified" or "NSF: Certified SPORT."

5. NUTRITIONAL SUPPLEMENTS

The class of dietary supplements most commonly used by older adults is micronutrients, which includes vitamins and minerals. There are a number of reasons that these products may be used, including for the improvement of overall health and bone health and for supplementation of the diet.

MULTIVITAMINS

Formulations

About 40% of all older adults that take dietary supplements report using a multivitamin [2]. Many people consider multivitamins to be a quick and easy well-rounded supplement to the diet. These products contain 20 to 30 different micronutrients. However, each multivitamin product contains different ingredients and different ingredient quantities.

All dietary supplement labels are required to provide the % daily value (DV) for each nutrient included in the product. This DV derives from the Dietary Reference Intakes established by the Institute of Medicine [13,14,15]. This can act as a helpful way to determine whether the product contains too much or too little of a specific micronutrient. In some cases, products will contain only a small portion of the dietary requirement (1% to 20%). In other cases, they may contain much more than is recommended in the daily diet (more than 1,000%). There is no legal limit on the amount of any micronutrient that can be included in a dietary supplement.

Although older adults may be using a wide range of specific multivitamin products, some of the best-selling multivitamins on the market are specifically targeted to older men and women, with formulas that claim to specifically address nutrient concerns related to age and biological sex. These best sellers (e.g., Centrum Silver) can be used as an example of the multivitamin composition that many older adults are likely to be taking. As with other multivitamins, these products contain more than 25 individual ingredients, with percent of DVs ranging from 17% to 1,042%.

Safety

The safety of taking doses that are much higher than the DV depends on the specific nutrient in question. Fat-soluble vitamins, which are stored in the body, can cause toxicity over time. These include vitamins A, D, E, and K. Water-soluble vitamins are typically eliminated by the kidneys when quantities exceed physiological needs. Thus, toxicity is much less likely when these vitamins are taken in large quantities.

In addition to developing DVs for each nutrient, the Institute of Medicine also developed tolerable upper intake levels (ULs) to help guide patients and healthcare professionals in preventing toxicity and adverse effects. Some ULs are based on the risk for long-term toxicity, as is the case for vitamin D [13]. Other ULs, such as that of vitamin C, are based on the risk for temporary adverse effects, including gastrointestinal upset [15].

It is important to keep in mind that many patients who take multivitamins also take individual vitamin or mineral supplements. For example, it is not uncommon for patients to take a multivitamin along with a vitamin D/calcium supplement. Healthcare professionals should be aware of these duplicate therapies so that they can prevent a total intake of doses above the UL.

One simple way to avoid consuming too much of any one micronutrient is to first attempt to obtain all of these nutrients from foods in the diet. If a patient is concerned about adequate intake, encourage them to consider how much of each nutrient is obtained from both food and drinks and to identify ways to boost dietary intake. If the patient is already taking a multivitamin or other supplements, remind them to also consider the quantity of each nutrient found in these products.

Another consideration that is not often addressed with multivitamins is the potential for reduced or enhanced absorption of various micronutrients in the presence of other micronutrients. For example, vitamin C (ascorbic acid) can increase the absorption of chromium and iron [16,17]. The presence of vitamin D increases the absorption of calcium in the intestine [18]. Iron and zinc can interfere with each other's absorption when taken on an empty stomach [19,20]. Thus, it can be difficult to predict the actual benefits and risks with these products, particularly in patients with specific nutritional needs or medical conditions.

Many multivitamin tablets and capsules are large, which may increase the risk of choking in some patients, particularly older adults. From 2006 to 2015, about 20% of the reports submitted to the U.S. Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) concerning dietary supplements involved choking or other swallowing problems. About 73% of these reports involved multivitamin supplements, and most of the adverse reports occurred in older adult patients [22]. Clinicians should ensure that older patients with swallowing difficulties are not placing themselves at risk for choking with the use of multivitamins.

Benefits

Despite the widespread use of multivitamin products, the evidence to-date, which includes many large randomized controlled trials, does not support their use. The U.S. Preventive Services Task Force (USPSTF) currently states that there is insufficient evidence to recommend the use of multivitamins for the prevention of cardiovascular disease (CVD) or cancer [21]. Research evaluating these products for reducing overall mortality has shown no benefit.

Considering this lack of benefit in the context of high product costs and variable quality, consider steering patients away from taking multivitamins or relying on them for adequate nutrition.

INDIVIDUAL MICRONUTRIENTS

Unlike multivitamins, there is supportive evidence for the use of various individual micronutrients in older adults. Although the recommended daily intake for the majority of nutrients is the same for older adults as for younger adults, there are some important exceptions.

Vitamin B12 (Cyanocobalamin)

The recommended daily intake for vitamin B12 is the same for all adults, regardless of age. However, as humans age, their ability to absorb vitamin B12 from the intestinal tract decreases. Additionally, many older adults take medications that have the potential to further reduce the absorption of vitamin B12. Some examples of these medications include metformin and proton pump inhibitors (PPIs), such as pantoprazole and omeprazole [22,23]. Due to this reduced absorption, it is recommended that older adults consume fortified foods, such as breakfast cereal. However, some may also require vitamin B12 supplements to meet their needs [24].

Vitamin B6 (Pyridoxine)

It is recommended that older adults obtain more vitamin B6 from the diet than younger adults. Prior to 51 years of age, all adults are recommended to consume 1.3 mcg per day. Beginning at 51 years of age, the recommendation for women increases to 1.5 mcg; for men, it increases to 1.7 mcg [24]. This recommendation is related to an increased rate of vitamin B6 deficiency in older adults, which is thought to be due to reduced absorption and increased catabolism [25]. As with vitamin B12, vitamin B6 can be obtained from fortified foods. Supplements can be considered if dietary intake is inadequate.

Calcium and Vitamin D

One of the most popular combination supplements available on the market is calcium-vitamin D. Although calcium and vitamin D have distinctive effects, they are often discussed, and provided, in combination for bone health. While calcium is the nutrient that directly builds and maintains bone, vitamin D is crucial to the appropriate absorption of calcium from the intestine. Thus, adequate vitamin D intake is an important component of adequate calcium intake and bone health.

Due to age-related bone loss, the recommended daily intake for both calcium and vitamin D increases with age. And due to hormonal changes associated with menopause, the recommended intake for calcium increases faster for women than for men [13]. The recommended vitamin D intake is [13]:

- 1 to 70 years of age: 600 IU (15 mcg)

- 71 years of age and older: 800 IU (20 mcg)

The recommended intake of calcium is [13]:

- Women:

- 19 to 50 years of age: 1,000 mg

- 51 years of age and older: 1,200 mg

- Men:

- 19 to 69 years of age: 1,000 mg

- 70 years of age and older: 1,200 mg

Many older adults take calcium-vitamin D supplements to improve bone health and ensure adequate intake of both nutrients. However, this may not always be necessary or even appropriate. Whenever possible, experts recommend obtaining these nutrients from the diet. In fact, due to a lack of strongly supportive evidence, guidelines have not recommended the routine use of calcium and vitamin D supplements in many older adults [26,27]. For the prevention of fractures in community-dwelling, postmenopausal adults, the USPSTF found insufficient evidence to assess the balance of benefits and harms when calcium and vitamin D are supplemented in doses of at least 1,000 mg daily and 400 IU daily, respectively. The USPSTF also recommends against daily supplementation with lower doses of calcium and/or vitamin D. For the primary prevention of fractures in men and premenopausal women, the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D and calcium supplementation, alone or combined.

The Bone Health and Osteoporosis Foundation (BHOF) recommends a diet with adequate total calcium intake based on the recommended daily intake, incorporating calcium supplements if intake is insufficient. They also recommend maintenance of serum vitamin D sufficiency (a 25-hydroxyvitamin D level of 30–50 ng/mL), with the use of supplemental vitamin D as needed to achieve sufficient vitamin D levels.

In 2024, the Endocrine Society published a new evidence-based guideline for using vitamin D supplementation in select patient populations [118]. The Endocrine Society Panel advises against routine use of vitamin D supplements in most healthy adults younger than 75 years of age and recommends against testing for vitamin D blood levels in the general population. The Panel does suggest empiric vitamin D supplementation for the following groups [118]:

- Children 1 to 18 years of age, to prevent rickets and potentially lower the risk of respiratory infections

- Adults older than 75 years of age, because of its potential to lower the risk of mortality

- Pregnant individuals, because of its potential to lower the risk of pre-eclampsia, intra-uterine mortality, preterm birth, and other neonatal complications

- Adults with prediabetes who are at high risk for progression to type 2 diabetes

The Panel advises that empiric vitamin D supplementation may include daily intake of fortified foods, vitamin formulations that contain vitamin D, and/or daily intake of a vitamin D supplement [118]. For nonpregnant older adults for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, approximating the age-adjusted dosage specified by the Institute of Medicine (600 IU for persons 1 to 70 years of age; 800 IU for those older than 70 years of age) rather than intermittent use of higher doses [13,118].

There has also been interest in the use of vitamin D supplements for reducing fall risk. However, high-quality research on this topic has yielded negative results. The USPSTF actually recommends against vitamin D supplementation to prevent falls in community-dwelling older adults [28].

Potassium

There is no recommendation for increased intake of potassium in older adults. However, the 2017 American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines recommend increased intake of potassium in patients with elevated blood pressure or hypertension [112]. This recommendation should be considered with caution in older adults, who may have reduced kidney function or be taking medications that reduce potassium excretion. In fact, the guideline specifies that potassium supplementation should be obtained through the intake of potassium-rich foods as opposed to potassium supplements. This reduces the risk of excessive potassium intake or hyperkalemia.

Magnesium

Magnesium is an important nutrient for bone health. Magnesium deficiency can increase the formation and activity of osteoclasts, which resorb bone. Increased bone resorption causes release of magnesium and calcium from the bone, which can increase magnesium levels in times of deficiency. However, no large prospective studies have been conducted to evaluate the benefits of magnesium supplementation for the prevention of osteoporosis.

Regardless, it is important for patients to ensure adequate intake of magnesium from the diet. The daily recommended intake for magnesium is 320 mg for all adults 31 years and older [24]. Many foods are rich in magnesium and will allow most patients to attain this intake level.

However, some older adults may be at increased risk for magnesium deficiency due to the use of certain medications. The most important culprits are diuretics and PPIs. For diuretics, loop diuretics are the greatest cause for concern. This risk increases when taken with other magnesium-depleting drugs like PPIs. For patients taking PPIs long-term, the FDA recommends checking serum magnesium levels at baseline and annually thereafter. Although some patients may need to discontinue the PPI permanently, others with hypomagnesemia can take a PPI and magnesium supplement concurrently [29].

OTHER NUTRITIONAL SUPPLEMENTS

Protein

Due to the loss of muscle mass that occurs with age, protein consumption becomes particularly important for older adults. However, research shows that many older adults do not consume enough protein to keep up with the daily requirements, and that protein consumption actually decreases with age. The recommended daily intake of protein for all adults 18 years of age and older is 0.8 grams/kg [24].

However, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommends a higher protein intake for women older than 50 years of age. This recommendation calls for 1–1.2 grams/kg, as postmenopausal women experience an even greater loss in muscle mass [30].

As with other nutrients, patients should be counseled to obtain adequate protein intake from a well-rounded diet whenever possible. Although protein supplements may be appropriate for some patients, most patients are able to obtain adequate protein by making healthy changes to their diet. Common protein supplements, including whey, pea, and soy protein, will be discussed later in this course.

Fibers

Fiber is an important component of the diet. It is recommended that older women consume 25 grams daily and that older men consume 28 grams daily [24]. These intakes are actually less than those recommended for adults younger than 51 years of age. However, research shows that, as with protein, many older adults are not obtaining enough fiber from the diet.

The FDA has an established definition for what can be called a dietary fiber on a product label. This definition essentially states that the fiber must be a naturally occurring, nondigestible carbohydrate obtained from plants that has beneficial effects in the body. Fiber can be either water-soluble or water-insoluble. Water-soluble fibers, such as oats, beta-glucans, and barley, help to lower both blood glucose and cholesterol levels. Water-insoluble fibers, such as wheat bran and rice bran, help the body digest food and improve bowel health [31].

Most people will be able to meet their dietary fiber needs by increasing their intake of certain foods, such as oatmeal, whole wheat cereals, and grains. However, some patients may wish to take a fiber supplement as well. Most of the popular fiber supplements on the market contain blond psyllium (Plantago ovata), which is a water-soluble fiber that has shown benefits for constipation, coronary heart disease, hyperlipidemia, and diabetes. In these studies, patients typically consumed 10–20 grams of supplemental psyllium daily [32].

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

Almost all systems of the body are affected by age. Some changes can be directly tied to specific events, such as menopause, whereas other changes simply happen slowly over time. This section will explore some of the natural products most commonly used to counteract the physical changes that occur with age.

MUSCULOSKELETAL HEALTH

As mentioned, one of the best ways to improve musculoskeletal health in older age is to ensure adequate dietary intake of calcium, vitamin D, and protein. However, for those who would like to improve their overall physical performance and ability to recover from exercise, other natural products may be considered.

Physical Activity

First and foremost, it is important to ensure that patients are getting adequate physical activity for their age. This can be key to combatting the increased weight gain that is seen after menopause. In addition, it can help to reverse age-related muscle loss (sarcopenia) and even slow bone loss in all older adults.

The Centers for Disease Control and Prevention (CDC) recommends that all adults older than 65 years of age [33]:

- Obtain at least 150 minutes of moderate-intensity activity per week, such as brisk walking. Alternatively, this can be replaced with 75 minutes of vigorous-intensity activity, such as hiking, jogging, or running.

- Participate in muscle-strengthening exercises at least two days per week

- Participate in activities that improve balance at least three days per week

Muscle-strengthening exercises can include a wide range of options and are not solely limited to weightlifting. Patients can also consider the use of resistance bands; exercises that use their own body weight for resistance, such as push-ups, sit-ups, and certain forms of yoga and Pilates; and even heavy gardening [33]. Balance exercises are more specific and involve activities such as walking backwards, standing on one leg, or using a wobble board [33].

If a patient has had only limited physical activity and is interested in initiating a new exercise program, encourage them to seek guidance from a physical therapist. To avoid injury, patients should also be evaluated before initiating a new exercise program involving compressive or contractile stressors (such as running or weightlifting).

Supplements for Physical Performance

Some older adults may struggle to complete these recommendations due to fatigue or reduced muscle mass. Others may wish to exceed these recommendations but feel that they do not have adequate strength or energy to do so.

Protein Supplements

Protein was briefly discussed in the last section, within the context of ensuring adequate protein intake throughout the day. For a small number of older adults who cannot obtain adequate protein from the diet, protein supplements may be considered. There is also increasing interest in the use of protein supplements to improve physical performance and exercise endurance.

There are many protein supplement products on the market. The majority of these products use whey protein, which is derived from milk [34]. Other products use pea protein or soy protein. All three of these are considered complete proteins, meaning they contain all essential amino acids, which are amino acids that cannot be made by the body and must be obtained from the diet. Collagen is also becoming popular as a protein supplement. It is important to note that all collagen protein products are derived from animals and that collagen is not a complete protein [35]. Older adults should not rely on collagen protein supplements as a primary source of protein in the diet.

It is not clear if the form of protein used affects outcomes. Some small studies in young athletes suggests that whey, soy, beef, chicken, and dairy protein are similarly beneficial for improving muscle strength [36]. However, there is no researching comparing protein sources in older adults, so it is unclear if different protein formulations can be interchanged.

Some research suggests that taking 35 grams of whey protein three times weekly, either before or after resistance training, can modestly increase muscle mass, muscle strength, and functional capacity [37,38]. However, it is unclear if these benefits are clinically significant. Additionally, it is unclear if there are any benefits to muscle mass in people who are not regularly exercising [39].

There is very little, inconclusive research available for using soy protein to improve physical performance in older adults. To date, pea protein and collagen have not been studied for this purpose.

Branched-Chain Amino Acids (BCAAs)

Although branched-chain amino acids (BCAAs) are not protein supplements, they are comprised of amino acids, the building blocks of protein. BCAA products typically contain leucine, isoleucine, and valine, which are all essential amino acids.

Research on the use of BCAAs in older adults has mostly been limited to those who are relatively malnourished or are known to have inadequate dietary protein intake. The small studies that are available have overall shown no benefit for muscle strength or physical function [40,41].

Creatine

Most research shows that taking creatine while taking part in a resistance training program can increase upper and/or lower body muscle strength in older adults. Research also suggests that creatine improves total muscle mass in older adults [42,43]. In the available research, most participants took a loading dose of up to 20 grams daily for up to 7 days, followed by a maintenance dose of 2.25–10 grams daily for up to 12 weeks. The benefits of creatine at larger doses or for longer than 12 weeks is unknown.

Some case reports have suggested that taking creatine can worsen kidney dysfunction in some people. Additionally, creatine has been reported to cause water retention and edema in some adults [44]. In most clinical studies, participants did not experience these adverse effects. However, because older adults are more likely to have reduced kidney function, as well as cardiovascular dysfunction, recommend that patients monitor their fluid intake and output when initiating creatine supplementation.

Hydroxymethylbutyrate (HMB)

Hydroxymethylbutyrate (HMB), a metabolite of the amino acid leucine, is a naturally occurring molecule that is thought to be involved in protein synthesis. This has led to some interest in its use for performance enhancement.

Studies in older adults suggest that it might increase muscle mass or minimize the loss of muscle mass, particularly in those adults who have already experienced a loss of muscle mass [45,46,47]. However, it does not seem to improve muscle mass or overall exercise tolerance when used in conjunction with exercise [48,49].

Beta-Alanine

Beta-alanine, a beta-amino acid, is naturally found in the diet. Over the years, it has become a popular supplement for improving exercise performance.

The available research in older adults does show that taking beta-alanine 2.4–3.2 grams daily for 4 to 12 weeks improves exercise capacity and reduces fatigue by a small amount. However, it does not improve strength or exercise performance [50,51,52]. Beta-alanine is generally well-tolerated, but some people experience a dose-dependent feeling of pins and needles, as well as skin flushing [53,54].

EYE HEALTH

One of the leading causes of vision impairment in adults older than 55 years of age is age-related macular degeneration (AMD). Although it does not cause complete blindness, this condition blurs a person's central vision. This can significantly limit the ability to complete activities of daily living by making it harder to see faces, read, drive, or do close-up tasks like cooking or repairs [55].

The most common form of AMD, dry AMD, occurs in three stages—early, intermediate, and late. People with early and intermediate AMD typically do not experience symptoms. However, those with late AMD tend to notice a blurry area in their field of vision, which may get bigger over time.

Evidence Based Practice Recommendation

According to the American Academy of Ophthalmology, antioxidant vitamin and mineral supplementation as per the Age-Related Eye Disease Study (AREDS2) should be considered in patients with intermediate or advanced AMD. There is no evidence to support the use of these supplements for patients who have less than intermediate AMD and no evidence of any prophylactic value for family members without signs of AMD.

https://www.aaojournal.org/article/S0161-6420(19)32091-3/pdf

Last Accessed: May 29, 2024

Level of Evidence: Expert Opinion/Consensus Statement

One of the recommended preventive measures for AMD is a multinutrient supplement. Extensive research, referred to as the Age-Related Eye Disease Studies (AREDS), has been conducted on the use of very specific nutrient formulations to limit the progression of AMD. The American Academy of Ophthalmology Guideline recommends one of these formulations, AREDS2, for all patients who have progressed to intermediate or advanced AMD in at least one eye [55].

Because there is still some confusion regarding the appropriate product to recommend for patients with AMD, it can be helpful to review the formulations that have been studied (Table 1) [55]. Both formulations contain the same quantities of vitamin C, vitamin E, and copper. However, they differ in relation to the type of carotenoid provided. Carotenoids are dietary precursors to vitamin A that are converted to vitamin A in the body. The Original AREDS formulation provided beta-carotene, whereas the AREDS2 formulation provides a mixture of two carotenoids, lutein and zeaxanthin.

Table 1: MULTI-NUTRIENT SUPPLEMENTATION FOR AMD

Nutrient

Dose

Original AREDS

Vitamin C

500 mg

Vitamin E

400 IU

Beta-Carotene

15 mg

Zinc (zinc oxide)

80 mg

Copper (cupric oxide)

2 mg

AREDS2

Vitamin C

500 mg

Vitamin E

400 IU

Lutein/zeaxanthin

10 mg/2 mg

Zinc (zinc oxide)

80 mg OR 25 mg

Copper (cupric oxide)

2 mg

Source: [55]

One of the primary reasons that beta-carotene was removed from the AREDS2 formulation was safety concerns. Multiple studies have shown that heavy smokers who take beta-carotene supplements have an increased risk of lung cancer and an increased rate of mortality. In fact, these known risks led the USPSTF to recommend against the use of beta-carotene supplements [21].

The quantity of zinc in these products also differs. In AREDS2 studies, two different doses of zinc were evaluated. Importantly, only the higher dose of zinc was found to be beneficial, suggesting that only products containing 80 mg of zinc should be used. Research also suggests that taking zinc alone, or taking the other ingredients found in AREDS2 without zinc, results in reduced benefits for patients with advanced AMD. Thus, patients should be counseled to take the specific combination product studied in AREDS2 providing 80 mg zinc [55].

CARDIOVASCULAR HEALTH

Another common area of concern for older adults is cardiovascular health. As discussed, many older adults experience elevated blood pressure and cholesterol. Additionally, there is interest in using supplements to assist in maintaining optimal cardiac function and health for as long as possible.

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer.

https://jamanetwork.com/journals/jama/fullarticle/2793446

Last Accessed: May 29, 2024

Level of Evidence: D (Evidence is insufficient to assess the balance of benefits and harms)

As noted, multivitamins are incredibly popular with older adults, and one of the stated reasons for use is cardiovascular health. However, the USPSTF has concluded that there is insufficient evidence to assess the balance of benefits and harms with the use of multivitamin supplements for the prevention of CVD or cancer in community-dwelling adults [21]. Similarly, the USPSTF has found that there is insufficient evidence to assess the balance of benefits and harms for the use of single or paired nutrient supplements for these purposes [21]. In general, multivitamins and vitamin/mineral supplements should not be recommended for cardiovascular health.

Omega-3 Fatty Acids

Some of the supplements most frequently used by older adults are omega-3 fatty acid supplements. These supplements typically contain fish oil, which is high in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Many fish contain large amounts of omega-3 fatty acids, and fish oil supplements can be derived from various fish, ranging from anchovy to mackerel to sturgeon. Fish oil supplements can vary significantly in contents and quality, with EPA content ranging from 18% to 51% and DHA content ranging from 12% to 32% [113].

Omega-3 fatty acids are generally considered "healthy fats" and are found in high concentrations in the human brain, retina, and spermatozoa. The reason that these are popular for cardiovascular health ties in to multiple purported and confirmed benefits. However, research has identified significant differences between the benefits of fish oil supplements and fish oil obtained from dietary intake of fish.

Prescription vs. Supplemental Fish Oil

Two prescription fish oil products have been approved by the FDA. The first product, with the original brand name Lovaza, provides omega-3 acid ethyl esters. It was approved for triglyceride levels greater than 500 mg/dL in patients who do not have adequate reduction in triglycerides after lifestyle and dietary modifications. For this purpose, the medication is taken as 4 grams daily. The other product, with the original brand name Vascepa, provides icosapent ethyl, which is a derivative of EPA. Similar to the omega-3-acid ethyl esters, this product is approved for the treatment of hypertriglyceridemia at a dose of 4 grams daily. For both products, the daily dose is obtained by taking four capsules [114].

It is important to note that the contents of these prescription products have been purified and standardized and that each capsule contains the exact amount of each omega-3 fatty acid stated on the label. In general, fish oil supplements have not been purified and also may not be standardized.

Another important note to consider is that the quantity of omega-3 fatty acids found in prescription products is significantly higher than that found in supplements. Although some fish oil supplements may have some benefit for reducing triglycerides, these forms of fish oil are generally considered inadequate in comparison to prescription products because doses of up to 12 capsules, as opposed to four capsules of the prescription preparation, may be needed to produce the same effect [56].

Cardiovascular Disease (CVD)

Clinical and observational research has found that routinely eating fatty fish, such as salmon or mackerel, as part of the diet may reduce the risk of developing heart disease and all-cause mortality in adults without a history of CVD [57,58]. In fact, the AHA recommends one to two weekly servings of non-fried fish in place of less healthy sources of protein and fat to reduce the risk of CVD [59]. However, the use of fish oil supplements for the primary prevention of heart disease does not seem to be beneficial. In addition, neither increased dietary intake of fish oil nor fish oil supplements are associated with a benefit in patients who already have CVD [57,58].

The best evidence to date shows that fish oil supplements, which are typically taken in doses of 1 gram daily, are not beneficial for primary or secondary prevention of CVD. Additionally, prescription fish oil products in higher doses of 4 grams daily do not seem to be beneficial for the prevention of CVD. Although the benefits of consuming fish oil as part of the diet might offer only modest benefits for the primary or secondary prevention of CVD, people should continue to eat fish and other foods that provide omega-3 fatty acids, as these foods make up part of a healthy diet. In fact, in 2019, the FDA determined that it would allow a qualified health claim stating that foods containing EPA and DHA may reduce the risk of CVD. However, the FDA states that this claim is based on supportive, rather than conclusive, evidence [60].

Hypertension

There is some promising research on using fish oil supplements for blood pressure reduction, although most research suggests that this benefit may only occur in patients with very elevated blood pressure as opposed to those with mild hypertension. A meta-analysis of clinical research shows that, overall, fish oil reduces systolic blood pressure by about 3–5.5 mm Hg and diastolic blood pressure by 2–3.5 mm Hg in patients with hypertension. It is not clear whether the hypotensive effect of fish oil is dose-dependent [61,62].

Interestingly, some studies have suggested that different antihypertensive medications can alter the effect of fish oil on blood pressure. Some clinical evidence shows that adding fish oil 5 grams daily for six weeks does not provide additive blood pressure reduction in patients being treated with ACE inhibitors. However, other clinical research shows that fish oil provides additive reduction of systolic and diastolic blood pressure in hypertensive patients taking beta-blockers or diuretics [63].

If patients are interested in taking fish oil to reduce blood pressure, remind them that fish oil supplements have not been shown to provide any benefit for preventing CVD. Also, counsel patients that supplements containing only DHA or EPA, the omega-3 fatty acids in fish oil, have not been shown to provide the same benefits as fish oil for either blood pressure or CVD. Finally, the doses used in studies of fish oil supplements for hypertension are very high and can be difficult to obtain. This is similar to the need to take 12 capsules of supplemental fish oil versus 4 capsules of prescription fish oil for the treatment of hypertriglyceridemia.

Safety Concerns

Older adults may be at risk for some specific potential side effects from fish oil products. One commonly discussed adverse effect of omega-3 fatty acids is a potential increased risk for bleeding. This concern is due to some older research which suggested that doses greater than 3 grams per day can inhibit blood coagulation and potentially increase bleeding risk [64]. The most rigorous research to date shows that short-term doses of fish oil 10 grams daily and long-term doses of 1.5 grams daily for up to one year do not increase the risk of bleeding or affect coagulation parameters in chronically ill patients [64]. However, the doses studied for hypertension and hypertriglyceridemia exceed 1.5 grams daily; use caution when recommending fish oil supplements for older adults.

More recently, large randomized controlled trials have identified a possible increased risk for atrial fibrillation in people taking prescription fish oil. One large clinical study, called the STRENGTH trial, found that taking prescription fish oil 4 grams daily for up to six years was associated with an increased risk for atrial fibrillation, with a number needed to harm of 114 when compared with a corn oil control [65]. Also, meta-analyses show that taking omega-3 fatty acid supplements increases the incidence rate ratio for atrial fibrillation by up to 37% when compared with placebo. This incidence rate seems to increase with doses of more than 1 gram daily [66,67]. Thus, fish oil supplements should be used with caution in older adults at risk for atrial fibrillation.

Other adverse effects of fish oil are milder in nature and are typically limited to the gastrointestinal tract. Some patients experience fishy hiccups and a fishy breath odor and/or aftertaste. If patients experience diarrhea, heartburn, bloating, discomfort, or indigestion, they should be encouraged to start at a lower dose and increase slowly, and to take their supplements with meals.

Some fish may contain unsafe levels of certain toxins, including dioxins, mercury, and polychlorinated biphenyls (PCBs). PCBs are found in fish living in polluted waters and in some farmed fish, such as salmon. Freshwater fish frequently contain high levels of these chemicals, which may be carcinogenic [68]. Dioxins may be found in high concentrations in the feed given to farmed fish. Farmed salmon, the most common store-bought salmon in North America, is more likely to contain high concentrations of dioxin than wild-caught salmon [69]. Thus, fish should be consumed in moderation.

For patients who would like to take a fish oil supplement, make sure to only recommend products with appropriate quality certifications, including USP-Verified and NSF: Contents Certified. These supplements have been verified to reliably contain what is stated on the label and to be free of unsafe levels of contaminants, such as pesticides and heavy metals.

JOINT HEALTH

Joint health is another common concern that comes with aging. While some people may already have osteoarthritis, others are interested in taking supplements to prevent the development or slow the progression of the condition.

Glucosamine and Chondroitin

The most popular supplements for joint health are glucosamine and chondroitin, often taken together in a combination product. Glucosamine is an amino sugar that occurs naturally in humans. It is necessary for the synthesis of glycoproteins, glycolipids, and glycosaminoglycans. These compounds are found in tendons, ligaments, cartilage, synovial fluid, mucous membranes, blood vessels, heart valves, and structures of the eye. There are multiple forms of glucosamine available on the market [70]. Glucosamine sulfate is the most common form. This form must be created semi-synthetically in a lab. Glucosamine hydrochloride is the second most common form. This salt occurs naturally and can be obtained from shellfish, fungi, or corn via a simple extraction process. N-acetyl glucosamine, the acetylated derivative of glucosamine, is the least common form found in supplements [71].

Chondroitin sulfate is a glycosaminoglycan found naturally in the body, particularly in connective tissues. It is a very large molecule; the species or tissue of origin, as well as the extraction method used, can affect its final size [72].

Extensive research has been conducted on the use of glucosamine for the management of osteoarthritis. Thus far, the best evidence is for glucosamine sulfate. Glucosamine hydrochloride has not shown any real benefit in clinical research.

Glucosamine

Most research has focused on the use of oral glucosamine sulfate for the management of knee osteoarthritis. Meta-analyses of the available research show that taking glucosamine sulfate 1,500 mg daily for up to three years modestly improves pain and function when compared with placebo [73]. Individual studies have shown a 28% to 41% pain reduction and 21% to 46% improvement in function [74]. Small studies comparing glucosamine sulfate with NSAIDs, such as ibuprofen 400 mg three times daily or piroxicam 20 mg daily, suggest that these treatments provide similar benefit. However, NSAIDs appear to relieve symptoms within two weeks, whereas glucosamine sulfate can take four to eight weeks [75].

The benefits of glucosamine sulfate seem to vary depending on the product used. To date, the most consistently positive evidence for glucosamine sulfate has been seen with Dona, a specific, pharmaceutical-grade, crystalline glucosamine sulfate product. This formulation of glucosamine sulfate has demonstrated high bioavailability resulting in high plasma concentrations, although the clinical relevance of this is unclear [76]. Experts currently disagree as to whether the benefit seen with this product is due to bias introduced by industry funding or due to a higher quality product.

Chondroitin Sulfate

Chondroitin sulfate, when taken alone, has demonstrated modest benefit for reducing pain and improving function in some patients with knee osteoarthritis. Meta-analyses of the available research show that taking chondroitin sulfate 800–2,000 mg in single or divided doses daily for at least three months can modestly reduce pain and disability when compared with placebo [77]. Other clinical research in adults with knee or hip osteoarthritis shows that taking chondroitin sulfate daily at a dose of at least 800 mg for two years might modestly reduce joint degeneration and narrowing when compared with placebo or celecoxib [78,79].

Glucosamine Sulfate and Chondroitin Sulfate Combinations

Although most evidence evaluating glucosamine sulfate or chondroitin sulfate alone suggests modest benefit for knee osteoarthritis, research on the use of combination products is less conclusive. Some long-term studies in patients with osteoarthritis show that taking this combination modestly reduces joint space narrowing when compared with a control group [71,80]. But not all research is positive. Some individual clinical studies, as well as meta-analyses of the available research, have not shown a reduction in pain in patients taking chondroitin sulfate in combination with either glucosamine hydrochloride or glucosamine sulfate [81].

The place of glucosamine and chondroitin in clinical practice is unclear. In fact, clinical guidelines provide conflicting recommendations [71,82]. The American College of Rheumatology (ACR) strongly recommends against the use of any glucosamine or chondroitin products for any form of osteoarthritis. Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends for the use of pharmaceutical-grade glucosamine sulfate or chondroitin sulfate products in patients with osteoarthritis. The ESCEO also provides a weak recommendation against the use of glucosamine and chondroitin in combination.

These conflicting recommendations are related to differing interpretations of the previously discussed evidence. The ACR has determined that the positive benefits identified in industry-funded studies indicates the introduction of industry bias [82]. The ESCEO, on the other hand, has determined that the positive benefits identified in industry-funded studies is due to the higher quality and bioavailability of the products used [71].

If a patient would like to use these products, be sure to recommend one that carries a third-party quality certification to minimize concerns related to product quality and potency.

Safety

Both glucosamine and chondroitin are relatively safe for most adults. The most commonly reported adverse effects are minor gastrointestinal disturbances, such as abdominal pain, bloating, constipation, diarrhea, and heartburn.

Some case reports have suggested that glucosamine and/or chondroitin may interact with warfarin, causing an elevation in international normalized ratio (INR). Although the likelihood of this risk is unclear, use caution in patients taking warfarin and monitor INR closely.

Collagen

Another supplement that has gained popularity for osteoarthritis and joint health is collagen. Collagen is a hard, insoluble protein that occurs naturally in the human body and is found in the bones, cartilage, muscles, skin, and tendons. It is a structural protein, meaning that it is crucial to the shape and structure of cells and tissues in the body [83].

Some supplements contain intact collagen, often either collagen type I, II, or III. However, much more often, collagen supplements contain hydrolyzed collagen, or collagen peptides, that are derived from these intact forms of collagen. This is also sometimes referred to on labels as collagen hydrolysate.

Benefits

Collagen types I and II have been evaluated for use in knee osteoarthritis, with small studies suggesting the potential for modest benefit with certain formulations. However, the most extensive research has been conducted with collagen peptides [84,85].

Some clinical studies in adults with knee osteoarthritis suggest that collagen peptides 5–10 grams, taken for three to six months, may modestly reduce pain. However, any improvements appear to be small, and not all research has yielded positive findings. One clinical study shows that taking oral collagen peptides reduces pain by at least 30% in 42% more patients when compared with placebo. However, there was no improvement when the Western Ontario and McMaster Universities (WOMAC) scale was used [84]. In another study, taking collagen peptides reduced pain by about two points on a 100-point scale, compared with a 0.9-point reduction in those taking glucosamine sulfate 1,500 mg. There was no reduction in the use of ibuprofen in these patients [85].

Although some research suggests the potential for modest benefit, it is not clear that collagen peptides can improve pain to a clinically meaningful degree. Patients should not rely on collagen peptides for the management of knee osteoarthritis, although it may be considered as an adjunct therapy in patients with more severe disease.

Safety

Overall, collagen appears to be safe for adults when taken by mouth at doses evaluated in clinical research. There are very limited reports of adverse effects with collagen products. Some minor gastrointestinal upset has been reported rarely with the use of collagen peptides.

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

One of the major concerns that comes with age is a decline in cognitive function, which can present as either cognitive impairment or dementia. Because there are no approved or confirmed preventive strategies for reducing the risk of age-related cognitive impairment or dementia, many people consider the use of supplements. Similarly, some people use supplements to slow the advancement of cognitive impairment and/or dementia.

It should be noted that many studies of supplements for the improvement of cognitive function in older adults are small and may be of low quality. For example, some studies do not use a placebo control, and the majority of these products have not been compared to prescription drugs for dementia. Although this does not invalidate all of the available research, the results should be interpreted with caution.

LIFESTYLE INTERVENTIONS

First, it is worth noting that lifestyle changes are the most commonly recommended preventive measures for mild cognitive decline or dementia. The World Health Organization (WHO) recommends that all adults, with or without cognitive impairment, get adequate physical activity (as discussed) to reduce the risk of cognitive impairment. The organization also recommends that all adults consume a Mediterranean-like diet in order to slow cognitive decline (Table 2) [86]. However, it should be noted that the research identifying a benefit for age-related cognitive impairment involved strict adherence to the Mediterranean diet; people who had only moderate adherence did not experience a benefit [87,88].

Table 2: WHAT IS A MEDITERRANEAN-LIKE DIET?

A Mediterranean-like diet emphasizes foods such as olive oil, fruits, vegetables, legumes, and whole grains. This is intended to provide a high ratio of monounsaturated-to-saturated fat. The diet also emphasizes fish and reduces overall meat intake, while allowing for moderate-to-modest amounts of red wine and dairy. In general, the diet avoids highly processed foods, refined grains, and sugars.

Source: Author

In general, regular consumption of fruits, vegetables, and fish is most consistently associated with a reduced risk of dementia. This has led to interest in the use of fish oil to prevent cognitive decline. However, the observational research that has been conducted to date has not found an association between risk of mild cognitive impairment or dementia and the use of fish oil supplements [89,90,91].

The WHO also recommends weight loss for people who are overweight or obese, as well as reducing alcohol consumption. Both of these changes can have multiple downstream health benefits, but there is also some early evidence suggesting that they can reduce cognitive decline [86].

Finally, the WHO recommends social participation and social support, which "are strongly connected to good health and well-being throughout life and social inclusion should be supported over the life-course" [86]. However, it is important to note that there is no evidence showing a direct association between social participation and cognitive function. For now, encourage social support and participation due to the many other benefits it can offer, including to mental health [86].

NUTRIENT SUPPLEMENTS

Vitamin E

Vitamin E is one of the most popular vitamin supplements for dementia and cognitive impairment. In fact, there is some evidence to show that taking vitamin E can modestly slow cognitive function decline in patients with Alzheimer disease. However, it does not seem to prevent the onset of Alzheimer disease or prevent cognitive decline in general. Thus, the WHO recommends against the use of vitamin E for prevention [86].

Additionally, there are concerns about the safety of vitamin E in older adults. Most of the studies showing benefit for Alzheimer disease used a dose of 2,000 IU daily. Some research in middle-aged and older patients with chronic diseases suggests that vitamin E in doses above 400 IU daily may increase the risk of adverse outcomes and mortality [115]. On the other hand, these doses appear to be safe in otherwise healthy adults. It is not entirely clear which population is safe to use large supplemental doses of vitamin E, but it should be used with caution in older adults, particularly those with multiple comorbidities.

Idebenone

Another nutrient-like supplement that is sometimes touted for cognitive function is idebenone. This is a synthetic analogue of coenzyme Q10. Some older studies have shown that taking 90–120 mg three times daily for six months slows the decline of cognitive function in adults with Alzheimer disease [92]. However, there is no available research in adults with mild cognitive impairment or other forms of dementia.

Idebenone seems to be well tolerated by most adults although it can cause some gastrointestinal side effects such as nausea and vomiting, abdominal pain, and loose stools.

HERBAL SUPPLEMENTS

Ginkgo

Ginkgo (Ginkgo biloba) is one of the most popular herbal supplements for dementia and cognitive impairment. The leaves of this plant have a long history of use in traditional Chinese medicine, and there is some evidence to support their use in people who already have dementia. Research in people with Alzheimer disease, vascular dementia, or mixed dementia shows that taking ginkgo 240 mg daily for about six months modestly improves cognition and activities of daily living when compared with placebo. A lower dose of 120 mg daily does not seem to offer the same benefit [93,94,95,96].

It is important to note that the product used in these studies was a specific ginkgo supplement—Egb 761. This supplement differs from other ginkgo products because it has been standardized to contain 22% to 27% flavone glycosides and 5% to 7% terpene lactones, which includes ginkgolides A, B, and C. Other ginkgo supplements may not be standardized to these same chemicals, and thus they may have different (or lower) activity [97].

As with vitamin E, ginkgo has not shown benefit for the prevention of dementia in those with normal cognitive function or in those with mild cognitive impairment. It also does not seem to prevent disease progression in people with Alzheimer disease. Thus, the WHO guidelines do not recommend ginkgo for the prevention of MCI or dementia [86].

Ginkgo is considered generally safe for most adults. There have been some rare reports of arrhythmia in patients who take ginkgo supplements. It is unclear if this relationship is coincidental or causative, but there have been enough reports to lead Health Canada and the WHO to release warnings about the use of these products [86,98].

There is also significant interest in the use of ginkgo supplements for tinnitus, another issue that becomes more common with age. In fact, tinnitus can even contribute to cognitive impairment and lack of social participation. Unfortunately, clinical studies show that taking ginkgo leaf extract does not improve symptoms of tinnitus [99,100]. It should not be recommended for this purpose.

Huperzine A

Huperzine A is a chemical that is isolated from a type of moss, called the Chinese club moss (Huperzia serrata). Because it is derived from moss, this chemical is sometimes sold as a supplement, either as a single ingredient or in combination with other ingredients. There are multiple reasons that this chemical is of interest for dementia and mild cognitive impairment, including its antioxidant and anti-apoptotic effects, as well as its possible activity against beta-amyloid.

Clinical research in adults with Alzheimer disease shows that taking huperzine A 200–800 mcg in divided doses daily for two to nine months improves cognitive function on the Mini-Mental State Exam (MMSE) when compared with placebo [101,102]. It should be noted that most research has been conducted in China, where this chemical is an approved drug. One clinical study conducted in the United States shows that taking 400 mg twice daily improves performance on the MMSE and the Alzheimer Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) when compared with placebo. A lower dose of 200 mg twice daily was not consistently beneficial [103].

Huperzine can cause cholinergic side effects such as dizziness, sweating, insomnia, nausea, vomiting, and diarrhea. However, it is generally well tolerated by most adults.

Bacopa

Another herbal supplement that is sometimes touted for cognitive health in older adults is bacopa (Bacopa monnieri). This plant is found in India and has been used for centuries in Ayurvedic medicine. There is interest in its use for dementia and cognitive impairment because it has demonstrated cholinergic activity in laboratory studies. However, only one small study has evaluated bacopa in adults with Alzheimer disease or mild cognitive impairment. This study showed that taking bacopa 300 mg daily for 12 months did not offer any benefits when compared with donepezil or baseline [104].

Bacopa has been reported to cause increased stool frequency, nausea, and abdominal cramps in 16% to 30% of patients in clinical studies [116]. Considering that it has not shown benefit for cognitive function in older adults, steer patient away from bacopa supplements.

ENDOGENOUS SUBSTANCES

Alpha-L-Carnitine

Alpha-L-carnitine is an ester of L-carnitine, which is an amino acid derivative that is found naturally in the body. It is made in the brain, liver, and kidneys, and the body can convert it to and from L-carnitine as needed. Alpha-L-carnitine is structurally similar to acetylcholine, which has led to interest in its use for dementia and mild cognitive impairment. Small clinical studies show that taking 1.5–2 grams daily for three months can improve some measures of cognitive function in older adults with mild cognitive impairment [105,106]. Similarly, small clinical studies show that taking 1.5–3 grams daily for three to 12 months can slow the rate of Alzheimer disease progression and improve some measures of cognitive function [107].

Alpha-L-carnitine is generally well tolerated by most adults, although it can cause headache, insomnia, and agitation in some people. Let patients know that it can also cause the breath, urine, and sweat to have a fishy odor, which is not harmful [108].

Phosphatidylserine

Phosphatidylserine is a phospholipid that is naturally made by the human body. It is a component of the cell membrane and is found in high quantities in the brain. Thus, there is interest in its use for improving cognitive function in all age groups.

To date, the best evidence for the use of phosphatidylserine is for the improvement of cognitive function in adults with age-related mild cognitive impairment or Alzheimer disease. This research shows that taking phosphatidylserine, usually as 300 mg daily in divided doses, for six weeks to six months improves attention, verbal fluency, and memory. However, it should be noted that these studies were very small, and some did not use blinding or a placebo control group. Additionally, the studies are old and may not be representative of current standards of care [109,110].

As for preventing the development of Alzheimer disease or mild cognitive impairment, clinical research has not shown a benefit. Also, there is currently no research on the use of phosphatidylserine in other types of dementia. However, phosphatidylserine is generally safe to use, with the most common adverse effects being flatulence and nausea. This may be a reasonable option for patients interested in taking a supplement.

Citicoline

Citicoline is a chemical that occurs during the synthesis of choline from phosphatidylcholine in the body. Some small clinical studies in older adults with MCI have shown that taking citicoline 500–2,000 mg daily for up to three months moderately improves memory scores when compared with placebo [111]. The research in patients with Alzheimer disease is relatively limited, and there is no available research in patients with other forms of dementia. Citicoline is well tolerated by most adults.

Alpha-GPC

Alpha-GPC is another chemical that is related to choline, except that this chemical is naturally produced by the body from choline. It is a precursor to acetylcholine, a neurotransmitter. There has been some research on the use of this supplement in patients with vascular dementia and Alzheimer disease that shows modest benefit, but these studies are small and should not be relied upon [117]. The most common adverse effects with alpha-GPC are diarrhea, heartburn, nausea, and vomiting.

8. CONCLUSION

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

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102. Cui CC, Sun Y, Wang XY, Zhang Y, Xing Y. The effect of anti-dementia drugs on Alzheimer disease-induced cognitive impairment: a network meta-analysis. Medicine (Baltimore). 2019;98(27):e16091.

103. Rafii MS, Walsh S, Little JT, et al. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology. 2011;76(16): 1389-1394.

104. Prabhakar S, Vishnu VY, Modi M, et al. Efficacy of Bacopa monnieri (brahmi) and donepezil in Alzheimer's disease and mild cognitive impairment: a randomized double-blind parallel phase 2b study. Ann Indian Acad Neurol. 2020;23(6):767-773.

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107. Hudson S, Tabet N. Acetyl-L-carnitine for dementia. Cochrane Database Syst Rev. 2003;2003(2):CD003158.

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111. Nakazaki E, Mah E, Sanoshy K, Citrolo D, Watanabe F. Citicoline and memory function in healthy older adults: a randomized, double-blind, placebo-controlled clinical trial. J Nutr. 2021;151(8):2153-2160.

112. Paul K Whelton, Robert M Carey, Wilbert S Aronow, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269-1324.

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Evidence-Based Practice Recommendations Citations

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90484 • Asthma: Diagnosis and Management

Sharon M. Griffin, RN, PhD

Patricia Walters-Fischer, RN, BS

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Asthma is one of the most common respiratory conditions affecting children, adolescents, and adults, and the number of individuals affected continues to grow each year. Diagnosis may be complex, especially in certain populations, but it is a vital key to providing the effective treatment and management of the disorder. This course reviews the signs and symptoms, pathophysiology, risk factors, diagnosis, treatment and management, and prevention strategies associated with asthma, allowing healthcare professionals to provide optimal care for the patient with asthma.

Table of Contents

90484 • Asthma: Diagnosis and Management

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. HISTORY OF ASTHMA

3. DEFINITION

4. EPIDEMIOLOGY

GLOBAL IMPACT

NATIONAL STATISTICS

THE PEDIATRIC POPULATION

RACE AND GENDER

5. RISK FACTORS

OVERWEIGHT AND OBESITY

GENETIC PREDISPOSITION/FAMILY HISTORY

PREMATURE BIRTH

6. PATHOPHYSIOLOGY

ANATOMY AND PHYSIOLOGY

INFLAMMATION AND THE IMMUNE SYSTEM

PATHOGENESIS OF ASTHMA

CAUSES OF HYPER-RESPONSIVENESS IN PERSONS WITH ASTHMA

ELEMENTS OF AN ASTHMA ATTACK

7. DIAGNOSIS

PHYSICAL EXAMINATION AND PATIENT HISTORY

PULMONARY TESTS

ASTHMA CHALLENGE TESTS

ALLERGY TESTING

DIFFERENTIAL DIAGNOSIS

8. MEDICAL TREATMENT AND MANAGEMENT

CREATING A TREATMENT PLAN

PHARMACOLOGIC INTERVENTIONS

NONPHARMACOLOGIC MANAGEMENT

9. SPECIAL POPULATIONS

ASTHMA IN PEDIATRIC PATIENTS

ASTHMA IN ELDERLY PATIENTS

ASTHMA IN PREGNANCY

10. PSYCHOSOCIAL MANAGEMENT

11. PATIENT EDUCATION

CONDITION MONITORING

COMPLIANCE

TRIGGER AVOIDANCE

12. CONCLUSION

13. RESOURCES

14. APPENDIX

COMMON FOOD SENSITIVITIES FOR PATIENTS WITH ALLERGY AND/OR ASTHMA

Works Cited

90484 • Asthma: Diagnosis and Management

Education Category. Medical / Surgical

Release Date. 11/01/2024

Expiration Date. 10/31/2027

Course Overview

Asthma is one of the most common respiratory conditions affecting children, adolescents, and adults, and the number of individuals affected continues to grow each year. Diagnosis may be complex, especially in certain populations, but it is a vital key to providing the effective treatment and management of the disorder. This course reviews the signs and symptoms, pathophysiology, risk factors, diagnosis, treatment and management, and prevention strategies associated with asthma, allowing healthcare professionals to provide optimal care for the patient with asthma.

Audience

This course is designed for nurses, physicians, physician assistants, pharmacists, and pharmacy technicians who may care for patients with asthma.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. NetCE designates this activity for 10 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-043-H01-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 10 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. NetCE is authorized by IACET to offer 1 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

Asthma is increasingly common, and most healthcare professionals will encounter patients with the condition. The purpose of this course is to provide nurses and pharmacy professionals with up-to-date, accurate information regarding the diagnosis and management of asthma and long-term outcomes for those with the condition.

Learning Objectives

Upon completion of this course, you should be able to:

1. Summarize the history of asthma, including current definitions.

2. Describe the impact of asthma both globally and nationally.

3. Identify risk factors that contribute to the development of asthma.

4. Define the pathophysiology of asthma.

5. Discuss the pathogenesis of an asthma attack in its five phases.

6. Discuss the process of diagnosing asthma, including differential diagnosis and available tests.

7. Outline the appropriate treatment and management of asthma, the medications used, and the application of the various guidelines.

8. Discuss specific population considerations.

9. Explain the importance of patient education when discussing prevention and management of asthma.

10. Identify triggers of asthma attacks.

Faculty

Sharon M. Griffin, RN, PhD, specializes in Health Education and Chronic Disease Management especially as it relates to her primary areas of study and research. She has more than 30 years of healthcare experience nationwide and is an accomplished author, presenter and consultant. She frequently lectures on the subjects of Attention Deficit/Hyperactivity Disorder (AD/HD), Obsessive-Compulsive Disorder (OCD) and related disorders. Dr. Griffin is the cofounder of the University Center for Assessment and Learning (UCAL) of Andrews University in Berrien Springs, Michigan. She enjoys writing and teaching and has been listed in Who’s Who in American Nursing, Two Thousand Notable American Women, and the eleventh edition of the World Who’s Who of Women, Cambridge, England.

Patricia Walters-Fischer, RN, BS, has worked in the healthcare field since 1992. Starting out as a nurse’s aide, she worked her way from LVN to ASN while working in several hospital units, including ICU/CCU and adult and pediatric trauma. During her career, she worked at the busiest pediatric emergency center in the country, Children’s Medical Center of Dallas Emergency Room. While there, she cared for and educated asthmatic children and their caregivers. Ms. Walters-Fischer is also an honors graduate of Washington University, St. Louis, with a Bachelor’s Degree in Communications and Journalism and has been writing for the past ten years in local, national, and international publications.

Faculty Disclosure

Contributing faculty, Sharon M. Griffin, RN, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Patricia Walters-Fischer, RN, BS, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Asthma has existed for thousands of years, but only in the past century has the medical community developed a better understanding of it. Even with the great progress made toward improved treatments and concepts of asthma, the disorder is frequently misdiagnosed and mismanaged in many healthcare settings. Furthermore, the condition is increasingly common, and most healthcare professionals will encounter patients with asthma.

In the United States alone, it is estimated that 8.9% of adults and 6.7% of individuals 18 years of age or younger have asthma, and cases have been trending upward in both age groups for decades[1,2]. This increase in the number of asthma cases extends globally. In 2019, it was estimated that there were 262 million individuals worldwide with asthma, although exact numbers are difficult to estimate due to differences in diagnosis and reporting methods [3].

Among the general population, 6.3% of patients seen by a physician in the office setting have a diagnosis of asthma in their medical records [2]. In 2021, 939,000 individuals in the United States visited an emergency department and received a primary diagnosis of asthma. In addition, there were 4.9 million office-based physician visits for asthma [2]. The utilization and costs associated with health care related to asthma put a tremendous burden on healthcare systems and professionals as well as on patients and public organizations.

Direct healthcare costs for asthma in the United States total more than $50.3 billion annually; indirect costs (mainly lost productivity) and mortality add an additional $3 billion and $29 billion, respectively [4]. In addition to direct and indirect costs, prescription drugs for the treatment of asthma represented the largest single direct medical expenditure, accounting for more than $17 billion annually [5].

Proper treatment and management can minimize the effects of asthma. Along with pharmacologic treatment, there are many contributing agents (known as triggers or asthmagens) that, once identified, can be addressed with the patient and successfully managed. Reviewing the signs and symptoms, pathophysiology, risk factors, diagnosis, treatment and management, and prevention strategies allows healthcare professionals to be prepared to provide optimal care for the patient with asthma.

2. HISTORY OF ASTHMA

The first record of asthma-like symptoms was documented in Egyptian manuscripts circa 1500 B.C.E. Hippocrates first referred to asthma as a specific condition, using the Greek word asthma, meaning the act of panting or labored breathing . Asthma-like symptoms and their treatments were described thousands of years ago in ancient Chinese writings. The herbal medicine ma-huang traditionally used in Chinese medicine to treat asthma-like symptoms, comes from the bark of trees of the genus Ephedra equisetina. The modern medication ephedrine, a common ingredient in some asthma medicines, is derived from this plant [6,7].

In the early 1700s, Bernardino Ramazzini, an Italian physician, noted links between people with asthma and their occupations. Ramazzini documented asthma resulting from mill workers' exposure to mill dust and farmers' contact with animal dander. This was one of the first attempts to identify asthmagens or triggers as causes of asthma attacks. Although most physicians in the 18th century were in agreement that asthma was a new disorder, it remained difficult to auscultate the lungs and examine the patients' lung tissue or secretions. By 1761, Leopold Auenbrugger, an Austrian physician, discovered a new technique for examining the lungs by percussion, or tapping on the patient's chest, to elicit differences in reverberating sounds. Approximately 60 years later, French physician René Laënnec, who had asthma, designed the first crude stethoscope—a rolled piece of paper held to the chest to listen to a patient's heart and lungs. The following decade would also bring improvements in microscopic technology that allowed physicians to examine lung tissue and secretions [6,7].

British surgeon John Hutchinson developed the first spirometer around 1850. It was originally intended for his research in respiratory physiology, as a tool to measure respiratory flow rates. Soon, smaller devices were being widely used by patients with lung disease in Europe, Australia, and the United States [6,7].

By the end of the 19th century, many companies were shipping asthma "medications" all over the country and around the world. These were in the form of powders, tablets, and liquids and often labeled as secret formulas. It was not uncommon to find alcohol, cocaine, and/or morphine as active ingredients. Until the late 20th century, inhaling medications via steam or smoke was one of the only ways of introducing medications directly into the bronchial tubes and lungs of a patient with asthma [6,7].

3. DEFINITION

Since 1958, several attempts have been made to establish a consensus definition of asthma but thus far have been unsuccessful, and ongoing research continues to evolve the definition. The Global Initiative for Asthma (GINA) defines asthma as a "heterogenous disease, usually characterized by chronic airway inflammation" [8]. It is defined by a history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness, and cough, that vary over time and in intensity, together with variable expiratory airflow limitation [8]. This definition comprises elements set forth by other organizations, including the National Asthma Education Prevention Program (NAEPP), that does not recognize asthma as a specific disease with a single cause, but instead is categorized as a "syndrome composed of multiple phenotypes" [9].

Asthma is considered a chronic, albeit reversible, respiratory disorder. This inflammatory condition produces hyper-reactive and hyper-responsive airway and lungs, causing episodic, reversible airway obstruction through bronchospasms, increased mucus secretions, and mucosal edema. The hyper-reactive lungs of a patient with asthma are more sensitive than most individuals' and may become inflamed or edematous when exposed to specific irritants (e.g., cold air, animal dander, dust, tobacco smoke, car exhaust fumes, grass) or by the respiratory involvement of viral infections, exercise, or laughter . The immune system of an individual with asthma will over-react to these irritants, constricting the airways and filling them with mucus; constricted airways interfere with the movement of air in and out of the lungs, making breathing difficult [8,9].

Asthma is marked by recurrent episodes of wheezing, breathlessness, chest tightness, and/or coughing. Usually, these periods are associated with widespread but variable airflow obstruction followed by a period of relief, either spontaneously or in response to treatment. Asthma has many puzzling aspects, and its symptoms may wax and wane, especially seasonally. Unlike other respiratory diseases, such as congestive obstructive pulmonary disease (COPD) and emphysema, in which air trapping and hyperinflation of the lungs also occur, asthma is reversible with the use of proper medications and therapies. Long-term lung tissue damage can occur when asthma attacks occur frequently or when the disorder is poorly controlled. Permanent damage would require many instances of severe attacks. In children, whose lungs are still developing, the risk of long-term damage is greater [8,9].

4. EPIDEMIOLOGY

GLOBAL IMPACT

As noted, approximately 262 million people worldwide are living with asthma. In 2019, there were approximately 461,000 deaths attributed to asthma [3,15]. The incidence and severity of the condition varies globally.

Although for many years asthma was characterized as a condition limited to industrialized countries, it is now recognized as a significant health issue in developing countries as well. More than 40 million people in Central and South America and more than 50 million people in Africa have asthma. More than 80% of asthma deaths occur in developing countries [3,16]. The 2019 Lancet Global Burden of Disease report indicates that countries on the lower and middle parts of the sociodemographic index spectrum sustain the greatest number of asthma deaths, while prevalence of asthma is greatest in countries higher on the sociodemographic index spectrum [15]. Disability-adjusted life-year rates are very high on most of the African continent, as well as in-and-around the Indian subcontinent, southeast Asia, and parts of the United States.

NATIONAL STATISTICS

The global increase in asthma incidence and its impact on public health are also evidenced in the United States. From 2019 to 2022, it was estimated that 8% of Americans had asthma [1,2]. The number of individuals diagnosed with asthma increased at a rate of 1.5% per year between 2001 and 2010, to a prevalence of 8.4% in 2010, and have remained nearly the same since, with 8% in 2013 and 7.8% in 2019 [1,2]. Historically, rates of asthma have decreased with age; however, data from 2023 show the prevalence of asthma at 6.7% in children and at 8.9% in adults [1,17,18].

The cause of the proliferation of asthma within the last few decades is not yet known, although some have attributed the rise to environmental factors and expansion of the condition's diagnostic criteria. The National Health Interview Survey questions, from which most of the statistics on asthma prevalence are obtained, changed slightly after 1997, causing a shift in how the condition and associated statistics were reported. In 2001, the Centers for Disease Control and Prevention (CDC) introduced a more precise measurement of asthma. Since then, the trend has remained stable at historically high levels [17,18].

THE PEDIATRIC POPULATION

Asthma remains an important influence on pediatric health. As noted, 6.7% of individuals younger than 18 years of age were reported to have current asthma in 2023, including 7.6% of boys and 5.7% of girls [2,17]. Childhood asthma contributes considerably to school absenteeism in the United States. In a typical year, school-age children miss 13.8 million school days due to asthma [22]. One study found that among elementary students 5 to 11 years of age in California, approximately 50% reported missing at least one day of school due to asthma. Additionally, it was found that 11% of elementary students met the criteria for excessive absenteeism (defined as 9 to 18 missed school days during the school year) as a result of their asthma [23]. Asthma is the most common chronic disease of childhood, making it a significant threat to pediatric health.

RACE AND GENDER

In 2023, 11% of women in America had asthma, compared with 6.8% of men [18]. The higher incidence of asthma among women may produce additional health consequences during pregnancy and/or childbirth. The CDC has found that the asthma rate is 13.3% among individuals with multiple non-Hispanic race/ethnicity, 9.8% among American Indian/Alaska Natives, and 11.7% among non-Hispanic Black individuals. Among Hispanic individuals, the rates are 6.2% for Mexican/Mexican Americans and 7% for people with other Hispanic heritage. Non-Hispanic White individuals have an asthma prevalence of 8.9%, and Asian Americans have an asthma prevalence of 4.9% [18].

5. RISK FACTORS

Although experts have been unable to definitively identify the cause or causes of asthma, there are several factors that increase the risk of developing the condition in one's lifetime. The following are some of the most common risk factors and will be addressed throughout this course [8,15]:

- Environmental allergens (e.g., mold, dander, pollen, dust mites)

- Skin or food allergies

- Overweight/obesity

- Genetic predisposition/family history

- Low birth weight

- Respiratory infections in childhood

- Vitamin D deficiency

- Living in an urban area

- Exposure to secondhand smoke

- Exposure to occupational triggers (e.g., chemicals used in farming, hairdressing)

- Gastroesophageal reflux disease (GERD)

OVERWEIGHT AND OBESITY

There have been many studies illustrating a link between obesity and asthma in adults and children. Research indicates that being overweight or obese significantly increases the risk of developing asthma, worsening asthma symptoms, and poor asthma control [15,19]. The obesity rate among adults with asthma was significantly higher than the rate among adults without asthma (38.8% vs. 26.8%) [19]. One meta-analysis involving more than 300,000 adults in the United States with asthma found that the prevalence is 7.1% in lean adults, compared with 11.1% in obese adults. In addition, the prevalence of asthma in women with obesity was found to be nearly double that of lean women (14.6% vs. 7.9%). Interestingly, men did not have a statistically significant difference in comorbid overweight/obesity asthma [20]. Patients who are excessively overweight place an additional burden on their bodies, especially on their heart and lungs, decreasing both functional residual capacity (the amount of air left in the lungs after exhalation) and tidal volume. These decreases were associated with several factors, including changes in lung development and chronic systemic inflammation, that may affect, induce, or exacerbate asthma symptoms. However, weight is a modifiable risk factor, and researchers have found that total weight loss of 5% or greater significantly improves lung function and asthma control [20].

Unless contraindicated, moderate exercise is encouraged for all people with asthma, as it strengthens the lungs and improves respiratory function. Patients whose asthma is triggered by activity may be advised to take a short-acting beta_2 agonist or other bronchodilator 30 minutes to one hour prior to exercising. Regular aerobic activity is essential for any person with asthma, taking into consideration contraindications or complications.

Asthma and obesity present a unique problem in pediatric patients. Similar to adults, children with obesity are significantly more likely to develop asthma than other children. This is of particular concern in the United States as nearly one in five children is obese. In addition, studies have found correlation between maternal obesity and weight gain during pregnancy and the development of asthma beginning in utero, with estimates showing that 15% to 30% of children born to mothers with obesity later develop asthma; however, it is important to note that asthma is a heterogenous disease and maternal obesity as a single cause is unlikely [19,20].

GENETIC PREDISPOSITION/FAMILY HISTORY

A genetic predisposition to develop immunoglobulin E (IgE) antibodies has been shown to increase the incidence of allergy and asthma. However, since the mapping of the human genome has been completed, more than 100 susceptibility genes contributing to the development of asthma have been recognized. The first gene associated with asthma susceptibility and airway hyper-responsiveness, ADAM33, was mapped in 2002. Researchers at Channing Laboratory, Brigham and Women's Hospital in Boston, were able to link variants of this gene to a familial history of asthma and asthma symptoms. In 2003, two more genes relating to asthma, PHF11 and DPP10, were identified [13,24]. Results have been mixed regarding the role of Clara cell secretory protein gene variants and the asthma phenotype on the development of asthma, but research seems to indicate a positive, but inconsistent link [25,26].

Although causative chromosomal regions and candidate genes are now being revealed, this has not ruled out the influence of environmental factors in asthma development. In 2013, the results of two studies were analyzed to determine the role of genetic and environmental factors, and the researchers found that variants at the 17q21 locus were implicated in the development of asthma in children with a history of rhinovirus infection with wheezing [27]. This indicates a possible synergistic relationship between genetic and environmental factors in the development of asthma in childhood.

These discoveries opened new avenues for research in asthma and allergy, and advances since the early 2010s in genomics technology and epigenetics now offer expanded methods to link genetic variants, providing important information about the molecular mechanisms underlying the complex (epi)genetics of asthma. Genome-wide association studies have highlighted that the majority of identified gene variants are not associated with altered protein function but are instead controlled by non-coding gene regulatory elements. In these studies, (epi)genetic variants were found to be identified in 25.6% of childhood-onset asthma heritability and 10.6% of adult-onset asthma [28],

Should a family have a history of allergies and asthma, the first two years of a child's life are critical; exposure to potential allergens during this time increases the likelihood that a child will develop asthma. In addition, early contacts to such potential allergens may contribute to the severity of the child's asthma. Genetic tendency toward lung sensitivity may not follow a direct line; asthma may bypass a generation or surface in other family branches. The exact mode of inheritance is unclear [8,15].

PREMATURE BIRTH

Premature birth and associated low birth weight have been considered a risk factor for asthma for many years. One study found that school-age children (3 to 17 years of age) who had been very low-birth-weight infants (i.e., less than 1,500 grams or 3.3 pounds) experienced several long-term health, educational, and social effects. This included asthma, which was reported in 20.9% of the children of very low birth weights, 10.7% of children with low birth weight (1,500–2,000 grams), and 8.1% of those who had been of normal weight at birth. However, it was found that very low birth weight was only shown to be a risk factor for asthma among Hispanic and Black children between 6 and 12 years of age, demonstrating racial and age disparities [29]. The causal link between low birth weight and premature delivery and asthma development has not been completely determined. Poor intrauterine growth and lung and immune system development have long been believed to be the cause; however, additional factors that are often present in premature infants, including antibiotic use in early life, respiratory syncytial virus (RSV) infection in infancy, vitamin D deficiency, and pneumonia in early childhood, have been associated with the development of asthma and require additional research [29,30].

Identifying possible risk factors specific to certain patients may allow lifestyle changes or more strenuous observation of symptoms for better control of asthma.

6. PATHOPHYSIOLOGY

ANATOMY AND PHYSIOLOGY

Asthma most prominently affects the respiratory and immune systems, and knowledge of the structures and workings of these systems is vital to an understanding of the condition.

The most obviously affected structures of the respiratory system are the bronchial tubes. As the bronchi stretch deeper into the lungs, they subdivide into smaller bronchioles. A pale, thin membrane, known as the bronchial mucosa, lines these bronchial tubes. Mucous glands, which keep airways lubricated with watery mucus, are embedded within the many layers of bronchial lining. Harmful substances stick to the mucus or sputum and are propelled out of the lungs by the movement of the cilia; this mucus production is one way the body fights infection [8,13].

The outer walls of the bronchial tubes are surrounded by smooth muscles; movement of these muscles controls the size of airway openings, permitting air in or out of the bronchioles. When muscles are relaxed, airways remain open, allowing air to pass through without effort. Upon exhalation, the muscles contract. Contraction can occur with amazing rapidity. When the lungs and/or bronchi are irritated, the muscles contract and narrow the diameter of the tubes. As with all muscle, continued contraction will cause growth or hypertrophy. The muscle itself may become chronically thickened even in its resting state, which narrows the tube further. When a stimulus is encountered, profound narrowing of the bronchial tubes due to muscle constriction, or bronchospasm, can occur within just a few seconds. Such narrowing in its most severe form can result in sudden death from asphyxiation. Usually, automatic reflexes control whether muscles contract or relax [6,13].

Deep inside the lungs, surrounding each bronchiole, are millions of tiny, balloon-like air sacs called alveoli. These structures provide the environment for the exchange of gases, allowing oxygen from inhaled air to pass into the bloodstream through the capillaries within the sacs [13].

Asthma is considered a disorder of exhalation, not inhalation. Patients with asthma are uncomfortable not because they cannot inhale enough air, but because obstructed airways are preventing them from exhaling the air that is already in their lungs. In fact, autopsies of patients who died of asthma complications have revealed lungs full of air. When bronchioles narrow during an asthma attack, upstream obstruction causes premature closure of airways with expiration, as pleural pressure becomes greater than the pressure inside the airway (the equal pressure point, or EPP). Downstream airways become compressed with expiration, trapping air in the alveolar sacs. Reduced respiratory muscle efficiency and function can be caused by lung hyperinflation and thoracic hyperexpansion, resulting in air trapping. Respiratory muscle advantage is compromised, and the flattened diaphragm is forced to contract with shortened muscle fibers, resulting in a feeling of chest tightness. This can lead to airway rupture, manifested as pneumothorax, pneumomediastinum, or subcutaneous emphysema [13].

INFLAMMATION AND THE IMMUNE SYSTEM

The most common features of asthma are inflammation and edema (swelling) of the airways, and treatments have focused on the connection between inflammation and asthma since the mid-1980s. At that time, researchers developed fiber-optic bronchoscopes with which they were able to view the lungs (and take samples of airway tissues) of those with chronic asthma. With this advancement, researchers concluded that airway inflammation in individuals with asthma never clears, even with mild asthma; therefore, treatment focusing on inflammation reduction was determined to be the most effective for long-term management. When the inflammatory cascade, the physiologic process of an asthma attack, is not treated, rebound of acute symptoms can occur, resulting in extreme damage and potentially permanent scarring [8,13].

Inflammation is a process involving the immune system's reaction to what it identifies as foreign or harmful items. The immune system consists of three primary components: the thymus gland, lymph nodes, and bone marrow. These parts produce two major types of blood cells: red blood cells, which transport oxygen from the lungs to the tissues of the body, and white blood cells, which defend the body against invasion and infection.

Lymphocytes, a type of white blood cell, are divided into two categories: B cells, which manufacture antibodies or immunoglobulins that identify foreign contacts as harmful agents, and T cells (from the thymus gland), which release chemicals known as cytokines that kill the invading antigen. Antibodies aid the immune system in recognizing organisms that have infected the body in the past, allowing the immune system to fortify and strengthen the body against future invasions by the recognized antigen [8,13].

PATHOGENESIS OF ASTHMA

The pathogenesis of an asthma attack can be described as an inflammatory cascade composed of triggered, acute inflammation and chronic inflammatory changes. In the body of a person without asthma, the immune responses in the bronchi (e.g., swelling, excretion of mucus, recruitment of inflammatory cells) are present in a lesser degree to protect the body against any infectious agents or foreign objects. However, a person with asthma produces an extreme reaction to otherwise relatively harmless irritants, referred to as asthmagens or triggers. Exposure to a trigger causes inflammatory mast cells to release specific inflammatory mediators, including histamine and interleukins, resulting in an acute response. Histamine causes local tissue edema; interleukins generally act as chemotactic factors and activate other inflammatory cells. Studies reveal that leukotrienes, another chemical released by mast cells, prolong bronchial muscle and airway constriction [8,12].

After the inflammatory cells are activated, bronchospasm occurs. Bronchospasm and local tissue edema cause narrowing of the airways. Release of interleukins and other chemotactic substances causes migration of other inflammatory cells, including eosinophils, airway macrophages, and neutrophils. The physical presence of these cells can also cause airway narrowing. The migration of the inflammatory cells starts within 30 minutes of exposure and may take hours to reach peak levels.

Several different types of antibodies contribute to the inflammation process. One group of antibodies has evolved to be particularly harmful: IgE. Researchers believe that IgE once helped individuals ward off common ancient parasites; although IgE is not needed today, the body continues to manufacture it. Most individuals are unaffected by the presence of IgE, as it only accounts for about 1% of all antibodies. However, millions of individuals have inherited the genetic predisposition to overproduce IgE; in some cases, B cells release up to 20 times the normal amount of IgE. If an excess of the antibody is produced, the immune system may overreact to routine substances. Each substance to which an individual is sensitive triggers a different IgE antibody; any one of these substances could result in allergies that can trigger asthma [8,12].

CAUSES OF HYPER-RESPONSIVENESS IN PERSONS WITH ASTHMA

The actual cause of the hyper-reaction by the immune system in persons with asthma is unclear. While many cases may be attributed to a reaction in response to exposure to an asthmagen, the possibility of nervous system involvement is also an accepted theory. Generally, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) work in harmony to balance the body's functions; the PNS stimulates the bronchial tubes to constrict while, at the same time, the SNS stimulates the bronchial tubes to dilate. Ideally, these two systems coordinate to maintain open airways, allowing an effortless flow of air during inhalation and exhalation. In the lung of a person with asthma, it is thought that the balance may be tipped toward the PNS and that this imbalance may result in narrowed bronchial tubes and asthma symptoms. There was once a belief that the PNS was solely responsible for airway sensitivity; however, studies now seem to indicate that, although the PNS is involved, it is not the major reason for inflammation in asthma[12,13]. Researchers continue to study the importance of these neurotransmitters relative to bronchial muscle tone.

Additionally, there is a proposed theory that some people with asthma have abnormal beta receptors and the proper neurotransmitters are blocked from reaching the appropriate receptors. When the nervous system becomes unbalanced due to this blockage, the parasympathetic nerves overreact and constrict the bronchial tubes. For some researchers, the "beta blockage theory" offers a better explanation of the cause(s) of asthma symptoms present in some patients after exposure to what are known as nonspecific triggers, such as viruses and extreme weather changes [12,13]. However, it is still not understood how and when beta receptors would become defective.

ELEMENTS OF AN ASTHMA ATTACK

There are essentially five key elements of an asthma attack: muscle spasm, excess mucus, coughing, wheezing, and fatigue. While not all five elements are present for all patients, they are the most common physical manifestations of an episodic attack of the condition and should be evaluated and treated urgently.

Muscle Spasm

In response to irritation and immune response, muscles on the outer layer of the bronchi contract, causing a bronchospasm. Tightened muscles restrict the movement of air. Depending on the degree of airway narrowing, which differs for each patient and with the severity of the attack, the characteristic breathing difficulty, chest tightness, wheezing, and coughing will follow [13].

Excess Mucus

Inflammation can produce excess mucus as a protective mechanism. During an asthma attack, glands secrete excessive amounts of thick mucus to compensate for the increased amount of irritants or allergens. The excess mucus clumps together in the airways, further narrowing the bronchial tubes by partially blocking the passageway and hindering breathing. This increased amount of mucus can also form plugs that clog very small airways. During an asthma episode, some patients attempt to clear their airways by coughing up what seems to be a mucus plug. However, patients may produce many plugs; consequently, they may have a continuous, irritating hacking cough. If left untreated, mucus plugs can prolong asthma episodes and increase the risk of infection [13].

Coughing

When secretions become too thick for cilia to handle, the system responds by coughing to remove the unwanted substance. Dry coughs in patients with asthma are generally the product of extra-thick mucus plugs or bronchioles so blocked that the mucus cannot be removed or moved through. Nasal and sinus drainage, a common symptom of allergies, may also irritate airways and produce a nagging, unproductive cough [13]. If a patient has been mouth breathing, the airways may become dry and have decreased elasticity, making it more difficult to clear them. If this is the case, the patient should be encouraged to take frequent sips of water or isotonic fluids (e.g., electrolyte replacement drinks).

Wheezing

Wheezing is considered to be a trademark of asthma, but it is not a definite indicator. The wheezing sound associated with asthma results from a forceful rush of air pushing through narrowed, constricted airway lumens. The surge of air causes vibrations that make the wheezing sound. In some cases, airways can be so constricted that the air flowing past a blockage is not sufficient to produce a wheeze. In very severe attacks, the absence of wheezing is a worrisome sign.

It is important to note that patients with severe asthma have acute airway inflammation during an episode, and as stated previously, patients with chronic asthma have continuous symptoms of airway inflammation, which can eventually destroy airway tissue and alter lung function. Prolonged inflammation may result in permanent obstruction as a result of alteration of the bronchial walls. Unfortunately, after this change occurs, the airways may not respond to common treatment as quickly or at all. This is why it is important to use medication to reduce airway inflammation, subsequently preventing permanent obstruction [13].

Fatigue

Breathing with asthma can fatigue the body. As exhalation is blocked and air is trapped in the lungs, more force is required to maintain adequate oxygen supply. To aid in exhalation, accessory muscles become involved, which can deplete the body of energy. Untreated asthma can produce severe degrees of fatigue for the patient, and this can become a critical situation warranting immediate intervention [13]. Lethargy, decreased response time, and weakness are all late signs of fatigue.

7. DIAGNOSIS

PHYSICAL EXAMINATION AND PATIENT HISTORY

In some instances, a physical examination and a thorough exploration of a patient's medical history offer enough information for an accurate asthma diagnosis. There are several main criteria that should be present for a diagnosis of asthma to be ascertained. It is vital that a history of episodic asthma symptoms, characterized by airflow obstruction, be established. Symptoms that increase the probability of an asthma diagnosis include episodic wheeze, chest tightness, allergic rhinitis, atopic dermatitis, shortness of breath, and cough. It should also be noted if symptoms worsen at night or in the presence of aeroallergens, irritants, or exercise. A family history of asthma, allergies, sinusitis, or rhinitis is also an indication of potential asthma. According to the National Institutes of Health (NIH), most recurrent episodes of coughing and/or wheezing may be attributed to asthma [9,10]. Clinical signs of airway narrowing generally consist of wheezing, increased respiratory rate, retractions, nasal flaring, and grunting. Later signs can include tripoding (using accessory muscles to breathe) and altered mental status. In general, asthma symptoms are revealed in different combinations and varying intensities. Due to the fact that asthma symptoms can vary throughout a day, month, or even year, absence of the symptoms during the examination does not exclude a diagnosis.

The physical examination should include an assessment of the upper respiratory tract, chest, and skin. One presenting sign is hyperexpansion of the thorax. Patients with severe asthma often develop a barrel-shaped chest due to the forced inhalation and exhalation, which may cause chest and rib muscles to overdevelop. In time, the chest walls stretch out of shape, assuming a rounded appearance. As the patient inhales and exhales deeply, the quality of the breath sounds can be assessed. Sounds of wheezing during normal breathing or a prolonged phase of forced exhalation may indicate asthma. Observing increased nasal secretions, mucosal swelling, sinusitis, rhinitis, nasal polyps, or edema under the eyes are possible signs of allergic asthma. Any of these indications should be noted. Lastly, the skin should be examined for evidence of atopic dermatitis, eczema, or other allergic skin reactions. Red, scaly skin with pruritus may indicate eczema and can signal other forms of allergy and possibly allergy-related asthma.

PULMONARY TESTS

Most physicians order tests to confirm an asthma diagnosis or to rule out any complications and evaluate the severity of the condition. The objectivity of pulmonary tests allows for a reliable analysis of lung function that patient history and physical examination may not provide; this information may be valuable to the diagnosis process. The most critical tests for evaluating asthma assess pulmonary function, which measures lung performance. Pulmonary tests calculate the amount and rate of air expelled during a single breath, helping to discern whether constricted airways are responsible for blocked airflow [10,21]. Guidelines for normal breathing are based on analysis of data obtained from large segments of the population. A patient's information is plotted on a continuum, allowing comparison to average breathing patterns for healthy individuals of the same sex, age, and size. Two common methods of measuring airflow assess forced expiratory volume (FEV_1) and peak expiratory flow (PEF) [9,10,21].

Spirometry

A spirometer is a simple machine used to determine both the total amount of air that can be forcefully exhaled after maximum inspiration, referred to as forced vital capacity (FVC), and how fully air can be expelled from the lungs, measured by the amount of air forced from the lungs in one second, which is expressed as FEV_1[9,21]. The spirometer is generally used in diagnosis to establish airflow obstruction and reversibility. Obstruction may be ascertained if the FEV_1 is less than 80% of the predicted value or if FEV_1 divided by FVC is less than 65%. Normally, the FEV_1 should account for more than 75% of the FVC; anything less than 75% indicates a possible obstruction and 65% or less may indicate a diagnosis of asthma [9,10,21].

Peak Flow Meter

A peak flow meter measures the speed of exhalation. The highest speed or best flow is PEF or peak flow. The peak flow meter is less sophisticated than a spirometer, which provides a more thorough assessment of lung function. However, the meter has the advantages of being less expensive, portable, and easy to use. The severity of a patient's asthma can be determined by careful and consistent monitoring of peak flow and comparison to a patient's best peak flow and to standard measurements. Studies confirm that short-term peak flow measurements assist healthcare providers in assessing asthma severity [8,9,21].

Exhaled Nitric Oxide

Studies have shown that measuring exhaled nitric oxide (FeNO) is helpful in evaluating and diagnosing asthma, particularly in cases of an uncertain diagnosis of asthma using history, clinical course, clinical findings, and spirometry (including bronchodilator responsiveness testing) or when spirometry cannot be performed [9,10,13]. Nitric oxide is a mediator for the inflammation that occurs during an asthma episode; the amount of nitric oxide measured during exhalation will directly correlate with the inflammation in the bronchial tubes. In general, higher concentrations of nitric oxide are a sign of more severe forms of asthma. However, the NAEPP notes that increased FeNO levels can be caused by allergic rhinitis and atopy, which can be present in individuals with and without asthma; taking these factors into consideration is important for accurate interpretation of FeNO test results [9,10].

Monitoring the concentration of nitric oxide in expired breath may allow healthcare providers to confirm the reversible nature of the inflammation and assess the effectiveness and adherence to the prescribed therapeutic treatment. It is not recommended, however, that asthma treatment be routinely tailored based on exhaled nitric oxide levels alone [9,10,13].

ASTHMA CHALLENGE TESTS

When an asthma condition is difficult to confirm or treat, asthma challenge tests may be undertaken to verify the diagnosis. Of course, any challenge test is potentially dangerous, as there is a risk that the test may induce a serious asthma emergency or unpredicted delayed reaction. So, preferably, challenge tests should be performed in a hospital setting under controlled conditions.

There are two main challenge tests that are useful in assessing a patient for a possible asthma diagnosis. The first is an inhalational or chemical challenge (i.e., direct challenge), whereby patients inhale a small amount of either a suspected asthma trigger or one of two chemicals: histamine, which occurs naturally in the body and may induce asthma-like symptoms, or methacholine, which is known to cause airway constriction only in people with asthma. After exposure, spirometry is performed. If a reaction does not occur initially, the concentration of the substance is increased and spirometry is repeated. The procedure is repeated until it is determined that there is no sensitivity or until FEV_1 decreases by 20%, which would be indicative of asthma [9,13].

Second, if respiratory distress increases with exercise, an exercise challenge (i.e., indirect challenge) may be recommended. Spirometry is performed before, during, and after the patient engages in moderate-to-strenuous activity, such as running on a treadmill or riding a stationary bicycle, in a controlled laboratory setting. If peak flow or FEV_1 drops more than 12% to 15% during or after the activity, the diagnosis will most likely be exercise-induced asthma [9,13].

ALLERGY TESTING

Because the comorbidity rate associated with asthma and allergies is so high, it is advisable to engage those patients suspected of having asthma in standard skin and blood tests to determine if they are atopic. The most common allergy tests involve introducing the suspected allergen into the skin's surface and monitoring the area for a reaction. This skin testing can be expensive, time consuming, and, if conducted improperly, results may be misleading. Nonetheless, skin testing can be useful in confirming suspected allergies. The three types of skin tests are prick, scratch, and intradermal, each of which involves adding small amounts of a given allergen to the skin, either percutaneously or intradermally. The test site should be assessed after approximately 15 to 20 minutes to determine if a reaction has occurred. A positive allergic reaction is characterized by a wheal at least 3 mm in diameter greater than the negative control. A few patients may experience delayed anaphylactic reactions to even the smallest amounts of allergen; untreated, these reactions can result in asthma attacks of increasing severity, especially in sensitive individuals [9,10,14]. Therefore, many physicians and allergists favor elimination diets over skin tests for differentiating food sensitivity.

In addition to elimination diets and skin testing, there are various blood tests that may be used to assess allergy or allergic reactions in a patient. These tests are able to calculate the proportion of the antibody IgE in the body. In infancy, IgE levels tend to be low, rising gradually over the following decades and decreasing beginning around 40 years of age. Lowest levels are recorded when an individual is 70 years of age. Therefore, high IgE levels can imply that allergies may be triggering the asthma. Elevated IgE levels in infants and young children are one test used to help predict future allergies. Although the analysis is fairly common, it is rarely used as a sole indicator of allergy or allergic asthma. A group of tests, the radioallergosorbent test (RAST), the multiple allergosorbent test (MAST), and the fluorescent allergosorbent test (FAST), evaluate blood levels of IgE for sensitivity to specific allergens [9,10,14].

Although the connection between asthma and allergies is compelling, it is vital to remember that not all people who develop asthma have allergies. Whereas allergies play a part in asthma for 80% to 90% of children, the figure is thought to be lower for adults [14,24]. Nevertheless, it is worth investigating the possible role of allergens in asthma because, quite simply, knowledge of allergic triggers associated with asthma will allow patients to avoid the harmful agents and better manage the condition. Allergen and asthmagen avoidance is one of the most effective treatments for asthma and allergy patients [9,10].

DIFFERENTIAL DIAGNOSIS

Because the signs and symptoms of asthma are similar to several other diseases and disorders, it is important to rule out other conditions that may have a similar outward appearance of asthma. This is particularly imperative for patients unable to express symptoms or history verbally.

In particular, panic disorders, physical airway obstructions, congestive heart failure (CHF), GERD, and other pulmonary conditions, such as COPD, pneumonia, and bronchitis, may either exacerbate or mimic the signs and symptoms of asthma. Shortness of breath, decreased exercise tolerance, chest tightness, and wheezing may occur with any of these conditions.

Although not all individuals with asthma wheeze, it is one of the characteristic symptoms of asthma, occurring either during episodic attacks or quite regularly, depending on the severity of the condition. However, there are several other potential causes of wheezing that should be investigated as part of the diagnosis process. For example, wheezing in children may be attributed to acute infections, including bronchiolitis or pneumonia. If these diseases are suspected, chest x-rays and/or blood gas tests may be ordered.

Pediatric Concerns

Differential diagnosis for children presenting with wheezing and recurrent lower respiratory infections should include cystic fibrosis, bronchopulmonary dysplasia (prevalent in premature infants), dysmotile cilia syndrome, alpha-1-antitrypsin deficiency, and immunodeficiencies [9,31].

Cystic Fibrosis

Cystic fibrosis is the leading cause of chronic debilitating pulmonary disease and pancreatic exocrine deficiency in the first three decades of life. The median age at diagnosis is 6 to 8 months; more than 75% of patients are diagnosed by 2 years of age. It occurs most often in White children, and it is estimated that 1 in every 20 White Americans is a carrier of the cystic fibrosis mutation. Among Black individuals, the incidence is approximately 1 in 16,000, and in Asian Americans, it is 1 in 31,000 [31,32]. Although cystic fibrosis can be a multisystem disorder, the respiratory system is almost always involved and tends to dominate the clinical picture. Common respiratory complications include air trapping and wheezing, chronic cough and sputum production, retractions, tachypnea, and recurrent or chronic pneumonia. However, the earliest signs of cystic fibrosis can be gastrointestinal and pancreatic, not respiratory. Signs of cystic fibrosis include radiograph abnormalities such as bronchiectasis, atelectasis, infiltrates, and hyperinflation. Therefore, a chest x-ray or computed tomography scan may be useful in determining the correct diagnosis, especially in children [9,31].

GERD

Excessive mucosal secretion secondary to GERD or gastrointestinal malformation may cause wheezing in both children and adults and should be considered during evaluation. It is reported that 34% of patients with GERD experience chronic cough and/or wheezing as part of their symptomatology. Additionally, bronchiole irritation resulting from repeated exposure to gastric acid may trigger asthma symptoms. Generally, asthma-like symptoms that stem from GERD can be controlled with initiation of reflux medications and lifestyle modification [9,31].

Structural Issues

If respiratory difficulties are suspected to be more of a structural issue, a bronchoscopy may be performed. This is especially important if congenital abnormality, such as laryngomalacia or tracheobronchomalacia, or tumors or growths are suspected. It can also rule out foreign body aspiration. Samples of tissue and sputum to be used in additional testing may be taken during the procedure, if necessary [9,31].

Adult and Geriatric Concerns

In adults, CHF and other cardiac conditions, such as mitral valve disease, should be considered in the differential diagnosis of asthma. Establishing an asthma diagnosis is difficult for patients older than 55 years of age due to the increased incidence of CHF and respiratory difficulties resulting from cardiac problems, or "cardiac asthma." Conversely, asthma can aggravate heart disease when oxygen supplied by the lungs is inadequate for the reduced blood supply to the heart. Any diseases or conditions that may cause dyspnea should be considered when determining a differential diagnosis of asthma [9,33].

A particular form of an infection-plus-allergy condition known as allergic bronchopulmonary aspergillosis, often shortened to aspergillosis or ABPA, should also be considered. The condition initiates with the introduction of the fungus Aspergillus fumigatus, a mold that is abundant in damp straw, compost heaps, birdcages, and any decomposing material. A. fumigatus does not usually have an adverse effect on those with normal immune systems. However, in individuals with asthma or immunocompromise, the spores from this mold may begin to grow in the lung tissue. An allergic reaction may then occur in response to the fungus. This is an important consideration for those who work in agricultural occupations and is one example of the usefulness of a thorough history and lifestyle questionnaire in the diagnosis and management of asthma [9,33].

ABPA may present comorbid with asthma or the similar symptoms may result in a false asthma diagnosis. The signs and symptoms of ABPA include rubbery plugs of golden-brown or green sputum; a fever apparent only when the asthma symptoms are severe; worsening symptoms despite treatment; dependence on steroid medications; and very high levels of serum IgE. ABPA is normally treated with steroids to control the allergic reaction and with physiotherapy to clear the mucus from the lungs [9,33].

There are also certain medications that may induce asthma-like symptoms. Specifically, there are two conditions, aspirin-sensitive triad and nonallergic rhinitis with eosinophilia syndrome (NARES), known for their similar presentation to asthma. The diagnosis of aspirin-sensitive triad is based on three distinct symptoms: perennial rhinitis, nasal polyps, and asthma. Patients with an aspirin-sensitive triad diagnosis tend to collect all three symptoms gradually, in no particular order, over a period of years or decades. Although it is not known how common nonsteroidal anti-inflammatory drug (NSAID) sensitivity is for adult patients with asthma, various reports site frequencies from 3% to approximately 40%. It is far less common in pediatric patients with asthma; women in their third decade are most commonly affected [9,33].

Quite often, aspirin-sensitie patients with asthma have other related respiratory conditions, including sinusitis, severe rhinitis, and nasal polyps. Nasal polyps are benign inflammatory growths that begin in the sinuses but protrude into the nostril. However, the absence of sinusitis and nasal polyps does not automatically rule out the presence of aspirin sensitivity. Aspirin sensitivity can develop suddenly and produce a reaction similar to anaphylaxis, but it usually builds over many years. Patients with asthma found to have a sensitivity, usually by an aspirin challenge test, are advised to avoid all NSAIDs even if they have not reacted to these medications in the past. Also, patients with aspirin-sensitive triad will often have cross intolerances with sulfides, particularly wine and other alcoholic beverages containing sulfides, and naturally occurring salicylates, which are found in citrus fruit, nuts, and grapes. Food additives may also be problematic [9,33].

NARES is caused by the invasion of eosinophils into the nasal passages, resulting in severe inflammation. Nasal secretions testing positive for the presence of eosinophils (usually greater than 20% of the cells on nasal smears) are used to confirm a positive diagnosis of NARES. NARES may develop as part of aspirin-sensitive triad or completely separately from any aspirin sensitivities. The cause of the eosinophil infiltration is not clear [9,33].

In general, a diagnosis of asthma may be reached if a patient has a strong family history, has repeated episodes of wheezing or other breathing difficulties, and responds to bronchodilators. However, because a wide spectrum of diseases and disorders have strikingly similar symptomatology, it is vital that those avenues are exhausted prior to establishing an asthma diagnosis [9,33].

8. MEDICAL TREATMENT AND MANAGEMENT

The treatment of asthma is generally divided into one of two categories, either short- or long-term management. Short-term treatments are used only in the case of an asthma attack for immediate relief from the devastating symptoms. The focus of treatment for stable asthma is long-term prevention, planning ahead for emergencies, and being alert to increased symptoms [11]. Asthma may be controlled with early, accurate diagnosis and a treatment plan that involves a patient's, and perhaps an entire family's, active participation.

Asthma exacerbations can be frightening experiences for both patients and their caregivers, especially the first time an attack occurs. A thorough explanation of all the treatments administered will better educate patients for future attacks and prepare them for future treatment.

CREATING A TREATMENT PLAN

The NAEPP advocates the use of a stepwise approach to asthma management [9,10]. In this program, the asthma classifications are treated as separate steps, beginning with mild intermittent at step 1 and advancing to severe persistent at step 6.

Asthma is classified based on symptom severity and frequency (Table 1) [9,10]. Patients for whom symptoms occur more frequently (i.e., more than two times per week) and who experience interference with normal activity as a result of asthma symptoms are classified as having persistent asthma. Patients who experience asthma less than two times per week, have less than two night-time awakenings due to asthma per month, use rescue inhalers less than two times per week, have no interference with normal activity, and have "normal" peak FEV_1 are categorized as having intermittent asthma. The asthma is then further classified as mild, moderate, or severe based on the extent of interference in daily life, lung function tests, and use of rescue medications. After asthma severity has been classified, the treatment step is determined and initiated (Table 2) [9,10].

Table 1: CLASSIFICATION OF ASTHMA SEVERITY IN PATIENTS 12 YEARS OF AGE OR OLDER

Component

Intermittent

Persistent

Mild

Moderate

Severe

Symptoms

≤2 days/week

>2 days/week but not daily

Daily

Throughout the day

Nighttime awakenings

≤2 times/month

3 to 4 times/month

>1 time/week but

not nightly

Often every night

Short-acting beta_2 agonist use for symptom control

≤2 days/week

>2 days/week but not daily and not more than once per day

Daily

Several times per day

Interference with normal activity

None

Minor limitation

Some limitation

Extremely limited

Lung function

Normal FEV_1 between exacerbations

FEV_1 >80% predicted

FEV_1/FVC normala

FEV_1 ≤80% predicted FEV_1/FVC normala

FEV_1 >60% predicted but <80% predicted FEV_1/FVCa reduced 5%

FEV_1 <60% predicted FEV_1/FVCa reduced >5%

Recommended step for initiating treatment

Step 1

Step 2

Step 3 or 4

Step 5 or 6

aNormal FEV_1/FVC values are 85% for individuals 8 to 19 years of age; 80% for those 20 to 39 years of age;

75% for those 40 to 59 years of age; and 70% for those 60 to 80 years of age.

Source: [9,10]

Table 2: STEPWISE APPROACH FOR MANAGING ASTHMA IN PATIENTS 12 YEARS OF AGE AND OLDER

Treatment Step

Preferred Treatment

Alternative Treatment

Considerations

Step 1

SABA

—

Use SABA as needed for symptoms in any step (as indicated), up to three treatments at 20-minute intervals depending on severity of symptoms.

Caution: Increasing use of SABA or use≤2 days a week for symptom relief generally indicates inadequate control and may require a step up in treatment.

Step 2

Daily low-dose ICS and SABA

OR

Concomitant ICS and SABA

Daily LTRAa and SABA

OR

Cromolyna; or nedocromila; or zileutona; or theophyllinea; and SABA

Steps 2–4: Conditionally recommend subcutaneous allergen immunotherapy as an adjunct treatment to standard therapy in individuals 5 years of age and older with asthma controlled at initiation, build up, and maintenance phases of immunotherapy

Steps 3–4: Preferred use of ICS/formoterol is 1 to 2 puffs as needed up to a maximum total daily maintenance and rescue dose of 12 puffs (54 mcg)

Step 3

Daily and as needed combination low-dose ICS/formoterol

Daily medium-dose ICS and SABA

OR

Daily low-dose ICS/LABA; or daily low-dose ICS + LAMA; or daily low-dose ICS + LTRAa; and SABA

OR

Daily low-dose ICS + theophyllinea or zileutona; and SABA

Step 4

Daily and as needed combination medium-dose ICS/formoterol

Daily medium-dose ICS/LABA; or daily medium-dose ICS + LAMA; and SABA

OR

Daily medium-dose ICS + LTRAa; or daily medium-dose ICS + theophyllinea; or daily medium-dose ICS + zileutona; and SABA

Step 5

Daily medium-high dose ICS/LABA + LAMA and SABA

Daily medium-high dose ICS/LABA and SABA

OR

Daily high-dose ICS + LTRAa and SABA

Steps 5–6: Consider adding asthma biologics (e.g., anti-IgE, anti-IL5, anti-IL5R, anti-IL4/IL13)

Step 6

Daily high-dose ICS/LABA + oral systemic corticosteroids + SABA

—

Steps 1–6

In each step, assess environmental factors, provide patient education, and manage comorbidities, then:

Step up if needed; reassess in 2 to 6 weeks

Step down if possible (if asthma is well controlled for at least 3 consecutive months)

ICS=inhaled corticosteroid; LABA=long-acting beta_2-agonist; LAMA=long-acting muscarinic antagonist; LTRA=leukotriene receptor antagonist; SABA=inhaled short-acting beta_2-agonist

Note: Medications linked with a slash (/) indicate combination formulations in a single inhaler.

aCromolyn, nedocromil, theophylline, and LTRAs including zileuton and montelukast were not considered in the 2022 update of the NAEPP guidelines, have limited availability for use in the United States, and/or have an increased risk of adverse consequences and need for monitoring that make their use less desirable. The FDA issued a boxed warning for montelukast in March 2020 due to the risk for serious neuropsychiatric events, including suicide.

Source: [9,10]

The goal of each step of treatment is to prevent asthma symptoms and provide the best therapy for the patient. Physicians and other healthcare providers may differ in their "step" approach to medication prescriptions. Some may treat symptoms with the weakest medications for a specific step and add stronger medications if symptoms are difficult or persist; others may prefer to rapidly control symptoms and then reduce medications to the smallest effective doses. The NAEPP recommends the step-down approach to managing asthma symptoms (if asthma is well controlled for at least three consecutive months) [9,10]. In any case, the goal of the treatment plan should be expressed to the patient and outlined clearly, to ensure the best patient adherence possible.

Each step of the management plan requires a short-acting inhaled beta_2 agonist or combination inhaled corticosteroid/formoterol for relief of sudden onset and/or infrequent symptoms. Steps 2 (mild persistent classification) and above include long-term control measures. There are separate step plans for children 0 to 4 years of age and children 5 to 11 years of age, as will be discussed later in this course [9,10]. Adolescents 12 years of age and older follow the plan established for adults.

Regular follow-ups are vital to monitor the progress in the management of asthma symptoms. A review of current symptoms and improvements should be undertaken every two to six weeks initially and then every three months, depending on the patient's condition, stage in treatment, and management process. If symptoms start to subside and appear controlled after 3 months, consider stepping down to less intense treatment [9,10].

The NAEPP also recommends that any patients who require treatment for steps 4 or above be referred to an asthma specialist. Other factors that may require referral include initiation of immunotherapy, difficulty achieving or maintaining control of asthma symptoms, or the presence of life-threatening asthma episodes. Referral to a specialist may also be considered for those who require step 3 treatment [9,10]. Asthma biologic therapies should be considered for patients who require treatment at step 5 or 6.

In each of the six steps, the NAEPP recommends assessment of environmental factors to provide applicable patient education and manage comorbidities.

PHARMACOLOGIC INTERVENTIONS

When considering pharmacologic treatment of asthma, the dosage, timing, and type of medication should be tailored to individual needs. Optimal treatment should include methods to reverse airflow barriers, stop symptoms from occurring, prevent serious attacks and need for emergency care and hospitalization, keep asthma from interfering with activities of daily living, minimize side effects, and control symptoms with the least amount of medication. As with the approach to management, medication therapy generally adheres to two possible uses: to relieve symptoms quickly with the use of bronchodilators or to reduce chronic airway inflammation with anti-inflammatory medications, preventing asthma from recurring in the future [9,10].

Medication Administration

Asthma medications may be inhaled, taken orally in pill, granule, or liquid form, or in emergency situations, injected intravenously.

Inhalers

There are several types of inhalers available including aerosol, dry powder, and nebulizers. Metered-dose inhalers (MDIs) rely on a mixture of medication, preservatives, and liquid propellant gas to deliver medicine into the lungs in aerosol form. As of 2008, inhalers that contain chlorofluorocarbon propellants are no longer permitted to be sold [34].

Some short-acting inhaled medications begin to reverse airway constriction within five minutes; however, long-acting medications have been developed in inhalant form as well. Inhaled medications have advantages over oral administration because the medication is able to enter directly into the lungs rather than through the circulatory system. Some MDIs discharge medication after a trigger is pressed, but newer versions are breath activated. For patients with poor coordination or impaired hand function, such as those with arthritis or with a history of stroke, breath-activated devices may improve medication delivery. The drawback of the breath-activated inhalers is that, during a severe attack, a lack of air may make device triggering difficult [9,11].

Some patients require the assistance of a spacer when using an inhaler. A spacer is a plastic tube that attaches to an MDI; its function is to momentarily trap medication as it exits the inhaler, allowing the medication to be inhaled more easily and preventing it from being lost. Spacers may benefit patients who find it difficult to squeeze the trigger and inhale at the same moment, such as young children or older adults. As medicine deposited in the mouth area can produce side effects, spacers can help limit this and ensure that more medication reaches the lungs instead of the tongue or back of the throat [9,11].

A major problem with MDIs is knowing when they are empty. Usually, a patient cannot see, hear, or taste when a canister is empty or delivering less medication than intended; in fact, at times, inhalers may feel heavy enough to hold medication but only contain propellant and preservatives. In some cases, empty inhalers may leave a strange taste or heavier spray in the patient's mouth [9,11].

Each inhaler should have a label that indicates how many measured metered doses the canister holds. For regularly scheduled medications, it is best to calculate the number of usable doses before a new inhaler is needed. Patients may mark calendars or the canister to remind themselves when to reorder another inhaler. In the past, some patients have used the so-called "float test" to determine the amount of medication remaining in the canister. This has been proven to be inaccurate and should not be recommended. Some canisters may require cleaning to prevent the accumulation of bacteria [9,11].

Breath-activated dry powder inhalers incorporate the same benefits as other breath-activated inhalers; patients are not required to coordinate inhaling with releasing medication. Some dry powder inhalers have a different delivery system involving the insertion of a capsule with medicated, fine powder into the canister. In general, each capsule contains a single dose that equals two sprays of medication (although double doses are available). One disadvantage of the dry powder is the amount of coordination needed to load the capsule into some inhalers. This can be a problem for the young or elderly or for people with arthritis, Parkinson disease, or other diseases affecting coordination or dexterity. Furthermore, depending upon the patient's ability to breathe in deeply, variable amounts of medication may be inhaled. Another concern involves the effect of humidity on dry powder, which may influence dose strength [9,11].

The nebulizer is a form of inhaler that acts as a vaporizer or humidifier, delivering microdroplets of asthma medication in spray form and allowing a patient to breathe it in through a mouthpiece or face mask. Larger doses from nebulizers may increase the risk of side effects, and studies have shown MDIs to be as effective as nebulizers in delivering medication to the lungs. Nebulizers are used frequently in children as they are easier to administer and provide more accurate dosing. In the past, hospitals frequently provided medication in nebulizers to treat emergency asthma episodes, but now many facilities have converted to the use of MDIs [9,11].

Oral Administration

In addition to inhalers, many asthma medications are manufactured as pills, granules, or liquids to be ingested orally. Oral medications benefit patients by reaching the small bronchial tubes that most inhaled medication cannot reach. Newer developments in longer-acting, timed-release oral medications adapt to the needs and lifestyles of many patients. However, the amount of medication absorbed over a given time period can vary. Some medications may take up to six times longer than others to reach peak concentrations, which means each patient may require a different dose and frequency of administration to reverse breathing problems [11,13].

The disadvantage associated with oral medications is the systemic distribution. If negative or unpleasant side effects occur, they last the entire time the medication is active in the body. Depending upon the form and dose, oral medication may be more difficult for the system to balance throughout a 12- or 24-hour period than inhaled formulations [11,13].

Bronchodilators

Bronchodilators are used to address the acute symptoms of an asthma attack. They act by relaxing the muscles surrounding airways, thereby dilating bronchial tubes. The primary categories of bronchodilators are beta_2 agonists, theophylline derivatives, and anticholinergics. Most often, bronchodilators are prescribed in inhaler or aerosol form. They are also available in liquid, tablet, and capsule forms, but these are generally not used due to gastrointestinal side effects. The bronchodilator inhaler is usually the first line of defense in an asthma attack [11,13].

Epinephrine

The first oral medication to become available for the relief of an acute asthma episode was epinephrine, a hormone produced by the sympathetic nervous system. Epinephrine was once the first choice for treating acute asthma, but it has proved to be a weak bronchodilator with quickly diminished action. Moreover, epinephrine has very potent systemic effects, causing tachycardia, high blood pressure, nervousness, headache, and in some cases, panic attacks. However, this medication may still be used intravenously or subcutaneously in severe asthma emergencies. Epinephrine can be described as nonselective; that is, the medication acts on both the lungs and the heart [9,13].

Despite its limitations, epinephrine remains the treatment of choice for severe asthma and airway constriction related to allergy. There is agreement that self-injectable epinephrine should be prescribed for patients who have had a previous allergic reaction involving the respiratory or cardiovascular system. The patient, as well as caregivers and all members of the family, should be instructed in how to administer the injection. Parents of children who have been prescribed self-injectable epinephrine should inform school personnel about the allergy and the availability of the medication. Instructions regarding the proper use of self-injectable epinephrine should be repeated frequently to ensure proper use during emergency situations [9,31].

Beta_2 Agonists

Bronchodilators that selectively act on the lungs have largely replaced the routine use of epinephrine. These drugs are called beta_2 agonists. Beta_2 agonists stimulate the sympathetic nervous system, similar to epinephrine. However, they only act on receptors located in nerve endings inside the lungs. These medications provoke specific beta_2 receptors in the muscles encasing the bronchial tubes to reverse; when the drug stimulates these receptors, bronchial muscles relax and bronchial tubes dilate. Beta_2 agonists last longer in the body than epinephrine and result in less risk of cardiovascular side effects, making them the drugs of choice for safe, short-acting bronchodilation [9,11,35].

Beta_2 agonists may cause negative side effects, especially if fast-acting forms are taken too frequently for too long. Overuse can lead to poor asthma control and possibly desensitization. Inhaling more than one canister a month indicates an excessive reliance on bronchodilators to improve asthma. Patients with severe asthma may prefer a beta_2 agonist for quicker action than anti-inflammatory medications, which take days to act. However, patients may then expose themselves to potentially fatal attacks due to decreased beta_2 agonist effectiveness if the asthma flares out of control [9,11].

Inhaled beta_2 agonist medications are associated with fewer major side effects than orally administered preparations. However, patients who use inhalers may report problems as well. The most common complaint is shakiness; other noticeable side effects may include tachycardia, heart palpitations, headache, dizziness, and increased serum glucose [35]. These side effects tend to diminish over time. Patients using oral beta_2 agonists have reported tremors, nervousness, tachycardia, muscle cramps, and sleeplessness [9,11].

There are several beta_2 agonists approved by the U.S. Food and Drug Administration (FDA) for use as bronchodilators. Beta_2 agonists come in every administration form, which can assist in individualizing treatment. Injections may work quickly in case of emergency, although the effect lasts only about 20 minutes. Two to four puffs of an inhaled beta_2 agonist taken before exercise or travel in cold air can block wheezing for up to four hours [11,35]. Long-acting beta_2 agonists are usually taken twice a day and last up to 12 hours. Their longer action can help prevent interruptions from night-time symptoms and/or allow patients to engage in activities that they would otherwise be advised to avoid.

However, even longer-acting beta_2 agonists cannot control unstable asthma. These medications are unable to reverse the chronic airway inflammation found in patients with asthma, necessitating the additional use of an anti-inflammatory drug to prevent symptoms in the long-term. And, as discussed, overuse of these medications can lead to poor asthma control, possible desensitization, and even death. FDA analyses of clinical trials have shown that use of long-acting beta_2 agonists without concurrent use of an inhaled corticosteroid is associated with an increased risk of severe worsening of asthma symptoms, leading to hospitalization and death in some patients with asthma, including children [9,36,37].

Theophylline Derivatives

Before inhalers became widely available, methylxanthines were the leading asthma medications. They could be administered intravenously or orally. Theophylline was formerly the most widely prescribed bronchodilator in the methylxanthine category and a keystone of asthma treatment in the United States. Theophylline reduces airway responsiveness to histamine, adenosine, methacholine, and allergens, and also relaxes airway muscles and pulmonary blood vessels, allowing the tubes to open and airflow to continue [35]. However, controversies over the medication's benefits and action, and higher efficacy of newer drugs have led to a decline in use [11,35].

Theophylline provides both a short- and a long-term alternative for patients who cannot tolerate beta_2 agonists. The drug reduces mucus buildup and blocks night-time symptoms in mild-to-moderate asthma. Its long-term benefits for preventing symptoms are well documented for up to 12 hours, although theophylline is generally less effective than beta_2 agonists. It should be noted that caffeine is considered a methylxanthine drug, so patients should be advised to monitor coffee, tea, and chocolate intake while using this medication. Many factors may affect the metabolism or serum concentration of theophylline, including diet, viral infections, hypoxia, age, some antibiotics, and smoking [11,35]. In addition, studies have shown that theophylline for asthma management is not as effective in patients with obesity [20].

Anticholinergics

Anticholinergics such as ipratropium bromide, atropine, and tiotropium are shown to be effective in relieving breathing disorders, including asthma. When used for asthma, these medications are not usually the first line of defense but rather are used to supplement beta_2 agonists. Anticholinergics act on different nerves than beta_2 agonists, although both block nerve pathways to the lung and alter muscle tone in the bronchial wall. Anticholinergics affect specific lung nervous system receptors, or cholinergics, in the vagus nerve; this nerve branches into the smooth muscles responsible for airway opening and the mucous glands that discharge thick secretions. The result is reduced inflammation and relaxed bronchial muscles. Throughout the respiratory tract, the drug stimulates nerve activity in other reactive cells to decrease mouth and lung secretions [9,11].

Anti-Inflammatory Medications

In 2007, a panel of experts, under the guidance of the NAEPP, noted that the critical role of airway inflammation in asthma has been further substantiated since the 1990s, when this inflammatory role was first acknowledged and treatment was shifted away from calming acute flare-ups to engaging in preventative measures. The NAEPP also noted that bronchodilators work best for acute asthma situations and for preventative treatment before exertion or exercise, but it emphasized anti-inflammatory medications as the foundation for long-term treatment of asthma; this was reaffirmed in the NAEPP 2020 Focused Updates to the Asthma Management Guidelines and in the 2024 GINA guidelines. This approach relies on daily medication to maintain healthy lungs. Patients who require regularly administered bronchodilators should switch to longer-acting drugs designed to reduce airway inflammation [8,9,10].

Anti-inflammatory medications block production of substances from cells involved in inflammation, such as mast cells; this action reduces or reverses the swelling that causes asthma symptoms. Equally important, these medications lessen airway sensitivity, which prevents edema. If asthma symptoms appear more than once or twice a week and less powerful options cannot control them, anti-inflammatory medication is indicated. Before newer drugs were developed, the only anti-inflammatory asthma medication available was an oral corticosteroid, such as prednisone. Long-term treatment with oral corticosteroids is associated with serious side effects, including stunted growth in children, hyperlipidemia, thinning skin, and immune system impairment, making patient compliance difficult. As a result, several inhaled anti-inflammatory drugs were developed, which greatly reduced negative reactions. The four primary types of anti-inflammatory drugs are corticosteroids, mast cell stabilizers, antiallergic medications, and antileukotriene medications [9,11,13].

Corticosteroids

The most common group of anti-inflammatory medications is oral corticosteroids. Oral corticosteroids are powerful anti-inflammatory medications. They are easy to administer and offer dramatic reversal of symptoms during life-threatening asthma situations. Although some corticosteroids take a few hours to work, their protection is long-lasting. Oral corticosteroids can be used for a brief period to gain control of asthma before moving to other long-term treatments that have fewer side effects, such as inhaled corticosteroids. Although reports about side effects from steroids may concern some patients with asthma, oral or inhaled corticosteroids can be a promising remedy for severe, uncontrolled asthma [9,11]. Patients and/or parents may require reassurance that these are not the same class of steroids used illegally by athletes.

Corticosteroids used in the treatment of asthma are adrenal hormones. Oral corticosteroid medications are absorbed into the circulatory system and are distributed throughout the body. In the lungs, they prevent the development of airway edema. Significant amounts of corticosteroids for prolonged periods can adversely affect other organ systems, such as bones and skin [9,11].

Severe asthma may require higher doses for longer periods, which may then be tapered off over a period of one to three weeks. Patients should be reminded that it is dangerous to abruptly discontinue oral corticosteroids. Corticosteroids are usually taken upon awakening, mimicking the body's natural steroid production schedule. Night-time symptoms may be managed with split doses taken in the morning and at night [9,35].

A major disadvantage of oral corticosteroids is the array of negative side effects associated with taking large doses over long periods of time. Because these medications enter the circulatory system, there is potential for damage to other organs. If taken for severe asthma, patients should be diligent about identifying and reporting any side effects [9,11].

Inhaled corticosteroids are the most consistently effective long-term control medication for both children and adults with persistent asthma, and the NAEPP recommends the use of inhaled corticosteroids, either alone or in combination, for most individuals with persistent asthma [9,10]. Inhaled corticosteroid therapy concentrates on reducing airway edema and improves results obtained from bronchodilators while eliminating extraneous effects to other systems. A beta_2 agonist may be prescribed in conjunction with an inhaled corticosteroid; the beta_2 agonist is used first to unblock airways so the corticosteroid can penetrate deeper. Common inhaled corticosteroids include beclomethasone, flunisolide, triamcinolone, and budesonide (available in a dry powder inhaler) [11]. Corticosteroids are often combined with formoterol in a single inhaler for ease of use and better asthma control [9]. In 2023, the FDA approved an albuterol/budesonide combination inhaler; this is the first inhaler combining both a corticosteroid and a beta_2 agonist [53].

In 2010, the FDA required a boxed warning for drugs that include both a long-acting beta_2 agonist and inhaled corticosteroid due to an increased risk of severe exacerbation of asthma symptoms that led to hospitalization and death in some patients using these drugs for the treatment of asthma. In 2011, the FDA required post-market safety trials for these drugs [36]. In 2017, clinical trials were concluded, and it was determined that there was no significant increase of serious risks in patients taking beta_2 agonists in conjunction with an inhaled corticosteroid; however, it was noted that taking a long-acting beta_2 agonist alone to treat asthma without an inhaled corticosteroid to treat lung inflammation increases the risk of asthma-related death. The boxed warning, therefore, only pertains to single-ingredient long-acting beta_2 agonists [37].

Patients who take inhaled corticosteroids may complain about the lack of immediate symptom relief and cite it as a reason for not taking the medication. It is important to stress the long-term benefits when discussing this therapy with patients. Although risks of corticosteroid side effects are greatly reduced with inhalers, they do exist; prolonged use of high doses can increase chances for the same types of unpleasant symptoms attributed to the oral or injected forms [9,11].

The doses of the inhaled corticosteroid must be very high to equal the risk of side effects associated with oral corticosteroids. Two more common adverse reactions to inhaled corticosteroids are throat irritation and candidiasis. Candidiasis can develop when a patient is taking antibiotic medications in addition to the corticosteroid inhaler or if other medical problems, such as diabetes, exist. To prevent candidiasis, advise patients to rinse their mouths after each inhaler treatment and to gargle with warm water to remove any medication left in the throat. The use of a spacer may also be advisable, as it should ensure that medicine particles are delivered to the lungs rather than to the mouth and throat [9,11].

Mast Cell Stabilizers

Mast cell stabilizers or inhibitors are considered mild-to-moderate anti-inflammatory agents and are most effective in the treatment and prevention of exercise- or allergen-induced asthma. Mast cell stabilizers interfere with the inflammatory process by stabilizing mast cell membranes and inhibiting the activation and release of mediators such as histamine and leukotrienes. They may also restrain the development of early and late bronchoconstriction responses to inhaled antigens. Mast cell stabilizers used to treat asthma are generally administered by inhalation, but eye and nasal drops are also available. One mast cell inhibitor available for the long-term management of asthma is cromolyn. However, this medication is considered less effective than inhaled steroids in the treatment of moderate-to-severe persistent asthma in adults and children and is not effective for immediate relief of acute asthma attacks [11,35]. The NAEPP recommends that they may be considered for treatment of persistent asthma for patients of all ages, but their use is not preferred [9,10].

Other Antiallergic Medications

Similar to mast cell stabilizers, the concept of antiallergic medications as a separate category is under intense study. The idea behind antiallergic drugs is simple—eliminate the allergic reaction so allergic asthma symptoms are greatly reduced. Particularly, some studies have been undertaken to research the effectiveness of antihistamine medications on the long-term control of asthma symptoms. However, research generally shows that the effect of antihistamines for the control of asthma is modest, especially if the patient is receiving the recommended treatment with corticosteroids. If the patient also has allergic rhinitis, as many patients with asthma do, antihistamine medications may help to control the rhinitis with secondary benefits to asthma symptoms. While second-generation antihistamines (e.g., loratadine, cetirizine) have been reported to decrease emergency department visits, the NAEPP recommends against their routine use for home management of asthma, as patient delays in seeking treatment have been associated with home use of antihistamines. Data on the use of second-generation antihistamines suggest that they are safe for use during pregnancy [9,10]. There are also some preliminary data that suggest that asthma and allergies may provide protection against adult malignant gliomas; however, it was also found that the long-term use of immune mediators such as antihistamine medications may be a cancer risk for developing gliomas [38,39,40]. Research is ongoing to determine the link between antihistamine response and cancer.

Antileukotrienes

Antileukotriene medications, introduced in 1996, were the first new class of asthma medications released in decades. Leukotrienes act as a communication system for the inflammation process. Antileukotrienes disrupt this communication process, reducing the effects of hyper-responsiveness in patients with asthma. There are two types of antileukotriene drugs: leukotriene synthesis inhibitors, which prevent these chemicals from being generated, and leukotriene receptor antagonists, which prevent the chemicals from delivering their messages by blocking their receptors [9,11].

Antileukotrienes are strong and very effective in preventing exercise-induced asthma; they can also prevent the development of bronchospasm caused by aspirin and may be useful in milder forms of asthma. These medications may be useful in the management of moderate-to-severe asthma when combined with an inhaled corticosteroid but may not be as effective as other approaches.

Common antileukotriene medications approved in the United States include montelukast, zafirlukast, and zileuton. Compared to other anti-inflammatory drugs, antileukotrienes may produce more serious side effects, including reversible liver problems, headache, and nausea. Healthcare providers should caution pregnant women against taking these medications. For patients receiving antileukotrienes, serum levels of the agent(s) should be checked regularly to monitor for potential liver problems. The use of antileukotrienes has been associated with the rare condition Churg-Strauss syndrome. This condition usually occurs in adult patients with asthma, with an initial presentation of flu-like symptoms and blood vessel inflammation. Other signs include eosinophilic rash, nasal polyps, and pulmonary infiltrates. Left untreated, Churg-Strauss syndrome can result in major organ damage and even death. The FDA issued a boxed warning for montelukast in 2020 [9,10,35].

Other Medications

Mucolytics may be prescribed to patients with asthma to destroy or dissolve mucus buildup in airways; expectorants may be used to thin and loosen mucus. With mucus thinned, coughing and clearing the airways should become easier. However, the value of mucolytics and expectorants for patients with asthma is the subject of debate, as they do not halt the production of excess mucus or treat the underlying causal factors [9,11].

Antibiotics are useful for combating bacterial infections throughout the respiratory system; most respiratory infections, however, are viral, and antibiotics would not be useful in these cases. In general, antibiotics do not eliminate common asthma triggers, nor do they contribute to shorter hospital stays after severe attacks [9,11]. The NAEPP and GINA recommend against the routine use of antibiotics for asthma [8,9].

Decongestants are found in over-the-counter cold remedies and can produce side effects of nervousness, nausea, and headache; these side effects increase when compounded with asthma medications with similar side effect profiles. Decongestants are usually not recommended for patients who have cardiac or prostate problems and should be carefully monitored if taken in conjunction with other asthma medications [11]. Research continues for new, improved decongestants.

NONPHARMACOLOGIC MANAGEMENT

The most effective nonpharmacologic intervention for the treatment and/or prevention of asthma at this time is trigger avoidance, which will be discussed in detail later in this course. Knowing and eliminating any possible asthma triggers is one of the most important elements of any management plan. Additionally, peak flow meter use and increased patient education contribute to an enhanced understanding and control of asthma symptoms. Immunotherapy and complementary medicine modalities have also been used by patients with asthma. Strong patient education and communication is vital to the successful management of asthma.

Immunotherapy/Biologics

For some patients, particularly those with allergy-induced asthma, immunotherapy may result in a reduction of airway sensitivity, which should help prevent asthma attacks. With immunotherapy, small amounts of diluted allergen are injected, causing the patient's immune system to produce the antibodies associated with an allergic reaction. This process is repeated once or twice a week for three to four months, sensitizing the patient with gradually higher concentrations of allergen, until the body is able to tolerate the trigger without reaction. The frequency of injections may be reduced, but the allergen dose may be increased for up to three to five years. Successful immunotherapy results in fewer symptoms and decreased need for medication to control allergies and allergy-related asthma. Immunotherapy is generally more successful in children than adults. Studies report that this preventive treatment is effective in reducing symptoms of allergic asthma if the allergies involve animal dander, house dust mites, pollen, or fungi; to date, research has not confirmed that the positive effects are lasting. Also, immunotherapy may be costly and time-consuming and may not result in a complete cure. Even without cure, lessening an allergic reaction can result in better control of asthma and asthma-like symptoms. It may also provide additional time for medical interventions in cases of severe asthmatic reactions [8,9,13].

Several biologics for moderate-to-severe allergic and/or eosinophilic asthma are currently approved by the FDA. Omalizumab has become a widely used option for patients with persistent allergic asthma not adequately controlled with inhaled corticosteroids, either alone or in combination with inhaled long-acting beta_2 agonist bronchodilators. Omalizumab is a humanized monoclonal antibody that binds circulating IgE antibody, which leads to a decrease in the release of mediators in response to allergen exposure. It is approved for the treatment of adults and children older than 12 years of age in conjunction with inhaled corticosteroids and long-acting beta_2 agonists. The agent is administered subcutaneously every two or four weeks (depending on the dosage schedule), and the dose used is based on pretreatment IgE serum levels and body weight. Possible adverse effects of omalizumab use include injection site pain and bruising, viral infection, headache, and sinusitis. Allergic reactions (e.g., urticaria, anaphylaxis) occur in 0.1% to 0.2% of patients [9,35,41].

Several other biologics have been approved to treat moderate-to-severe allergic and moderate-to-severe asthma with levels of blood eosinophils (i.e., eosinophilic asthma). These therapies include three monoclonal antibodies that treat eosinophilic asthma by targeting IL-5 pathways (mepolizumab, reslizumab, and benralizumab), and one that treats both eosinophilic and allergic asthma by targeting IL-4/IL-13 pathways (dipilumab). Patients with eosinophilic asthma should have their blood eosinophils tested several times per year, as studies have shown that eosinophil count may shift over time into a range that may warrant immunotherapy [11,35,42].

Another novel monoclonal antibody (tezepelumab-ekko) binds to human thymic stromal lymphopoietin (TSLP) and blocks the interaction with the TSLP receptor. The interaction reduces the biomarkers and cytokines associated with inflammation, including blood eosinophils, airway submucosal eosinophils, IgE, IL-5, and IL-13. Tezepelumab-ekko is the first biologic approved for all types of severe asthma [35,43]

Mepolizumab was approved in 2015 for use in patients 12 years of age and older. Patients with uncontrolled asthma who are receiving NAEPP step 5 or 6 treatment, with an initial blood eosinophil count of ≥150 cells/mcL and at least two asthma exacerbations requiring systemic corticosteroids in the past year are good candidates for therapy ]. Mepolizumab is administered as a subcutaneous injection every four weeks at a fixed dose of 100 mg [9,35,42].

Reslizumab is approved for patients 18 years of age and older. Patients with severe eosinophilic asthma (initial blood eosinophil count of ≥400 cells/mcL) that is not controlled with high-dose corticosteroids and inhalers and who have a history of exacerbations may be good candidates. Reslizumab is administered as an IV infusion every four weeks at a dose of 3 mg/kg [35,42].

Benralizumab is approved for patients 12 years of age and older as add-on maintenance treatment for uncontrolled severe eosinophilic asthma (recommended for blood eosinophil count of ≥300 cells/mcL). Benralizumab is administered at a dose of 30 mg subcutaneous every four weeks for the first three doses and then once every eight weeks [35,42].

Dupilumab is also approved for patients 12 years of age and older as an add-on maintenance treatment for moderate-to-severe allergic and/or eosinophilic asthma. Indications for use include NAEPP steps 5–6, inflammation characterized by increased blood eosinophils and/or elevated FeNO. Dupilumab is initially administered as two 200-mg (total: 400 mg) or two 300-mg (total: 600 mg) subcutaneous injections, followed by one 200-mg or 300-mg injection (depending on initial dose) every other week [35,42].

Tezepelumab-ekko was approved in 2021 for patients 12 years of age and older as an add-on maintenance treatment for patients with severe asthma (with or without inflammatory markers) and a history of severe exacerbations. Tezepeluab-ekko may be used for any type of asthma and is administered subcutaneously at a dose of 210 mg once every four weeks [35,43]

Complementary or Alternative Treatments

There are many alternative or complementary therapies available to patients with asthma. In general, these therapies should be regarded as adjuncts, not replacements, to conventional treatment. The most common complementary therapies used in the management of asthma include breathing exercises, acupuncture, yoga, postural drainage, massage therapy, homeopathy, and herbal medications. There has been relatively little research into the effectiveness of complementary treatments in the management of asthma. However, some inconclusive, small trials support the further investigation of these treatment modalities. For example, studies focusing on magnesium's role in lung function have found that the element appears to block chemicals that inflame the lungs by stabilizing mast cells and T cells released during exposure to allergens. The results are relaxed airway muscles and open bronchioles, which contribute to improved lung function and a reduction in wheezing and other allergy-induced asthma symptoms. Magnesium is often used in the emergency department, but it is not recommended in the management of chronic asthma. Patients and/or their caregivers should be cautioned not to self-prescribe these and other agents without consent or supervision by a qualified healthcare provider [8,11].

9. SPECIAL POPULATIONS

ASTHMA IN PEDIATRIC PATIENTS

Asthma in pediatric patients may be difficult to diagnose, as children are more susceptible to respiratory viruses and reaction from allergens. Parents or caregivers of children with asthma may suspect the condition is present if the child begins to have repeated episodes of wheezing and coughing with or without illnesses. This is especially true if there is a strong family history of asthma and/or allergies. Parents or caregivers should be encouraged to keep an asthma journal detailing asthma symptoms, triggers, and response to treatments.

The treatment plan for infants and children younger than 5 years of age is modified according to the specific condition manifestations and treatment limitations specific to pediatrics (Table 3). In this population, lung function tests are difficult to impossible to administer; therefore, information regarding the severity and frequency of symptoms as observed by healthcare practitioners or caregivers may be used to determine the classification of each child's asthma [9,10,31]. As with patients 12 years of age and older, the NAEPP recommends the stepwise management plan be followed according to age groups (0 to 4 years of age and 5 to 11 years of age) (Table 4 andTable 5) [9,10]. However, the medications and/or dosages may vary for this population due to compliance, history, family dynamics, environmental triggers, physiologic response, or medical coverage.

Table 3: CLASSIFICATION OF ASTHMA SEVERITY IN CHILDREN YOUNGER THAN 12 YEARS OF AGE

Components

Intermittent

Persistent

Mild

Moderate

Severe

0 to 4 Years

5 to 11 Years

0 to 4 Years

5 to 11 Years

0 to 4 Years

5 to 11 Years

0 to 4 Years

5 to 11 Years

Symptoms

≤2 days/week

>2 days/week but not daily

Daily

Throughout the day

Nighttime awakenings

0

<2 times/

month

1 to 2 times/

month

3 to 4 times/

month

3 to 4 times/

month

>1 time/week but not nightly

>1 time/week

Often nightly

Short-acting beta_2 agonist

use for

symptom control

≤2 days/week

>2 days/week but not daily

Daily

Several times per day

Interference with normal activities

None

Minor limitation

Some limitation

Extremely limited

Lung

function

N/A

Normal FEV_1 between exacer-bations

FEV_1 or peak flow >80% predicted

FEV_1/FVC >85%

N/A

FEV_1 or peak flow >80% predicted

FEV_1/FVC >80%

N/A

FEV_1 >60% predicted

but <80%

predicted FEV_1/FVC 75% to 80%

N/A

FEV_1 <60% predicted FEV_1/FVC <75%

Recommended step for initiating treatment

Step 1

Step 2

Steps 3–4

Steps 5–6

Source: [9,10]

Table 4: STEPWISE APPROACH FOR MANAGING ASTHMA IN PATIENTS 0 TO 4 YEARS OF AGE

Treatment Step

Preferred Treatment

Alternative Treatment

Considerations

Step 1

SABA

AND

At the start of respiratory tract infection, add a short course of ICS

—

Use SABA as needed for symptoms in any step (as indicated), up to three treatments at 20-minute intervals depending on severity of symptoms.

Caution: Increasing use of SABA or use >2 days a week for symptom relief generally indicates inadequate control and may require a step up in treatment.

Consider short course of oral systemic corticosteroid if exacerbation is severe or individual has history of previous severe exacerbations.

Step 2

Daily low-dose ICS and SABA

Daily cromolyna; or montelukasta; and SABA

Step 3

Daily medium-dose ICS and SABA

—

For children 4 years of age only, see Step 3 and Step 4 in Table 5

Step 4

Daily medium-dose ICS/LABA and SABA

Daily medium-dose ICS + montelukasta and SABA

Step 5

Daily high-dose ICS/LABA and SABA

Daily high-dose ICS + oral montelukasta and SABA

Step 6

Daily high-dose ICS/LABA + oral systemic corticosteroid and SABA

Daily high-dose ICS + montelukasta + oral systemic corticosteroid and SABA

Steps 1-6

In each step, assess environmental factors, provide patient education, and manage comorbidities, then:

Step up if needed; reassess in 2 to 6 weeks

Step down if possible (if asthma is well controlled for at least 3 consecutive months)

ICS=inhaled corticosteroid; LABA=long-acting beta_2-agonist; LAMA=long-acting muscarinic antagonist; LTRA=leukotriene receptor antagonist; SABA=inhaled short-acting beta_2-agonist

aCromolyn and montelukast were not considered in the 2022 update of the NAEPP guidelines, have limited availability for use in the United States, and/or have an increased risk of adverse consequences and need for monitoring that make their use less desirable. The FDA issued a boxed warning for montelukast in March 2020 due to the risk for serious neuropsychiatric events, including suicide.

Source: [9,10]

Table 5: STEPWISE APPROACH FOR MANAGING ASTHMA IN PATIENTS 5 TO 11 YEARS OF AGE

Treatment Step

Preferred Treatment

Alternative Treatment

Considerations

Step 1

SABA

—

Step 2

Daily low-dose ICS and SABA

Daily LTRAa; or cromolyna; or nedocromila, or theophyllinea; and SABA

Steps 2–4: Conditionally recommend subcutaneous allergen immunotherapy as an adjunct treatment to standard therapy in individuals 5 to 11 years of age and older with asthma controlled at initiation, build up, and maintenance phases of immunotherapy

Step 3

Daily and as needed combination low-dose ICS/formoterol

Daily medium-dose ICS and SABA

OR

Daily low--dose ICS/LABA; or daily low-dose ICS + LTRAa; or daily low-dose ICS + theophyllinea; and SABA

Steps 3–4: The preferred option includes the use of ICS-formoterol 1 to 2 puffs as needed up to a maximum total daily maintenance and rescue dose of 8 puffs (36 mcg).

Step 4

Daily and as needed combination medium-dose ICS/formoterol

Daily medium-dose ICS/LABA and SABA

OR

Daily medium-dose ICS +LTRAa; or daily medium-dose ICS + theophyllinea; and SABA

Step 5

Daily high-dose ICS/LABA and SABA

Daily high-dose ICS + LTRAa; or daily high-dose ICS + theophyllinea; and SABA

Steps 5–6: Consider omalizumab

Step 6

Daily high-dose ICS/LABA + oral systemic corticosteroid and SABA

Daily high-dose ICS + LTRAa + oral systemic corticosteroid; or daily high-dose ICS + theophylline + oral systemic corticosteroid; and SABA

Steps 1-6

In each step, assess environmental factors, provide patient education, and manage comorbidities, then:

Step up if needed; reassess in 2 to 6 weeks

Step down if possible (if asthma is well controlled for at least 3 consecutive months)

aCromolyn and montelukast were not considered in the 2022 update of the NAEPP guidelines, have limited availability for use in the United States, and/or have an increased risk of adverse consequences and need for monitoring that make their use less desirable. The FDA issued a boxed warning for montelukast in March 2020 due to the risk for serious neuropsychiatric events, including suicide.

Medications linked with a slash (/) indicate combination formulations in a single inhaler.

Source: [9,10]

In school-aged children (5 to 11 years of age), it is recommended that the same stepwise treatment and management principles established for adults be followed, with some modification [9]. Healthcare providers should prepare and make available a written asthma plan for pediatric patients, not only for the patient and the patient's caretaker(s), but also for the child's school. This plan should detail any medications that may be appropriate (both short- and long-term medications), identify any known asthma triggers, and establish an action plan (including preferred or required medication usages) for any asthma attack [9,10]. Additionally, if the use of a bronchodilator prior to outdoor exercise or activity, especially in cold weather, is indicated, this should be noted in the action plan. Annual influenza and pneumococcal vaccination, particularly in pandemic years, can assist in preventing respiratory inflammation in an already compromised system.

Asthma is a highly individual condition, and treatment and management will be specifically tailored to each patient's symptoms and needs. Emphasizing compliance with the prescribed treatment and management plan and establishing good communication with the parent or caregiver of the pediatric patient will contribute greatly to the successful control of asthma symptoms. In some states, law requires a child's physician or healthcare provider to provide written instructions and an asthma plan to the child's school and/or childcare center.

Asthma and obesity present a unique problem with pediatric patients. In recent decades, studies have found that children with obesity are at increased risk of asthma. In addition, children with obesity who have asthma have greater severity and poorer control of their asthma symptoms, more frequent asthma exacerbations, and overall lower asthma-related quality of life than children with asthma who have a healthy weight. The causative link between childhood obesity and asthma remains unclear, but sedentary lifestyle may be a risk factor for both. Further research is underway to determine the impact of obesity on pediatric lung development and possible implications in the development of asthma.

Some learning and behavioral disorders have been found to coexist with asthma. One of these disorders is attention deficit hyperactivity disorder (ADHD), a chronic neurobiochemical condition that normally presents at an early age and includes primary behavior characteristics such as impulsivity, distractibility, short attention span, difficulty concentrating, extreme tempered mental characteristics, and in some cases, hyperactivity. Studies suggest an association between asthma and ADHD, but this association is likely the result of complex and possibly multiple pathways [44]. Results of a systematic review of literature and meta-analysis published in 2018 continued to show a positive association between ADHD and asthma after controlling for possible confounders. More research is needed to determine the cause of the association [45].

Case Study

Patient J is a boy, 5 years of age, residing in Southwest Michigan. One March evening, Patient J was home with a conscientious babysitter. He had experienced several coughing episodes during the previous days and began to cough while playing hide-and-seek with the babysitter. She noticed that the coughing was continuing and that the more he coughed, the more he cried. She was not able to calm the patient and telephoned his parents at a nearby restaurant. Within 20 minutes, the parents returned home and found Patient J upset, crying, and coughing. They could hear audible wheezing on exhalation and could see the young boy's chest retract on inspiration. A physician was called immediately, and the parents were instructed to meet the pediatrician at his office located next to the area's hospital; they arrived within 30 minutes. The pediatrician administered a nebulizer treatment with albuterol in a 0.083% solution for inhalation, which seemed to resolve the cough, wheeze, and labored breathing after 15 to 20 minutes.

The patient's history was reviewed. According to his parents and office records, Patient J's first few years of life were essentially medically uneventful with the exception of occasional benign rashes, several that were specifically found to be related to a wood sensitivity. By 4 years of age, Patient J had experienced a number of cold viruses and allergies, with severe bouts of nasal and chest congestion. He had no history of medical emergencies related to labored breathing or otherwise.

As a precaution, the physician was prepared to recommend hospital admission to provide intensive respiratory tent therapy in the event that the symptoms did not improve. However, the symptoms seemed to resolve completely, and Patient J was sent home with his parents and placed on a 10-day period of antibiotic therapy and an albuterol aerosol inhaler, one or two inhalations every four to six hours as needed. It was also recommended that a nebulizer be kept at home, for faster results in case of sudden onset of moderate-to-severe coughing, chest congestion, wheezing, and/or tightness in the chest.

Patient J was subsequently diagnosed with an extrinsic, mild-intermittent asthma, triggered by several sensitivities, specifically to wood, dust, pollen, and cold weather. Recommendations for control of the patient's asthma symptoms were made to the patient and his family in an effort to manage the condition. He was encouraged to sleep with his head propped up with pillows about 30 degrees. Outdoor play and activities at home or at school were evaluated for appropriate participation based on severe weather, particularly when accompanied by wind. On very cold days or days with high mold or pollen counts, Patient J was instructed to wear a mask. Spring and fall proved to be difficult times for outdoor activities. His lungs became sensitive to the smoke from burning leaves and the mold-infested fallen leaves in autumn.

At home, Patient J's room was evaluated for sources of asthma triggers. Stuffed animals, carpeting, and heavy draperies were kept to a minimum. He had no feather-filled pillows, and his bedding was washed weekly in hot water. He slept with a room air purifier. When his asthma flared up, the patient was given his prescribed medications and warm liquids. A soothing bath or shower allowed him to be in an area of humidified, misty air, which often relaxed and dilated the bronchial airways.

One decade later, Patient J's asthma remains in control. At 15 years of age, he continues to take his medication and stays aware of his asthma triggers. The frequency and severity of asthma episodes have gradually lessened over time. He and his family, however, are aware that the condition is capable of changing or worsening at any time and may return with increased frequency and severity in later years. For now, Patient J is living a normal, healthy, active adolescent life.

ASTHMA IN ELDERLY PATIENTS

The management and diagnosis of asthma in the elderly population may be difficult due to the frequency of additional medical complications or diseases, any of which may aggravate or be aggravated by asthma and/or asthma medications. Specifically, the high incidence of other obstructive lung diseases makes it vital to fully explore possible causes of airway obstruction. Asthma may usually be diagnosed if the obstruction is determined to be reversible. Also, due to the higher prevalence of co-existing diseases, healthcare providers should be aware of possible drug interactions. As mentioned, theophylline in particular has several possible interactions, as well as reduced clearance in the elderly, all of which should be considered. Use of the asthma classification standards and the NAEPP treatment plan is also approved for elderly patients, but individual condition and drug interactions should be closely monitored [9,10]. Many medications may also trigger asthma symptoms; this may be more prevalent in the elderly population, as more medications may be prescribed.

Various asthma medications can adversely affect elderly patient health. Corticosteroids have been shown to cause confusion and agitation in older patients [35]. There also appears to be a reduction in bone mineral concentrations in patients taking inhaled corticosteroids, particularly in those with pre-existing osteoporosis. However, in low-to-moderate doses, there seems to be no major adverse effect. The NAEPP recommends concurrent treatment with calcium supplements and vitamin D, if appropriate [9,10].

ASTHMA IN PREGNANCY

Reliable data regarding the prevalence of asthma among pregnant women and women of childbearing age are limited, although research indicates that it is the most common chronic medical condition to be reported during pregnancy. Estimates show that approximately 8% of pregnant individuals in the United States are affected by asthma symptoms. Furthermore, asthma during pregnancy may cause complications such as high blood pressure and pre-eclampsia, preterm delivery, and low infant birth weight. For women who have experienced asthma symptoms prior to becoming pregnant, it is estimated that one-third of these women will each experience a decrease, increase, or no change in their experience of the condition. It is unclear which, if any, of the physiologic changes associated with pregnancy may cause changes in the symptomatology of asthma [9,13,46].

The NAEPP has established practice recommendations for the management and treatment of asthma in pregnant patients and is supported by the American Congress of Obstetricians and Gynecologists [9]. The goal for pregnant patients with asthma should be to maintain control of asthma, as it is for all patients, and to maintain normal fetal and maternal health throughout gestation. Severe asthma attacks or persistent asthma may cause fetal hypoxia. Therefore, treatment of maternal asthma should be aggressive and complete. Assessment, including PEF and FEV_1 measurements and patient history, should continue throughout the pregnancy. If a woman is found to have persistent asthma or if she has a severe asthma attack, additional fetal monitoring, through ultrasound and antenatal fetal testing, may be indicated. According to the NAEPP, all patients should be instructed to be attentive to fetal activity [9,46].

As with asthma experienced outside of pregnancy, trigger avoidance and patient education are among the most important aspects of controlling the condition. Patient education can increase adherence to the management plan and may be used to stress the importance of controlling asthma symptoms for the benefit of the fetus. In previously untested women, allergy tests may be useful to determine if any controllable allergies are present. Immunotherapy is not generally recommended in pregnant individuals, but omalizumab therapy may be considered if standard treatments are not sufficient to control severe asthma, as the benefits to the patient and fetus may outweigh the risks [9,35,46].

Pharmacologic treatments for asthma are generally considered more beneficial than the possible harmful side effects and are therefore recommended for the management of asthma during pregnancy. Antileukotrienes may be considered for patients whose pre-pregnancy response to the drug was favorable. However, the drug should be considered an alternative, not a preferred, treatment option for control of mild persistent asthma in pregnant patients. The goal of pharmacologic treatment should be to gain and maintain control of asthma symptoms. After control is obtained and asthma symptoms stabilize for several months, less intensive treatment should be initiated. In some patients with severe or persistent asthma, the risk of a possibly harmful asthma episode may outweigh the benefits of lessening the intensity of asthma therapy. If this is the case, the step down to less intensive treatment may be deferred until after giving birth. The greatest amount of efficacy and safety data support the use of albuterol as the beta_2 agonist for use during pregnancy. Albuterol is a selective beta agonist and has a good safety record for both pregnant and nonpregnant patients. The recommended inhaled corticosteroid for long-term management is budesonide, as more research has been conducted regarding the effects of this medication on pregnant individuals. No data regarding the unsafe or safe properties of other corticosteroids in pregnant patients have been published [9,35,46].

10. PSYCHOSOCIAL MANAGEMENT

Asthma does not just affect the lungs. It is a condition that touches all aspects of life. As such, treatment of the patient with asthma should include treatment of the whole person. Because so much of the success of treatment depends on the individual's adherence to the prescribed management plan, patients and caregivers may be stressed by the added responsibility. By managing these and any other stresses, patients may experience increased quality of life and, by extension, may be more compliant to treatment plans.

Successful adaptation to this chronic, cyclical, sometimes unpredictable condition demands attention to emotional, mental, and social issues as well as to the physical pulmonary problems. The biopsychosocial approach to treating asthma appears to be one of the most successful; healthcare practitioners have found that clearing away psychological and social obstacles positively affects treatment compliance and improves the patient's experience of asthma. Additionally, as discussed, ADHD and other learning and behavioral disorders commonly co-occur with asthma. Most would agree that managing and treating asthma emotionally and mentally, as well as physically, leads to a happier, healthier lifestyle. Referring a patient with asthma to a counselor or psychologist may help alleviate some of the stresses of managing the illness. Connection with others with asthma, through support groups or community involvement, may also be helpful.

11. PATIENT EDUCATION

As stressed throughout this course, patient education and communication are imperative to the treatment and management of asthma symptoms. It is important that healthcare providers are able to discuss the different aspects of asthma symptoms as well as treatment and management to ensure that patients are able to understand and follow the established plan. In addition to the treatment plan and common symptoms associated with asthma episodes, patient education should outline the importance of compliance, trigger avoidance, and the continuous monitoring of their condition.

CONDITION MONITORING

Continuing with follow-up consultations and symptom monitoring allows for better treatment of asthma. Peak flow meters may be used by the patient to monitor FEV_1 levels and have been useful for some in determining when and if asthma is exacerbated. Peak flow and FEV_1 readings may also be useful in determining the efficacy of an established treatment plan. If possible, encourage patients to keep asthma diaries, in which they may record occurrences of symptoms and attacks. These diaries have been useful in identifying possible asthmagens and in determining the extent and severity of asthma in certain patients. It also helps patients feel more in control, as they will begin to see changes in their lung function even before they notice symptoms. Such awareness can help patients address changes earlier in the course of possible illness (using their action plan) and avoid medical intervention or hospitalization.

COMPLIANCE

The main problem seen in both the adult and pediatric asthma populations is compliance with a prescribed treatment plan and control of asthma symptoms. It is important that, as a part of patient education, adherence to the treatment plan is stressed. As noted, much of the treatment and management responsibilities associated with controlling asthma and asthma symptoms falls on the patient. The more patients understand their treatment and the value of each aspect, the more likely they will be to adhere to the established treatment plan. Healthcare providers should take into account the possible barriers to care, such as income level, education, language, and cultural beliefs. When a child is seen frequently for uncontrolled asthma, it may also be a parenting and caretaking issue.

Education of patients regarding proper administration of medications can be time consuming, and healthcare providers are often limited in the amount of time they can spend with patients or their families. Managed care has caused many hospitals, private offices, and clinics to reduce the number of staff members while increasing the patient loads to cover basic costs. However, patient education is one of the most vital steps in effectively managing and treating asthma and should not be ignored.

TRIGGER AVOIDANCE

In addition to the importance of treatment plan adherence, trigger avoidance should be covered in detail. If a patient has known asthma triggers, avoidance of these items, substances, or situations may greatly improve, or even eliminate, asthma symptoms. Information regarding these asthmagens, where they may occur, and ways to avoid triggering an attack should be incorporated into initial patient education.

Asthma symptoms begin when lungs react to a stimulus, referred to as a trigger or asthmagen. It is important for patients with asthma to discover what triggers their asthma symptoms in order to prevent episodes and more serious lung damage. Asthma symptoms may appear slowly over several years, become noticeable only in specific environments or conditions, or result from the accumulation of repeated exposure to irritants in the environment [2,13]. While any stimulus that induces an asthma attack is considered a trigger, the most common of these agents may generally be grouped into either the allergen or irritant categories.

Allergens are specific—either pollen is an allergen for a patient or it is not, depending on the response of the patient's immune system. In many cases, allergens are a basic cause of asthma. Allergy has attained this prominent role in the study of asthma not only due to the frequency with which it produces asthmatic episodes and the number of patients with asthma affected with it, but also because the allergic reaction serves as a model for the pathophysiology of asthma. However, numerous other asthma triggers exist as well [13,48].

Irritants are nonspecific; in fact, irritants affect every person, if sufficiently concentrated, causing bronchospasm and aggravating the airway lining. These irritants include, but are not limited to smoke, some industrial fumes, ozone, sulfur dioxide, insecticides, air freshener, perfumes, and other aerosols. At levels usually encountered, irritants do not adversely affect most individuals. Patients with asthma, however, can have dramatic responses to exposure to some or most irritants due to the chronic inflammation of their airways and their hyper-responsive system [13,47]. For these patients, an allergy test would reveal no specific allergies.

There are many different types of triggers; some act in isolation, and others work together. The severity of an asthma attack depends upon the number of irritants, allergens, or other stimuli in the environment and the degree of lung sensitivity to these triggers [13,47]. The following information regarding specific asthmagens and how they may be effectively avoided may be constructive to the patient education process.

Pollen

Pollen is likely the most difficult allergen to avoid. To a great degree, this is because pollen release occurs at different times of day for different plants. For example, most grasses release pollen from about 7:30 a.m. throughout the day; however, if the ground is damp, the release will be delayed until the moisture has evaporated. A few species of grass and other plants delay pollen release until afternoon hours, so pollen may be entering the air all day. All types of plants generally favor warm, sunny days for releasing pollen and avoid rainy, wet weather. Rain also washes residual pollen out of the air. So, days of rain may be a relief to pollen-sensitive individuals with asthma. However, on cloudy and/or wetter days, there is a pollen buildup, which results in a massive release of pollen on the next day of good weather. These pollen release patterns may correspond with incidences of asthma symptoms in sensitive patients [8,47,48].

For certain patients with asthma, it may be useful to realize that pollen settles quickly in rural areas, reaching ground level between 8:00 p.m. and 10:00 p.m. In the city, hot pavements and buildings keep upward air currents going and pollen stays aloft longer. As most pollen lands in the city between roughly midnight and 2:00 a.m., it may contribute to night-time symptom aggravation in urban patients with asthma. If a patient with asthma has a noticeable response to a specific type of pollen, staying indoors or avoiding heavily wooded areas at release times may help alleviate symptoms. A daily pollution index figure should be available from a regional office of your state's Department of Environmental Conservation [8,47,48]. Many local and online weather stations include pollen counts in their daily reports as well.

Outdoor Pollution

The verdict regarding the effects of outdoor pollution on the condition of asthma remains controversial. Consider two main types of outdoor pollution: industrial smog (such as sulfur dioxide) and photochemical smog (a combination of ozone and nitrogen oxides). Physicians and scientists are cautious about implicating these and other environmental pollutants as asthma triggers. But the findings of several studies confirm a relationship between pollutants and asthma, particularly when nitrogen oxide, acid aerosols, and ozone are involved [8,47,48].

Air pollution plays a variety of roles in asthma and allergy. Some pollutants irritate the nose, airways, and/or skin, making them more sensitive to allergens. Specifically, ozone can increase the effects of allergens and may take 4 to 24 hours to produce its effects on the lungs and airways. Such pollutants can worsen existing asthma symptoms and may even promote development of allergies and/or asthma, particularly in children, whose airway membranes are more permeable. Other chemical pollutants may affect the immune system directly, which would tend to increase any existing tendency to allergic reactions [8,47,48].

In many regions, air quality is also reported. A government-backed program, AIRNow, is available online to monitor the air quality in various areas around the United States [49]. This information can be used to determine when indoor activities should be encouraged. Local air quality monitoring services may also be available.

Tobacco Smoke

One of the worst irritants in indoor air, and perhaps the most obvious, is tobacco smoke. Cigarette, cigar, or pipe smoke can trigger asthma attacks in the short term and generally worsen asthma symptoms in the long term. Passive, or second-hand, smoking may also adversely affect the immune system. Smoking should not be permitted around a patient with asthma or in rooms an individual with asthma uses. Patients who smoke should be advised to stop smoking. Patients should also be advised of the many techniques available to assist in smoking cessation, including the various nicotine replacement agents [8,47,48].

Smoking during pregnancy significantly increases the risk of the infant developing allergies and asthma. In addition, research also reveals that, for those who had asthma as children for whom symptoms have resolved, cigarette smoking greatly increases the chance of the asthma returning. Generally, pediatric patients with asthma who have one or more parents who smoke indoors tend to have more severe and frequent asthma symptoms. It has been found that teenagers can be just as affected by passive smoking as young children [8,50]. Smoking has many distressing effects on patient health, and smoking cessation should be integrated into all care plans and general assessments.

Gases, Chemicals, and Foreign Contacts

In addition to tobacco smoke, other air pollutants can irritate the lungs of patients with asthma. Such pollutants can worsen existing allergic symptoms and may promote development of allergies in pediatric patients. Common household soaps, detergents, and cleaners may be very irritating for a patient with asthma; contact with strong odors and sprays should be reduced. The use of natural cleaning products can be helpful; however, even the safest products and thorough cleaning may still leave an environment with airborne pollutants. Other chemical contaminants may affect the immune system directly, which would tend to increase any existing tendency to allergic reactions [8,47,48].

Nitrogen Oxide

Traffic pollution, most often characterized by the presence of nitrogen oxide, has long been considered a trigger or cause of asthma symptoms; yet, some research reveals the link between traffic pollution and asthma to be, for the most part, tenuous. However, there have been several studies confirming the negative impact of exposure to freeway traffic on lung development in children and on respiratory infections, allergy, and asthma [8,47,48]. The exact mechanism responsible for this association is still being investigated.

Cooking with a gas stove generates a significant amount of nitrogen dioxide, the same pollutants emitted from motor-vehicle traffic. But, peak levels of nitrogen dioxide in kitchens with gas stoves are often ten times the average level on city streets, frequently exceeding standards for outdoor air set by the WHO. Other sources of nitrogen dioxide include cigarettes, gas fireplaces, and kerosene heaters. If a patient has a nitrogen oxide sensitivity, he or she should be encouraged to use electric stoves and heaters as often as possible and to always use a ventilation fan or open windows when cooking with a natural gas appliance [8,47,48].

Formaldehyde

Patients with asthma seem to have more frequent symptoms if exposed to high formaldehyde levels. Formaldehyde is common in both gas and liquid forms; the vapors expelled by the compound may irritate the lining of the eyes, nose, and lungs when inhaled. A formaldehyde solution is often used as a preservative in laundry detergents, air fresheners, shampoos, dish soaps, medications, cosmetics, cigarettes, and some processed foods. Additionally, it may be found in manufacturing plastics, wrinkle-free clothes, and some building materials, such as particle board, plywood, pressed board fiberboard, carpet backing, glues, and foam insulation. The frequent use of formaldehyde in the production of so many different items makes it a very commonly encountered irritant. Materials that produce formaldehyde should be eliminated from the environment of patients with asthma as much as possible. If a manufactured product contains formaldehyde, it should be noted that the emissions generally decrease as the item ages. Formaldehyde is also created by the combustion of wood and natural gas. Flues for wood burning fireplaces and stoves must be clear; if smoke can be smelled, there is formaldehyde present in the air. When a natural gas appliance is used, adequate ventilation, preferably with a powered vent, is necessary [8,48,51].

Aerosol and Scented Sprays

Cleaning products, furniture polish, and even deodorant were never intended to enter the nasal airways, but substances sprayed from aerosols do just that and can trigger asthma attacks. Patients with asthma should be advised to avoid the use of aerosols as much as possible. Additionally, air fresheners and perfumes with strong odors can trigger asthma attacks in sensitive individuals. Avoidance of strong fragrances may help alleviate symptoms [8,47].

Sulfur Dioxide

The FDA estimates that 1 out of every 100 people is sulfite-sensitive and that 5% of those who have asthma are at risk of experiencing an adverse reaction to the substance. Patients with asthma should be aware of instructions and ingredients listed on all usable or edible products. It is important not only to be knowledgeable as to what is in the product but also as to what gases may be given off when used. One such example is sulfur and sulfur dioxide gas. "Sulfuric," "sulfate," or "sulfite" in a list of ingredients should serve as a warning for a patient with asthma; the product may give off sulfur dioxide gas [8,52].

In 1986, the federal government established guidelines for sulfites, and a partial ban on sulfites was enacted for restaurant and market fresh salad bars. Regulations also require labels to indicate if sulfites have been added to prepared products. Many medications and processed foods, including some wines, juices, and shellfish, contain sulfites. Due to the fact that inhaled asthma medications may include sulfur-based preservatives, care should be taken when prescribing or administering medications to patients with sulfite sensitivity [8,9,52].

Chlorine

For a patient with asthma, bleach and other chlorine-based cleaning products, such as toilet cleaner and scouring powder, should be used sparingly and with plenty of ventilation. These products release chlorine gas, which, in large amounts, can irritate air passages. Bleach and toilet cleaner should not be mixed with any other products, as chemical reactions may exacerbate the amount of chlorine gas expelled. Patients should be instructed to be careful when using any manufactured good containing hypochlorite, chloramines, ammonia, acids, morpholine, or chemicals used for swimming pool water, as all of these agents have the ability to trigger asthma attacks [8,47,48].

Paint

The possible harmful effects of paint for people with asthma are mainly due to the presence of solvents; these solvents can act as irritants to nasal air passages. Areas where paint is being used should be well ventilated. Solvent-free, odorless paints are also available and may be useful for patients who are unable to avoid paint fumes as part of their occupation or daily lives [8,47,48].

Isocyanate

One of the most powerful asthmagens is isocyanate. "Instant foam" kits sold for do-it-yourself insulation can provoke asthma in those who were previously not asthmatic. This is due to two different substances that are mixed to create the polyurethane foam, one of which is unreacted isocyanate. The combination of these substances results in the release of isocyanate at potentially harmful levels[ [8,48]. The most common incidences of isocyanate asthma occur in patients who have high exposures in their occupation. The National Institute for Occupational Safety and Health has published an alert regarding the risks to U.S. workers exposed to diisocyanate [54]. Although IgE antibodies against isocyanate may be detected by a RAST, this test is positive in only a minority of cases of isocyanate asthma.

Occupational Asthmagens

Any job may present a worker with some environmental hazards. For a patient with asthma, this risk is heightened as a result of the many harmful agents that may be released into the environment and inhaled into the lungs. Some of the most potent irritants are hard metal dusts, such as silica, asbestos, and talc, used in mining and refineries. Fumes from fluorocarbon propellants and oxide of such metals as copper, zinc, manganese, and iron are also on a long list of agents that provoke lung diseases and disorders, including asthma. Other work-related agents that can cause asthma include animal proteins, enzymes, wheat flour, and certain reactive chemicals [8,55].

Since the healthcare industry has required personnel to wear protective gloves, more healthcare professionals have discovered that latex allergies trigger airway sensitivity. Healthcare providers who have known sensitivities should also be aware of contact with irritants such as disinfectants, formaldehyde, sulfathiazole, chloramine, and psyllium [8,55].

Office workers in insulated office buildings with central air conditioning systems may never find the source of their symptoms; fewer than 40% of those who feel sick on the job ever discover exactly which pollutant to avoid. Common office triggers include paper dust, perfumes or colognes, industrial cleaners, and mold. Additional and ongoing research continues to provide information about irritants and occupational asthma [8,55].

Viruses

Many consider upper respiratory tract infection or rhinoviruses to be the most important (and for many patients, the most significant) asthma trigger other than allergy. Viral infections such as these, also referred to as "the common cold," are known to cause complications for many (30% to 40%) patients with asthma. For those without asthma, these infections are usually single nuisances characterized by spontaneously resolving symptoms typically lasting about 7 to 10 days. Symptoms include nasal congestion and drip, postnasal drainage, sore throat, edematous glands, and at times, fatigue. In some instances, the lower respiratory tract may also be involved, and individuals without asthma can develop bronchitis with cough; these symptoms can be confused with allergic reactions in atopic patients. There are more than 200 viruses capable of causing what is generally recognized as a cold. It may be worth noting that colds, especially versions produced by RSV, are often the event that precipitates the onset of asthma in children and adults. In fact, these infections not only often precipitate acute events, but they seem to alter the immune system response to initiate the development of allergy or asthma [8,47,56].

Asthma episodes that are the result of viruses may be severe and sudden in onset; lower respiratory tract symptoms of coughing, wheezing, and shortness of breath can occur within 24 hours after the onset of upper respiratory tract viral symptoms, such as nasal congestion. Occasionally, wheezing may occur without any premonitory upper respiratory tract warning, so the patient with asthma should be alert to the earliest onset of chest symptoms as well as the premonitory upper respiratory tract symptoms that usually precede them. It is known that early treatment, especially with oral corticosteroids, may prevent the often serious asthmatic consequences of a viral infection. It is imperative, therefore, that patients are able to recognize early warning signals. Vaccination for typical respiratory viruses, such as influenza, measles, varicella (chicken pox), and pertussis, should be considered as a preventive measure, especially in children. The CDC Advisory Committee on Immunization Practices and GINA recommend that people with asthma receive either the Moderna or Pfizer-BioNTech COVID-19 vaccine series [8,57].

Weather

Some patients with asthma will indicate that they are able to predict weather because they notice their symptoms worsen or disappear with fluctuating barometric pressures and sudden, extreme temperature shifts. Symptoms such as chest tightening and excess mucus production may warn of high humidity, thunderstorms, snowstorms, or freezing temperatures [8,47,48].

Cold air, which usually does not limit airflow with other lung diseases, is a major trigger for many individuals with asthma. Bronchial muscles constrict in cool, dry air, and muscles may not relax until temperatures rise. Even ingesting cold foods or drinks can cause muscle constriction. Exercise during cold weather increases the risk of bronchial constriction by forcing inhalation of cold air [8,47,48].

Diet

An anti-asthma diet is generally neither an avoidance diet nor a diagnostic diet, but rather a health-promoting diet, designed to protect against asthma and asthma symptoms. However, if specific food allergies or triggers are identified, they should be avoided as much as possible. Patients with asthma with food sensitivities and/or those who care for them should be made aware of potentially allergenic-specific food ingredients (Appendix).

Because overweight and obesity have been linked to an increased risk for asthma, some patients may benefit from weight loss and limiting their calorie intake to lose weight. Dieting patients with asthma should be taught that some packaged goods, including some recommended by several diet plans, contain sugar substitutes, food coloring, and preservatives, all of which have been associated with exacerbation of asthma symptoms in sensitive individuals [8,19,47].

Before any dietary treatment, investigation, or recommendation is initiated, a physician or healthcare provider should be aware of assessed risks; referral to a dietician or nutritionist may also be necessary.

Physiologic Triggers

Hormone Changes

The relationship between hormonal changes and asthma is unclear. However, there are types of asthma that are triggered by changes in hormone levels. The number of girls who develop asthma at puberty, when large amounts of estrogen are produced, is growing. A higher incidence of asthma among women, as compared to men, continues through reproductive years [8,18].

Many women have reported that their asthma worsens when they menstruate. Indeed, research suggests that the decreased levels of progesterone and estrogen during menstruation alter the body's water and salt balance and may negatively affect bronchial muscles and smooth muscles. A few studies concur that premenstrual hormone changes stimulate airway constriction [8,47,18].

Contraceptive pills and hormone replacement therapy (HRT) during menopause are being studied as possible asthma stimulants. A Harvard research team surveyed 23,035 women in the Nurses' Health Study and revealed that asthma was twice as prevalent among women who took hormones for 10 years or more, during and after menopause, compared to those women who did not take HRT [58]. However, more research is necessary to discover how and when hormonal changes during the menstrual cycle or menopause affect lungs and asthma symptoms.

Stress

There was once a theory that asthma was the body's way of communicating emotions. The current understanding of asthma is that emotions and mental disorders do not cause asthma in otherwise healthy patients. However, there is evidence that strong emotions may arouse symptoms in individuals with asthma; extreme bouts of laughter or fear can cause bronchial lumens to narrow abruptly. Also, any activity that stresses the respiratory system, including crying or shouting, can stimulate nerves to constrict bronchial lumens. If asthma seems worse during particularly stressful times, specific activities and medications may be used to reduce asthma symptoms [8,9,47]. Referral to a counselor, psychologist, or support group may be helpful for patients whose stress is prompting asthma symptoms.

Exercise

Exercise is a proven asthmagen in some individuals. Exercise-induced asthma (EIA) refers to airway changes following activity, which distinguish it from chronic asthma. In patients with chronic asthma, symptoms surface any time, in response to one or more triggers. With EIA, the trigger is more obvious, as symptoms appear when the patient is engaged in exercise and can persist for several hours after activity ends. It is estimated that between 80% and 90% of patients with chronic asthma experience symptoms from exercise at some time [8,9,59].

It is very important to realize that any burst of exercise or sustained exercise can trigger asthma flare-ups; reactions can be immediate or delayed, in some cases occurring several hours later. The exact cause of EIA is unknown. One theory focuses on the loss of warmth and moisture from the airways during exercise. After the activity concludes, patients with asthma warm their airways four times faster than those without asthma; some researchers believe that this warming is a sign of edematous airways. Exercise-related airflow problems result in coughing, wheezing, and shortness of breath. The earliest symptoms, such as wheezing, may not be apparent at first because exercise stimulates the increased production of epinephrine, which can mask the symptoms associated with the onset of an attack. Patients with EIA usually begin to have difficulties about 10 minutes into strenuous activity or within 5 to 20 minutes of ending the activity [8,9,59].

Another theory suggests that the major cause of EIA is hyperventilation. In fact, the bronchial constriction that occurs during exercise in those with EIA may also be induced by hyperventilation, even in the absence of vigorous physical activity [59].

Some exercises are more likely than others to cause asthma. Team sports that require short bursts of energy (e.g., baseball, football) are less likely to cause symptoms than sports such as soccer or long-distance running that require ongoing activity. Cold weather activities (e.g., cross-country skiing, ice hockey) also tend to make symptoms worse. Swimmers are exposed to warm, moist air, which does not tend to trigger asthma symptoms. Walking, leisure biking, and hiking also are good activities for individuals with EIA [8,9,59].

Generally, patients with EIA would be categorized as having mild intermittent asthma and their treatment plans would reflect this categorization. Practitioners should discourage any patients known to experience EIA from engaging in high-risk activities without access to fast-acting medications. This is not to say patients with asthma should not be active. On the contrary, the majority of individuals with asthma benefit greatly from daily exercise, as better physical conditioning generally results in decreased asthma symptoms. The trick is to map out a routine and group of exercises that work best for the patient.

Medications

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

It is important to realize, as mentioned before, that at least some patients with asthma are particularly sensitive to NSAIDs, which are used to treat pain and inflammation. Several of these medications, such as aspirin, naproxen, ibuprofen, and ketoprofen, are available over the counter. NSAIDs available by prescription only include [35,60]:

- Diclofenac sodium

- Indomethacin

- Meclofenamate

- Naproxen

- Piroxicam

- Sulindac

- Tolmetin

Known NSAID sensitivity should be noted in a patient's record, as prescribing any of these medications may be extremely hazardous. Other medications, such as paracetamol, may be prescribed instead.

Beta Blockers

The beta-adrenergic system includes the neurologic system, which relaxes the smooth muscle of the bronchial tree and stimulates the heart. Blockage of this system can calm the heart but may also constrict the muscles of the bronchi. This bronchoconstrictive tendency can occur in an exaggerated form in patients with asthma. Beta blockers are used in treating a number of conditions, including hypertension, cardiac arrhythmias, glaucoma (as ophthalmic drops), and migraines. Medications within this category include propranolol, labetalol, atenolol, and timolol [35,60].

Patients with asthma should be educated regarding the risks of beta blockers and instructed on the appropriate steps to take if they begin to experience asthma symptoms after taking these agents.

Common Household Triggers

Pets

The number of household pets is on the rise; surveys indicate that there are 62 million dog-owning households in the United States and 37 million cat-owning households [61]. These domestic animals, as well as mice, guinea pigs, and even horses and sheep, give off saliva, fur, and dander as they live their normal lives—rubbing against or licking their owners or other individuals. Exposure to any of these elements may trigger asthma symptoms in sensitive individuals.

Certain breeds of dogs and most cats shed clumps of fur throughout the year; saliva holds and spreads dander and fur throughout a house. Further, animals that explore outdoors bring pollen and mold spores indoors on their fur, another potential problem for those with asthma[8,47].

For very sensitive patients, even the slightest exposure to dander can result in airway constriction. The situation can become dangerous for a child with allergies who keeps rodents in a bedroom or sleeps with a dog or cat. In fact, those with asthma may react whether or not the animal is in the room because dander and/or other allergens may remain in the air for long periods of time [8,47].

Cat dander is one of the smallest allergens; most of the particles are less than 2.5 microns and the smallest may be only 0.5 micron. A sensitive individual would require a very good dust mask or high efficiency particulate air (HEPA) filter to eliminate these particles in a contaminated indoor area. It should be noted that, in many cases, dander can linger in house dust for approximately six months after a pet has been removed from the environment [8,47,48]].

Other, less common pets may produce allergens through shedding of fur or dander. For example, horses are known to produce very powerful allergens. In the case of small mammals, such as mice or guinea pigs, urine is usually the main cause of allergic and asthmatic reactions. Proteins in the urine become airborne and are carried throughout the environment. Allergic reactions to reptiles and amphibians are extremely rare; however, cases of reactions have been documented [62]. With pet insects and snakes, lizards, and other reptiles, the allergens are found in tiny skin particles that float in the air. In addition, live grasshoppers and other insects used to feed reptiles may cause allergic reactions. Because reptiles and amphibians are known to carry Salmonella, which can cause life-threatening infection in young children, the CDC recommends against keeping them in homes with children younger than 5 years of age [8,47,48].

Dust Mites, Cockroaches, and Rodents

Allergy research reveals that dust mites play an important role in the development of asthma symptoms. The dust mite allergen provokes immune cells, and after an allergy to dust mites has developed, other allergies become more likely.

It should also be noted that researchers have demonstrated that 18% of children in urban areas in the United States have an allergic reaction to mice, and this can surely contribute to asthma. Cockroaches are another significant cause of asthma symptoms in urban environments. Meticulous cleaning to combat cockroach allergen is advisable, as even slightly reducing exposure can be of great benefit to individuals with asthma. One study of children with asthma who were allergic to cockroaches concluded that the levels of the allergen in the homes were directly related to the severity of the asthma symptoms; children exposed to the highest levels of cockroach allergen were more likely to be hospitalized for asthma, miss more school due to asthma, and have sleepless, wheezy nights [8,47,63].

As noted, the NAEPP updated guidelines include recommendations for the assessment of environmental factors during any stage of asthma management, to provide applicable patient education and manage comorbidities. For example, [9,10]:

- In individuals with sensitization (or symptoms) related to exposure to pests: Conditionally recommend integrated pest management as a single or multicomponent allergen-specific mitigation intervention

- In individuals with sensitization (or symptoms) related to exposure to identified indoor allergens: Conditionally recommend a multi-component allergen-specific mitigation strategy

- In individuals with sensitization (or symptoms) related to exposure to dust mites: Conditionally recommend impermeable pillow/mattress covers only as part of a multicomponent allergen-specific mitigation intervention, but not as a single component intervention

Mold

Except in very dry climates, mold spores are the predominant particulate in the air. In the United Kingdom, a relatively damp country where molds flourish, the record count is more than 160,000 spores/m3, compared to a record pollen count of only 2,800 grains/m3. The size of most mold spores is between 2 and 10 microns, but a few species have spores that are smaller than 2 microns[8,47,64].

Molds and fungi reproduce through the release of spores. Often, healthcare providers will refer to mold allergies singularly, because molds are the most common offenders, but layer fungi, including mushrooms and toadstools, also produce allergenic spores. There are different species of mold in different environments, and these species can grow in a very wide range of situations, including indoors. A sensitive individual may have cross-reactions between some molds, meaning that a sensitive individual will react to a variety of mold species [8,47,64].

One mold allergy in particular has a risk of severe reaction. During the spore-producing season, healthcare professionals should consider increasing the dose of preventive inhaler medications for individuals with asthma who also have allergy to the mold Alternaria. Research shows that severe, near-fatal asthma attacks often occur during the Alternaria spore season among those allergic to this mold. These individuals may also be referred to a local pollen/spore monitoring service. Alternaria spore release usually occurs in the summer or fall, although timing varies from one part of the world to another. Alternaria may colonize outdoors, in soil, seeds, or plants, or indoors, in window frames, carpets, or textiles [8,47,64].

Mold-sensitive individuals with asthma should be advised to avoid the following places as much as possible; if avoidance is not possible, the use of HEPA facemasks is recommended when patients are in these environments [8,47,64]:

- Fields of cereal crops in late summer, due to molds that may be present on the leaves. Symptoms are most exacerbated at harvest time, when the harvesting process results in the dispersal of spores.

- Forests and old orchards

- Gardens with compost piles or piles of dead leaves

- Greenhouses

- Springs, waterfalls, or any damp, shady places

Healthcare professionals should note that mold-sensitive individuals, just as those with pollen allergy or sensitivity, often experience more frequent or intense asthma symptoms during certain times of the year. Increased symptoms during late summer and autumn, when molds flourish outdoors, or following the first frost, which prompts spore release by fungi living in the soil, may indicate a mold allergy. Patients with asthma should be advised to avoid disturbing compost piles, damp straw or hay, piles of grass clippings, or heaps of fallen leaves, all of which are likely to be full of molds. These same patients should not collect fallen leaves or fruit, remove dead leaves or flowers from plants, or water gardens because mold spores are released when water hits dry soil [8,47,64].

Indoor molds and the indoor conditions that promote mold growth can be difficult to endure for mold-sensitive patients. Sensitive patients should be advised to avoid the following places, wear a mask while in these areas, or correct the problem areas at their source [8,47,64]:

- Buildings that are damp or display mold infestation

- Houses with central evaporative cooling systems (i.e., "swamp coolers")

- Buildings built in damp environments, near lakes, rivers, or the ocean

- Rooms with humidifiers

- Bathrooms and shower rooms, unless the rooms are well ventilated

- Buildings with dry rot, although not all mold-sensitive individuals react to the spores of these timber-rotting fungi

- Buildings where central heating has recently been installed

- Buildings with many indoor plants

- Cellars and basements

- Sun rooms, unless well-maintained

- Antique shops and vacation homes

- Farms or mills

- Portable school classrooms

Nocturnal Asthma

Asthma symptoms can be influenced by the time of the day. Often, asthma worsens at night, especially between 2:00 a.m. and 4:00 a.m., or in the early morning prior to or upon awakening. Many patients with asthma awaken with a choking cough, wheezing, breathlessness, or chest tightness; symptoms may last a short period or may persist for minutes or hours. For patients with persistent nocturnal asthma, symptoms disrupt sleep and may affect ability to function normally during waking hours. Nocturnal asthma not only leads to sleep loss but also usually indicates uncontrolled asthma [8,13,65]. There are many possible causes of nocturnal asthma.

In sensitive individuals, increased amounts of dust mites and other allergens, such as fungal spores, embedded in bedding may trigger allergic asthma. This would, of course, only affect those patients with specific sensitivities. Levels of the hormones epinephrine and cortisol, which play an important role in keeping bronchial airways open, reach their lowest point between midnight and 6:00 a.m. Additionally, histamine levels, which may worsen asthma symptoms, peak at night. Reduced adrenal gland function at night may also be responsible for the decreased amounts of epinephrine and corticosteroids in the blood [8,13,65].

The cold night air may lower bronchial airway temperatures, inducing lumen constriction and triggering asthma symptoms. Furthermore, about half of individuals with asthma notice that their symptoms intensify 4 to 12 hours after the first reaction, suggesting that a nocturnal attack may result from a trigger encountered earlier in the day. Lastly, a reclining sleep position may increase the likelihood of gastric reflux symptoms, which may exacerbate or mimic an asthma episode [8,13,65].

12. CONCLUSION

Asthma is one of the most common respiratory conditions affecting children, adolescents, and adults, and the number of individuals affected continues to grow each year. Diagnosis may be complex, especially in certain populations, but it is a vital key to providing the effective treatment and management of the disorder. Affected individuals' signs and symptoms vary in severity, and treatment plans should be determined accordingly. Healthcare professionals should keep current with the latest treatments and medications as well as the latest studies and theories for asthma treatment and exacerbation prevention in order to provide the best patient-centered care.

13. RESOURCES

AIRNow

https://airnow.gov

American Lung Association

https://www.lung.org

Asthma and Allergy Foundation of America

https://www.aafa.org

Centers for Disease Control and Prevention

https://www.cdc.gov/asthma

National Heart Lung and Blood Institute

Asthma Action Plan Template

https://www.nhlbi.nih.gov/resources/asthma-action-plan-2020

National Institute of Allergy and Infectious Diseases

https://www.niaid.nih.gov/diseases-conditions/asthma

14. APPENDIX

COMMON FOOD SENSITIVITIES FOR PATIENTS WITH ALLERGY AND/OR ASTHMA

The following items could, even unexpectedly, contain problem food ingredients for individuals with food-allergies. Though it is not an exhaustive list, the most commonly encountered sensitivities are addressed [8,9].

- Corn: May appear in an ingredient list as cornmeal, cornstarch, dextrose, or polenta

- Eggs: Known to cause anaphylactic shock in sensitive patients

- Fish and shellfish: Fish meal is used in some Asian sauces and other foods as a usual flavoring or condiment

- Milk: Also appears as casein, caseinate, lactalbumin, and whey

- Tree nuts: Be very cautious about nut oils. Also, almond essence may be produced chemically, in which case it is safe, but it may also be manufactured from true almonds. It may also be listed as frangipane, marzipan, or praline.

- Peanuts: Are highly allergenic and may have cross-reaction with soy and/or lupin (a novel food ingredient), but reactions with other legumes are rare. Cross-reactions with tree nuts are quite common. If a patient is highly allergic to peanuts or any nuts, they should be instructed to carefully read labels on all prepared foods and on sweets, including jelly beans, ice cream, and milkshakes. Also, caregivers should be advised to be wary of homemade playdough and some animal foods, such as mixes for birds or gerbils or the pellets used at petting farms, if a child reacts to skin-contact with peanuts.

- Sesame: May also appear as furikake, gomashio, halva, hummus or houmus, or tahini

- Soy: Is present in such foods as miso, soy protein, soy protein isolate, soy sauce, textured vegetable protein, tofu, and vegetable protein

- Wheat: Often listed as bran, flour, graham flour, hard flour, strong flour, or whole-wheat flour. There are non-wheat brans and flours, but the word "bran" or "flour" without any qualification usually means wheat.

- Yeast: Leavening for many products

- Latex: Certain individuals with latex allergy may react to very small traces of it in food, particularly packaged food or restaurant food that has been prepared by workers wearing latex gloves. There are also reports of certain individuals with latex allergy reacting, usually very mildly, to cold-seal adhesives in food wrappers, such as those used for ice cream. The reaction only occurs if the wrapper actually touches the lips or mouth.

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94280 • Pharmacologic and Medical Advances in Obesity Management

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2023 NetCE, All rights reserved.

Obesity is a chronic, progressive, relapsing, multifactorial disease resulting in metabolic and biomechanical morbidities and premature mortality, and its prevalence has risen to unacceptable levels in the United States and worldwide. Healthy diet, exercise, and behavioral interventions are crucial components of management but are largely unsuccessful in achieving and maintaining weight reduction sufficient to reduce morbidities and prevent premature mortality because the chronic neuroendocrine disease of obesity remains unaddressed. Despite recognition that long-term antiobesity medications and potentially bariatric procedures are required to mitigate the effects of obesity, knowledge gaps, misperceptions, and bias are highly prevalent. Recently approved and emerging antiobesity medications are revolutionizing obesity treatment by achieving long-term weight loss previously unattainable without surgical intervention. Reversing the low utilization of medication and surgical treatment begins with ending the stigmatization of patients with obesity.

Table of Contents

94280 • Pharmacologic and Medical Advances in Obesity Management

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. DEFINITIONS OF OBESITY

CLINICAL ASSESSMENT

3. EPIDEMIOLOGY

POPULATION PREVALENCE

INCIDENCE

PERSONAL AND SOCIETAL BURDEN OF OBESITY

MORTALITY

4. ETIOLOGY OF THE OBESITY EPIDEMIC

DIET, PHYSICAL ACTIVITY, AND BMI

ENERGY EXPENDITURE RESEARCH

OTHER POTENTIAL ETIOLOGICAL FACTORS

SUMMARY

5. THE REGULATION OF BODY WEIGHT

ENERGY BALANCE

DEFENSE OF BODY WEIGHT

6. OVERVIEW OF CLINICAL MANAGEMENT

THE FOUR PILLARS OF OBESITY MANAGEMENT

OBESOGENIC MEDICATIONS

PRIORITIZATION FOR PATIENTS WITH OBESITY AND CARDIOMETABOLIC DISEASE

TREATING TO TARGET WITH ANTIOBESITY MEDICATIONS

7. ANTIOBESITY MEDICATIONS

INDICATIONS FOR USE

FDA-APPROVED AGENTS

INVESTIGATIONAL ANTIOBESITY MEDICATIONS IN CLINICAL TRIALS

CLINICAL USE OF ANTIOBESITY MEDICATIONS

8. BARIATRIC SURGICAL PROCEDURES AND DEVICES

TERMINOLOGY

PROPOSED MECHANISMS

INDICATIONS FOR BARIATRIC SURGERY

PRE- AND POSTPROCEDURE RECOMMENDATIONS

SURGICAL APPROACHES

ENDOSCOPIC BARIATRIC TECHNIQUES

OTHER OPTIONS

IMPACT ON OBESITY-RELATED CARDIOMETABOLIC ENDPOINTS

POSTBARIATRIC INTERVENTIONS

9. CONCLUSION

10. APPENDIX: PHYSIOLOGY AND PATHOPHYSIOLOGY

NEUROHORMONAL REGULATION OF ENERGY BALANCE AND BODY WEIGHT

PATHOPHYSIOLOGY

Works Cited

Evidence-Based Practice Recommendations Citations

94280 • Pharmacologic and Medical Advances in Obesity Management

Education Category. Infection Control / Internal Medicine

Release Date. 12/01/2023

Expiration Date. 11/30/2026

Course Overview

Obesity is a chronic, progressive, relapsing, multifactorial disease resulting in metabolic and biomechanical morbidities and premature mortality, and its prevalence has risen to unacceptable levels in the United States and worldwide. Healthy diet, exercise, and behavioral interventions are crucial components of management but are largely unsuccessful in achieving and maintaining weight reduction sufficient to reduce morbidities and prevent premature mortality because the chronic neuroendocrine disease of obesity remains unaddressed. Despite recognition that long-term antiobesity medications and potentially bariatric procedures are required to mitigate the effects of obesity, knowledge gaps, misperceptions, and bias are highly prevalent. Recently approved and emerging antiobesity medications are revolutionizing obesity treatment by achieving long-term weight loss previously unattainable without surgical intervention. Reversing the low utilization of medication and surgical treatment begins with ending the stigmatization of patients with obesity.

Audience

This course is designed for all physicians, nurses, and allied professionals involved in the care of patients who are overweight or obese.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 15 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 15 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 15 ANCC contact hour(s). NetCE designates this continuing education activity for 12 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 12 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 18 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 15 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 15 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 15 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1.5 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to ensure that providers have current and accurate knowledge regarding the available pharmacologic and surgical options to improve outcomes among their patients, with the ultimate goal of improving patient care and outcomes.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define obesity and related conditions.

2. Outline approaches to the clinical assessment of patients who are overweight or obese.

3. Review the epidemiology of obesity, including the evolving obesity epidemic.

4. Compare and contrast available energy expenditure research.

5. Describe the role of diet, physical activity, and body mass index (BMI) on the etiology of obesity.

6. Identify other etiologic factors contributing to the obesity epidemic.

7. Evaluate current knowledge of energy balance and defense of body weight in the regulation of body weight.

8. Define the four pillars of obesity management.

9. Analyze pharmacotherapeutic options for monogenic obesity syndromes.

10. Compare available pharmacotherapy for short- and long-term management of obesity.

11. Identify investigational antiobesity medications in development.

12. Review prescribing tips to improve the clinical use of antiobesity medications.

13. Outline available metabolic and bariatric surgical interventions, including indications, contraindications, and efficacy.

14. Discuss the role of endoscopic bariatric therapies in the management of obesity.

15. Describe the physiology and pathophysiology underlying obesity and driving advances in the management of obesity.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

During 2017–2018 in the United States, 42.4% of adults were obese and 9.2% were severely obese [1]. By 2030, the expected prevalence will increase for both obesity (49%) and severe obesity (24%) [2].

Obesity is a chronic, progressive, relapsing, multifactorial disease involving far more than excessive fat. Obesity leads to biomechanical complications such as obstructive sleep apnea and osteoarthritis. The pathogenic adipose tissue promotes insulin resistance, metabolic syndrome, hypertension, dyslipidemia, and type 2 diabetes, progressing to cardiometabolic endpoints of nonalcoholic steatohepatitis (NASH), cardiovascular disease, and premature mortality [3].

Weight loss maintained long-term dose dependently reduces the cardiometabolic morbidity—the more weight lost, the better the outcome. This may require 16% to 20% to reduce endpoint risks, which is seldom possible with standard lifestyle intervention [4,5,6].

Patients may lose 5% to 10% of initial weight over 16 to 26 weeks with caloric restriction and increased physical activity, but maintaining the lost weight is very difficult because complex biological mechanisms defend the established body-fat mass [7,8,9]. Weight loss triggers biological pressures to regain weight through increased hunger, enhanced neural responses to food cues, heightened drive to consume energy-dense foods, and reduced metabolic rate [10,11,12]. Healthy diet, exercise, and behavioral interventions are crucial components of management, but seldom achieve and maintain weight loss sufficient to reduce cardiometabolic morbidities [13,14].

However, more recent and investigational antiobesity medications show average long-term weight loss previously unattainable by nonsurgical treatment, including semaglutide (15%), combination cagrilintide/semaglutide (CagriSema) (17%), tirzepatide (21%), and retatrutide (24%) [3]. Bariatric surgery can result in dramatic weight loss (≥30%) and remission of type 2 diabetes persisting years if not decades. Minimally invasive procedures show promising results while reducing the risks of surgery. A newer treat-to-target approach with antiobesity medications uses percent weight loss as a biomarker for individualized weight reduction necessary to improve clinical outcomes [3]. Obesity requires the treatment intensity and chronicity of other complex, chronic metabolic diseases, which may involve both bariatric surgery and multi-year antiobesity medications [15].

The widely accepted causes of the obesity epidemic, increasingly sedentary lifestyles and reduced physical activity with increased fatty food intake, are largely unsupported [16,17]. Similarly, the notion of obesity as a consequence of unhealthy personal choices reversible through diet and exercise, and other erroneous beliefs, are widely held by healthcare professionals [18].

Knowledge gaps, misperceptions and bias are highly prevalent; foremost is the failure to recognize and treat obesity as a disease [19,20]. Among patients eligible for antiobesity pharmacotherapy and bariatric surgery, only 2% and 1%, respectively, receive the respective treatment [15,20].

The prevalence of obesity continues increasing, but obesity medicine is in its infancy, and formal education and training in obesity care is absent from most medical curricula. Primary care practitioners are among the only providers numerous enough to address the number of patients affected. The lack of any significant education in obesity biology, prevention, or treatment in most medical/nursing schools and postgraduate training programs makes the need for continuing education that much more critical [21].

2. DEFINITIONS OF OBESITY

The World Health Organization (WHO) codified the body mass index (BMI) as a screening index for obesity in 1995. Using weight in kilograms (kg) and height in meters (m), BMI is calculated by dividing weight (kg) by height squared (m^2), or kg/m^2 [22].

In adults, population-based actuarial studies placed the upper limit of normal BMI at 25.0, defined obesity as BMI >30.0, and designated a BMI between these values as overweight. BMI categories were created, in part, to emphasize the increased mortality risk associated with a BMI both below and above the normal range (18.5–24.9). The WHO further categorized obesity severity as Class I, II, and III ( Table 1 ) [7,23]. Pediatric overweight, obesity, and severe obesity are defined by sex-specific BMI for age using the Centers for Disease Control and Prevention (CDC) growth charts [24].

Table 1: BMI DEFINITIONS OF WEIGHT

Weight Category

BMI Definition (kg/m^2)

Adult

Adult, East Asian

Pediatrica

Underweight

<18.5

<18.5

<5th percentile

Normal

18.5–24.9

18.5–22.9

5th–85th percentile

Overweight

25–29.9

23–24.9

≥85th percentile

Class I obesity

30–34.9

25–29.9

Obesity: ≥95th percentile

Class II obesity

35–39.9

30–34.9

Class III obesity (severe obesity)

≥40

≥35

Severe obesity: ≥120% of the 95th percentile

aBased on sex-specific BMI for age

Source: [22,25,26]

Subsequent studies in Korea and Japan found higher obesity-related morbidity and mortality at BMI levels below the WHO cutoff; thus, these national guidelines defined BMI ≥23 as overweight and ≥25 as obese [22]. In addition to these specific modifications to BMI, race and cultural issues related to obesity, eating, and physical activity should be considered.

In some cases, waist circumference is more accurate in clinical diagnosis, e.g., abdominal obesity. Abdominal or central obesity is defined as waist circumference ≥102 cm (40 in) in men and ≥88 cm (35 in) in women; and among East Asians, ≥90 cm in men and ≥85 cm in women [22,31]. These are of value only for those with a BMI between 25.5 and 34.9. It is not useful to measure waist circumference in individuals with BMI >35, as such patients are already at increased risk.

The American Association of Clinical Endocrinology (AACE) designated obesity a chronic disease in 2012 [3,27]. This was based on several points, including the fact that, like other chronic diseases, obesity has a complex pathophysiology involving interactions among genes, biological factors, the environment, and behavior. It meets the three criteria that constitute a disease established by the American Medical Association (AMA) [28]:

- Outward signs or symptoms: In patients with obesity, an increase in adiposity, commonly assessed via BMI, is the primary outward sign or symptom.

- Causes morbidity or mortality: Obesity is associated with multiple complications that confer morbidity and mortality.

- Involves impaired function of ≥1 tissue. Two examples of abnormal tissue function are readily identified:

- With expansion, adipose tissue becomes inflamed and the secretion of adipocytokines is dysregulated, resulting in alterations in metabolism and vasculature and the progression of cardiometabolic disease.

- Interactions involving satiety hormones and central nervous system (CNS) feeding centers are abnormal, resulting in increased caloric intake and body mass.

The AMA formally recognized obesity as a chronic disease in 2013 and acknowledged it had become an alarming public health threat [28].

The Obesity Medicine Association (OMA) defines obesity as a chronic, progressive, relapsing, and treatable multifactorial, neurobehavioral disease in which increased body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial outcomes [29,30].

CLINICAL ASSESSMENT

In 1990, the U.S. Department of Health and Human Services' Dietary Guidelines for Americans defined overweight as a BMI of at least 27 and obesity as a BMI of at least 30. Eight years later, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) released guidelines that lowered the cutoff for overweight to a BMI of 25 but maintained the definition of obesity as a BMI of at least 30 [31]. (Note: Roughly, a BMI >25 corresponds to about 10% over one's ideal weight; a BMI >30 typically is an excess of 30 pounds for most people. These are rough estimates.) The term extreme (or morbid) obesity refers to obesity with a BMI greater than or equal to 40. These final definitions are consistent with definitions used by other national and international organizations, such as the WHO. BMI does have limitations as a measurement of overweight and obesity. Although BMI provides a more accurate measure of total body fat compared with body weight alone, it can be misinterpreted in some circumstances.

Although BMI is important, there is a growing body of evidence demonstrating the impact of central adiposity on obesity-related metabolic diseases, including diabetes [32]. A study was published that compared BMI, waist circumference, and waist-to-hip ratio in predicting the development of type 2 diabetes [33]. Researchers used information collected in the Health Professionals Follow-Up Study, a prospective cohort study of 27,270 men who were followed for 13 years. During the follow-up period, 884 men developed type 2 diabetes. Waist circumference was the best predictor. Men with waists greater than 34 inches were twice as likely to develop diabetes compared to men with smaller waist sizes (i.e., <34 inches); men with waist sizes greater than or equal to 40 inches were more than 12 times more likely to develop diabetes than men with smaller waist sizes [33]. In another study, researchers looked at waist circumference, waist-to-hip ratio, and central and subcutaneous adipose tissue measured by computed tomography (CT) as predictors of diabetes in people participating in the Diabetes Prevention Program [34]. They found that waist-to-hip ratio and waist circumference predicted diabetes; CT measurement of central adiposity also predicted diabetes but was not found to offer an important advantage over the simpler measurements. Subcutaneous adipose tissue, on the other hand, did not predict diabetes.

In 2023, the AMA adopted a policy that recognizes the issues with BMI measurement (e.g., historical harm, no consideration of gender/ethnicity) and suggests that it be used in conjunction with other valid measures of risk, including but not limited to visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic or metabolic factors [35].

The AMA policy recognizes that [35]:

- BMI is significantly correlated with the amount of fat mass in the general population but loses predictability when applied on an individual level.

- Relative body shape and composition heterogeneity across race and ethnic groups, sexes, genders, and age-span are essential to consider when applying BMI as a measure of adiposity.

- BMI should not be the sole criterion used to deny appropriate insurance reimbursement.

The AMA also modified existing policy on the clinical utility of measuring BMI, body composition, adiposity, and waist circumference to support greater emphasis on education about the risk differences within and between demographic groups.

3. EPIDEMIOLOGY

The National Health and Nutrition Examination Survey (NHANES) is considered the authoritative source for data on obesity, diet, and related health trends [16]. NHANES is a nationally representative cross-sectional study on the health and nutritional status of noninstitutionalized U.S. civilians selected through a complex, multistage probability design. Following NHANES I (1971–1975), NHANES II (1976–1980), and NHANES III (1988–1994), biennial implementation of NHANES began in 1999 [36,37,38]. The U.S. Department of Agriculture (USDA) Household Food Consumption Survey (1965) and the National Health Examination Survey (NHES; 1960–1962) preceded NHANES [36].

All NHANES are conducted in-person by trained interviewers using anthropometric measurements and 24-hour dietary recall questionnaires with standardized probe questions to facilitate memory. Past-month assessment of physical activity began with NHANES III [39]. A follow-up phone interview was added in 2003 [37].

The time point used as baseline for evaluating obesity prevalence trends can importantly impact the conclusions. Because prevalence estimates can fluctuate markedly between study waves, including data from several study waves before and after the period of interest can help determine whether prevalence changes at any given time point reflect a transient anomaly or a true trend [40].

In this section, all prevalence data from 1971 to the present was obtained from NHANES except where noted. In addition, all data pertain to the United States unless otherwise mentioned.

POPULATION PREVALENCE

Adults 20 Years of Age and Older

NHES 1960–1962 included adults 18 to 79 years of age. NHANES 1971–1974 and 1976–1980 excluded individuals age older than 74 years. Therefore,Table 2 is limited to adults 20 to 74 years of age for consistency in long-term trends. Prevalence rates are age-adjusted to the U.S. Census 2000 estimates. As the table demonstrates, the 1980s and 1990s mark the onset of the obesity epidemic.

Table 2: PREVALENCE OF OBESITY AND SEVERE OBESITY AMONG ADULTS AGED 20–74 YEARS

Year

Percent of Population Considered Obese (BMI ≥30 kg/m^2)

Percent of Population Considered Severely Obese (BMI ≥40 kg/m^2)

Total

Male

Female

Total

Male

Female

1960–1962

13.4%

10.7%

15.8%

0.9%

0.3%

1.4%

1971–1974

14.5%

12.1%

16.6%

1.3%

0.6%

2.0%

1976–1980

15.0%

12.7%

17.0%

1.4%

0.4%

2.2%

1988–1994

23.2%

20.5%

25.9%

3.0%

1.8%

4.1%

1999–2000

30.9%

27.7%

34.0%

5.0%

3.3%

6.6%

2001

31.2%

28.3%

34.1%

5.4%

3.9%

6.8%

2003

32.9%

31.7%

34.0%

5.1%

3.0%

7.3%

2005

35.1%

33.8%

36.3%

6.2%

4.3%

7.9%

2007

34.3%

32.5%

36.2%

6.0%

4.4%

7.6%

2009

36.1%

35.9%

36.1%

6.6%

4.6%

8.5%

2011

35.3%

33.9%

36.6%

6.6%

4.5%

8.6%

2013

38.2%

35.5%

41.0%

8.1%

5.7%

10.5%

2015

40.0%

38.3%

41.6%

8.0%

5.9%

10.1%

2017–2018

42.8%

43.5%

42.1%

9.6%

7.3%

12.0%

Source: [41]

Following slow increases during the 1960s and 1970s, obesity rates increased sharply through the early 2000s, modestly from 2005 to 2011, then continued climbing through 2017–2018. Male obesity surpassed female rates for the first time in 2017–2018.

Female severe obesity increased 36.4% from 1960–1962 to 1976–1980, in contrast to slowly increasing obesity and male severe obesity rates, and have exceeded male rates throughout 1960 to 2018 by a wide margin. Including ages 20 years and older lowers the 2017–2018 prevalence for obesity (42.4%) and severe obesity (9.2%), which increased approximately 39% and 96%, respectively, from 1999–2000 [1].

During 2017–2018, non-Hispanic Black Americans (49.9%) had the highest age-adjusted obesity prevalence, followed by Hispanic Americans (45.6%), non-Hispanic White Americans (41.4%), and non-Hispanic Asian Americans (16.1%), who also have lower BMI thresholds for adiposopathic (adipocyte and adipose tissue dysfunction) complications [1,29].

The association between obesity and income or educational level is complex and differs by sex and race/ethnicity. Overall, men and women with college degrees had lower obesity prevalence compared with those with less education [43].

The same obesity and education pattern occurred among non-Hispanic White, non-Hispanic Black, and Hispanic women, and non-Hispanic White men, but the differences were not all significant. Among non-Hispanic Black men, obesity prevalence increased with educational attainment. No differences in obesity prevalence by education level were noted among non-Hispanic Asian women and men or Hispanic men [43].

Among men, obesity prevalence was lower in the lowest and highest income groups compared with the middle-income group. This pattern occurred among non-Hispanic White and Hispanic men. Obesity prevalence was higher in the highest income group than in the lowest income group among non-Hispanic Black men [43].

Severe obesity patterns illustrate demographic differences, by sex (women 11.5%, men 6.9%), age (40 to 59 years 11.5%, 20 to 39 years 9.1%, and ≥60 years 5.8%), and race/ethnicity (non-Hispanic Black 13.8%, non-Hispanic White 9.3%, Hispanic 7.9%, and non-Hispanic Asian 2.0%) [1].

By 2030, it is projected that 48.9% of adults will be obese, 24.2% will have severe obesity, with severe obesity projected to become the most common BMI category among women (27.6%), non-Hispanic Black adults (31.7%), and low-income adults (31.7%) [2].

Obesity prevalence studies using higher BMI cut-offs suggest a population shift toward the upper end of the BMI distribution. For example, BMI ≥35 was greater than men than women in 1959 (1%/5%), 1988–1991 (5%/9%), and 2007–2008 (11%/19%) [40].

Defining abdominal obesity as waist circumference in men (≥102 cm) and women (≥88 cm), increasing prevalence rates were found [40]:

- Overall: 52.5% in 2006–2010, compared with 36.0% in 1986–1990

- Men: 42.0% in 2009–2010, compared with 27.5% in 1986–1990 and 29.1% in 1988–1994

- Women: 61.5% in 2009–2010, compared with 44.3% in 1986–1990 and 46.0% in 1988–1994

Military-Aged Population

Obesity and physical inactivity among the military-aged U.S. civilian population (17 to 42 years of age) are considered potential national security threats because of their impact on military recruitment. Fitness eligibility for military service is defined as BMI 19.0–27.5, and adequate physical activity as ≥300 minutes per week of moderate-intensity aerobic physical activity [44].

Among military-aged participants in the 2015–2020 NHANES, only 34.3% were BMI- and activity-eligible. The prevalence of eligible and active status was higher among men, persons who were younger and non-Hispanic White, college graduates, and those with higher family income than among their counterparts [44].

The BMI-ineligibility in this study exceeds those in previous studies. This upward trend in military ineligibility mirrors the increase in population prevalence of obesity. This study also draws attention to the military preparedness repercussions of the inequitable distribution of unhealthy weight and inadequate physical activity [44].

Pediatric Population

Although adult obesity is the focus of this course, long-term population trends in pediatric obesity (age 2 to 19 years) provide an informative companion to adult trends. InTable 3, note that pediatric obesity increased >300% from 1976–1980 to 2003, but only 11.4% from 2003 to 2017–2018. Compared with adult obesity, pediatric obesity shows a smaller relative increase over the past 20 years, and pediatric severe obesity has consistently greater prevalence in boys.

Table 3: PREVALENCE OF OBESITY AND SEVERE OBESITY AMONG THOSE 2 TO 19 YEARS OF AGE

Year

Obese

Severely Obese

Total

Boys

Girls

Total

Boys

Girls

1966–1970

4.6%a

N/A

N/A

N/A

N/A

N/A

1971–1974

5.2%

5.3%

5.1%

1.0%

1.0%

1.0%

1976–1980

5.5%

5.4%

5.6%

1.3%

1.2%

1.3%

1988–1994

10.0%

10.2%

9.8%

2.6%

2.7%

2.6%

1999–2000

13.9%

14.0%

13.8%

3.6%

3.7%

3.6%

2001

15.4%

16.4%

14.3%

5.2%

5.1%

4.2%

2003

17.1%

18.2%

16.0%

5.1%

5.4%

4.7%

2005

15.4%

15.9%

14.9%

4.7%

4.9%

4.5%

2007

16.8%

17.7%

15.9%

4.9%

5.5%

4.3%

2009

16.9%

18.6%

15.0%

5.6%

6.4%

4.7%

2011

16.9%

16.7%

17.2%

5.6%

5.7%

5.5%

2013

17.2%

17.2%

17.1%

6.0%

5.6%

6.3%

2015

18.5%

19.1%

17.8%

5.6%

6.3%

4.9%

2017–2018

19.3%

20.5%

18.0%

6.1%

6.9%

5.2%

N/A = not available.

aAges 12 to 17 years only

Source: [42]

INCIDENCE

Using the nationally representative Panel Study of Income Dynamics (PSID), the incidence of new obesity cases (i.e., the first time a person has a BMI ≥30) was examined from 2001 to 2017 among 13,888 adults ≥20 years of age [45]. Obesity incidence, stable over 2001–2005 to 2009–2013, increased 18% in 2013–2017 to 40.7 per 1,000 person-years. This means that, on average, 4% of the adult population entered obese BMI each year during 2013–2017 (Table 4). This is similar to obesity prevalence, which began rising notably after 2011 following modest increase from 2005 to 2011.

Table 4: PREVALENCE OF OBESITY AND SEVERE OBESITY AMONG THOSE 2 TO 19 YEARS OF AGE

Group

Incidence per 1,000 Person-Years

2001–2005

2005–2009

2009–2013

2013–2017

Total (2001–2017)

Overall

34.1

36.4

34.5

40.7

28.1

Female

30.9

35.6

33.7

38.1

26.5

Male

37.6

37.1

35.6

44.0

30.2

White

31.6

33.8

32.0

39.1

26.2

Black

60.3

62.0

61.4

57.9

47.9

Less than high school

44.8

55.8

46.1

50.3

39.4

High school diploma

38.1

45.1

45.8

50.1

34.5

More than high school

30.6

30.9

28.7

36.8

24.7

Source: [45]

During 2001–2017, Black individuals had higher obesity incidence than White individuals, which was particularly high in Black women (57.9 per 1,000 person-years) and Black young adults 20 to 29 years of age (65.5 per 1,000 person-years). Over the study period, the relative difference in obesity risk between Black and White persons decreased from 92% to 43%, but large race disparities remained in 2013–2017, consistent with obesity prevalence data.

By educational level, the incidence of obesity increased most for those who had a high school diploma (32% increase) followed by those with an education beyond high school (20%), whereas it remained roughly the same for those with less than a high school diploma. Those with less than high-school education had higher obesity incidence than those with education beyond high-school (39.4 per 1,000 person-years vs 24.7 per 1,000 person-years) [45].

By age, obesity incidence was highest in young adults (34.1 per 1,000 person-years) and declined with age (70+ years: 18.9 per 1,000 person-years). As obesity prevalence climbs, the pool of never-obese adults who may develop first-time obesity becomes smaller, which partly explains the higher incidence at younger ages [45].

With the obesity risk of overweight persons seven times higher than normal-weight persons (62.1 per 1,000 person-years vs 8.8 per 1,000 person-years), the authors state overweight should not be considered a "new normal," but a transition phase that often cascades into obesity. The obesity incidence of young adults with overweight (97.0 per 1,000 person-years) was the highest of any subgroup examined [45].

PERSONAL AND SOCIETAL BURDEN OF OBESITY

As noted, obesity is a progressive, chronic disease associated with a spectrum of complications and poor outcomes, including premature death [46]. Common clinical consequences of obesity are adiposopathic or metabolic (e.g., type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, cancer) and biomechanical stress damage from the pathogenic physical forces of excessive body fat (e.g., orthopedic abnormalities leading to immobility, sleep apnea) [29,46]. Obesity shares many pathogenic processes of aging. The greater the age or obesity, the greater the mortality. In patients with BMI 55–60, an estimated 14 years of life is lost primarily from heart disease, cancer, and type 2 diabetes [18].

Excessive body fat is a cause of 13 cancers, including esophageal, gastric, cardiac, colorectal, liver, gallbladder, pancreas, meningioma, postmenopausal breast, endometrium, ovary, kidney, thyroid, and multiple myeloma [47]. A 5-point increase in BMI is strongly associated with increased risk of thyroid and colon cancers in men, endometrial and gallbladder cancers in women, and esophageal adenocarcinoma and renal cancers in both sexes [46]. From 2004 to 2015, the prevalence of these cancers increased 7% while cancers not known to be related to excessive body fat decreased 13% [46]. Overweight- and obesity-related cancers account for about 40% of all cancers. With approximately 70% of adults overweight or obese, promoting the maintenance of weight loss to decrease cancer risk is critical [47].

Obesity is also associated with increased susceptibility to nosocomial infections, wound infections, and influenza pandemics. Obesity increased the risk of COVID-19-related hospitalization (113%), intensive care admission (74%), and death (48%) [48].

Previously associated with high-income Western countries, obesity has become a growing problem in developing countries and among low-income populations. For the first time in human history, the number of overweight people exceeds the number of underweight people. Globally, the estimated $2.0 trillion annual economic impact of obesity is similar to smoking ($2.1 trillion), or armed violence, war, and terrorism combined ($2.1 trillion) [49].

In the United States, medical expenditures by BMI show a J-shaped curve, with higher costs in general for women and the lowest expenditures at a BMI of 20.5 for women and 23.5 for men. Among persons with BMI greater than 30, predicted costs continued to increase linearly, with each one-unit increase in BMI associated with an additional cost of $253 per person on average [2]. In 2019, the medical cost of adult obesity was $173 billion, with most costs from severe obesity; pediatric obesity was associated with medical costs of $1.32 billion. Adults with BMI 20–24 had the lowest medical costs in all ages [50].

Obesity-related costs increase with age starting around 30 years of age. This is similar to findings of increased relative risks of obesity-related morbidity and mortality starting at 25 to 29 years of age and 35 years of age and older, respectively. The high costs at higher levels of BMI are especially concerning given that the adult prevalence of severe obesity is projected to increase further [50].

MORTALITY

In 2013, an influential meta-analysis by Flegel et al. concluded that, relative to normal weight, class 1 obesity (BMI 30.0–34.9) was not associated with excess all-cause mortality and overweight was associated with lower all-cause mortality [51]. The hypothetically protective metabolic effects of increased body fat in apparently healthy individuals was advanced to support this claim [52].

However, uncontrolled variables may have biased the results. A subsequent meta-analysis of 239 prospective studies on BMI and mortality limited bias from confounding factors and reverse causality. Of 10.6 million participants in North America, Europe, Australia and New Zealand, and Asia, analyses was restricted to 3.9 million never-smokers without specific chronic diseases at enrollment who were still followed after five years (median follow-up: 13.7 years). The six WHO-defined BMI categories were subdivided into nine BMI groups to avoid merging importantly different risks [53].

All-cause mortality (Table 5), lowest at BMI 20–24.9, increased significantly with greater distance below and above this range, (e.g., 51% for BMI <18.5 and 276% for BMI ≥40 compared with BMI 20–24.9). Each 5-point increase in BMI above 25.0 increased the risk of all-cause mortality by 39% in Europe and east Asia, 31% in Australia/New Zealand, and 29% in North America, and was greater in younger than older people (52% at 35 to 49 years of age; 21% at 70 to 89 years of age) and in men than women (51% vs 30%). The hazard ratio for class 1 obesity in men (1.70) and women (1.37) suggests that men have almost double the proportional excess mortality of women (70% vs 37%).

Table 5: ALL-CAUSE MORTALITY BY BMI

Weight Category

BMI

Hazard Ratio

Underweight

15.0–18.4

1.51

Healthy or normal

18.5–19.9

1.13

20.0–22.4

1.00

22.5–24.9

1.00

Overweight

25.0–27.4

1.07

27.5–29.9

1.20

Class I obesity

30.0–34.9

1.45

Class II obesity

35.0–39.9

1.94

Class III obesity

≥40

2.76

Source: [53]

The proportion of all-cause mortality attributable to overweight or obesity was 19% in North America, 16% in Australia/New Zealand, 14% in Europe, and 5% in east Asia [53].

The results challenge assertions that overweight and class I obesity are not associated with higher mortality risk. The results section in this paper also reproduced the findings of Flegal et al., before applying restrictions that yielded the final results [53]. The results also suggest a J-shaped curve for mortality risk below and above BMI 20–25, which includes normal-range BMI 18.5–20.

4. ETIOLOGY OF THE OBESITY EPIDEMIC

The development of obesity is commonly understood through the energy balance model. Energy refers calories from macronutrients (carbohydrate, protein, and fat) in meals. Energy (i.e., calories) can be ingested (intake) or burned (expenditure). Energy balance is when energy intake and expenditure are equal. In positive energy balance, energy intake exceeds expenditure. Long-term positive energy balance is considered the cause of adult obesity. Obesity, both societal and individual, is abundantly blamed on increasingly sedentary lifestyles and reduced physical activity, combined with increased fatty food intake.

Utilizing the NHANES and International Atomic Energy Agency (IAEA) databases, researchers have investigated population-level trends that may be affecting energy balance, including changes in diet, activity, and energy expenditure. The results challenge conventional wisdom about the causation of the obesity epidemic. These data are limited to U.S. adults.

DIET, PHYSICAL ACTIVITY, AND BMI

Dietary recommendations represent an important but neglected backdrop of population trends in weight-gain over the past 70 years. In the 1950s, the Diet-Heart Hypothesis (DHH) connected rising rates of coronary heart disease after World War II to high saturated fat intake: Because dietary saturated fat raises serum cholesterol and high cholesterol contributes to coronary heart disease, then saturated fat intake must also cause coronary heart disease [54]. The American Heart Association (AHA) promulgated the DHH and advocated reducing total fat consumption to 25% to 35% of calories and substituting polyunsaturated for saturated fatty acids to palliate high cholesterol in 1961 [55,56,57].

With little data to support the AHA's recommendation, the Minnesota Coronary Experiment (MCE) (1968–1973) was expected to provide definitive evidence. Ancel Keys, the co-investigator, had invented K-rations for the U.S. Army in WWII, devised the DHH and was also President of AHA. This double-blind randomized controlled trial, the largest and perhaps the most rigorously executed trial ever conducted on dietary change and mortality, included complete postmortem assessments. Replacement of saturated fatty acids with polyunsaturated fatty acids predictably lowered serum cholesterol. Paradoxically, MCE participants with greater reductions in cholesterol had higher mortality. The results of what would have been a landmark study remained unpublished for 43 years, until 2016 [58].

During this time, Congress formalized AHA's position and the DHH with the Dietary Guidelines for Americans, introduced in 1980 and updated every five years. The Surgeon General, National Research Council, and American Cancer Society also recommended low-fat/saturated fatty acid diets to reduce coronary heart disease and cancer. The Dietary Guidelines for Americanswas pivotal in linking saturated fatty acids as a major cause of heart disease, obesity, and cancer, yet was initially opposed by some experts over potential unintended consequences, lack of evidence that lower dietary fat reduced heart disease, and evidence implicated sugar and refined carbohydrates instead of fats [57,59,60].

The 1980s Dietary Guidelines for Americans recommended reducing all fats and increasing carbohydrates to 55% of total calories, which was also proposed to help prevent overweight and obesity [36]. In 1990, total fat was capped at 30% of calories, later revised to 20% to 35%, which remained until 2010 [60]. Federal agencies and medical associations strongly supported a low-fat/saturated fatty acid, high-carbohydrate diet for everyone older than 2 years of age, and through 2008, advocated sugar as healthy for persons with diabetics and the general population [61]. The belief that dietary fat drives obesity and heart disease persists [1].

Macronutrient Intake and BMI: 1965–2011

Changes in macronutrient proportion of average daily calories and BMI have been examined in the context of dietary recommendations [36]. U.S. adults have largely followed dietary guidelines. From 1965 to 1999, total calories from fat decreased (46% to 32%) while carbohydrates concurrently increased (39% to 52%) [36]. From 1965 to 2011, the increased caloric share from carbohydrate explained 85% of increased BMI in men and 91% in women. Increases in total caloric intake since 1971 were unlikely to explain the increase in BMI [36]. In other words, increased carbohydrate proportionality, not total calories, drove rising BMI.

As discussed, the onset of rising obesity occurred during the 1980s and 1990s as the DHH became an ideology propagated by federal government dietary recommendations, public health policies, and popular health media, which these authors suggest may have initiated the obesity epidemic [36,54,63]. While observational data cannot establish causality, these and other findings suggest the origin of the obesity epidemic may be partially iatrogenic.

Dietary Changes: 1999–2016

From 1999 to 2016, data showed increases in total fat (1.2%) as proportion of diet, including saturated (0.36%), monounsaturated (0.19%), and polyunsaturated (0.65%) fatty acids; decreases in total (-2.02%) and low-quality (mostly sugar) (-3.25%) carbohydrates; increases in high-quality (1.23%) carbohydrates; and increased intake of whole grains, poultry, and nuts [37].

Opposing trends during 1999–2016 partly reversed those of 1971–2000, when emphasis on low-fat diets was associated with decreased fat intake and increased refined grains and added sugar intake. During the 2000s, the benefits of healthy fats and plant sources of protein and harms of excess sugar became popularized, independent of dietary guidelines. Regardless of influence, dietary macronutrient intake during 1999–2016 shows clear evidence of improvement [37].

Caloric Intake, Physical Activity, and BMI: 1971–2008

Changes in physical activity, macronutrient intake, and BMI during 1971 to 2008 were examined using NHANES dietary (1971–2008) and physical activity (1988–2006) data of participants with BMI 18.5–50.0. Physical activity was defined as the weekly frequency of leisure time activities of moderate or greater metabolic intensity [39].

Between 1971 and 2008, BMI increased 10% in men and 11% in women, most of which occurred after 1988 [39]. Total calories per day increased by approximately 10% in men and 14% in women from 1971 to 1999, peaked in 2003, and declined to 1999 levels for both sexes by 2008. Relative caloric intake (i.e., total calories converted to cal/kg of body weight) in 2008 was similar to 1971 but increased modestly between 1988 and 1994 in both sexes. Percent of daily calories (men and women) increased for carbohydrate (13% and 10%) but decreased for fat (9% and 8%) and protein (5% and 7%) [39].

Between 1988 and 2006, physical activity per week increased 47% in men and 120% in women [39]. Adjusted for physical activity and carbohydrate and fat intake, for an equivalent amount of energy intake or physical activity, BMI was up to 2.3 higher in 2006 than in 1988. Thus, BMI increased between 1988 and 2006, even after holding energy intake, macronutrient intake, and physical activity constant.

Decreased physical activity and increased caloric consumption do not fully explain this increase in BMI. The authors conclude that other unrecognized factors may be significantly modifying how energy intake and expenditure influence body weight over time [39].

Weight Loss Attempts: 1999–2016

Over the past 40 years, as obesity prevalence increased about threefold, the prevalence of weight loss attempts by adults increased from 34% in 1999–2000 to 42% in 2015–2016. During 2013–2016, past-12-month attempts to lose weight were made by 49% of adults overall and by 67% of those with obesity. Since the late 1980s, the prevalence of dieting to lose weight has been ≥40% among women and ≥25% among men [64,65].

Repeated weight loss efforts may also contribute to weight gain, which experts have suggested has created a ''weight-loss futility cycle'' that characterizes the rising prevalence of both obesity and weight loss attempts since 1980. The increasing prevalence of obesity and weight loss attempts has also been paralleled by an increase in body weight stigma, which in turn is associated with many adverse health outcomes, including higher risk of all-cause mortality, and disproportionately affects individuals with obesity [65].

ENERGY EXPENDITURE RESEARCH

Understanding the relative contribution of lower energy expenditure to the obesity epidemic is a crucial task that requires accurate measurements of energy expenditure [66,67,68]. The terms used in discussions of this concept should be clearly defined [70,71,72]:

- Basal energy expenditure: Also known as resting energy expenditure or basal metabolic rate, the minimum energy required to maintain vital physiological functions

- Activity energy expenditure: Exercise and non-exercise activity

- Physical activity: Work-time (occupational) or leisure-time energy expenditure

- Total energy expenditure: Expressed in calories/day, the sum of basal energy expenditure and activity energy expenditure

Doubly labelled water (DLW) is the criterion-standard for measuring energy expenditure and the only method that can assess this during a person's normal daily living. This method uses water with the added stable isotopes deuterium and oxygen-18 to measure energy expenditure (i.e., calories burned) [67,73].

DLW studies began in the early 1980s. The IAEA database houses four decades of DLW study data. With the size of this database and its ongoing expansion, big questions about the causes of the obesity epidemic are being addressed [74].

Additive versus Constrained Models of Metabolic Physiology

The dominant additive model assumes a dose-dependent, additive effect of physical activity on total energy expenditure; with each increment of physical activity, total calories burned correspondingly increases [75]. This calories in/calories out paradigm of obesity led to energy restriction diets and exercise as the standard obesity intervention to reverse positive energy balance for weight loss [76,77].

Energy compensation, or metabolic adaptation, is a normal physiobehavioral response to a change in activity or diet such that the impact of the change is blunted [12]. DLW data suggest the relationship between physical activity and total energy expenditure is more complex than additive models allow [75].

An earlier DLW study involved Hadza people, traditional hunter-gatherers who live off of wild plants and animals in Tanzania expending hundreds of calories a day on activity. Hadza men ate and burned about 2,600 calories per day and Hadza women consumed and burned about 1,900 calories per day. Even after controlling for effects of body size, fat percentage, age, and sex, the Hadza burned about the same daily calories as city dwellers in the United States [78].

DLW evidence led to the constrained model, where total energy expenditure increases with low physical activity but plateaus at higher activity levels as the body adapts to maintain total energy expenditure within a narrow range. By accounting for energy compensation, the constrained model provides a unifying framework for seemingly contradictory results from studies of physical activity and total energy expenditure [12,75].

The compensation may take several weeks or months. Exercise will raise energy expenditure in the short-term, and lifestyle change may also affect total energy expenditure until compensation occurs, after which physical activity will have little measurable effect on total energy expenditure [12].

Energy Compensation

Increasing activity levels may bring diminishing returns due to compensatory responses in nonactivity energy expenditure [66]. In 1,754 adults with DLW measured seven years apart, only 72% of the extra calories burned during activity translated into extra calories expended that day, because the body offset the calories burned in activities by 28%. Among those with BMI ≥34, compensation of burned activity calories increased to 46% [72].

To explain the causality of this relationship, individuals with greater body fat are either predisposed to adiposity because they are stronger energy compensators or because they become stronger compensators as they gain adiposity. Prescribing increases in activity to increase total energy expenditure and thus control weight gain or promote fat loss assumes that costs of activity are additively related to basal costs, which this study suggests is untrue [72].

Resting Energy Expenditure in Healthy Underweight Adults

Contrary to popular belief that lean individuals "eat what they want" and exercise more, a cohort of 150 healthy underweight (BMI <18.5) adults exhibited significantly lower physical activity and food intake relative to 173 normal-BMI controls and much higher than expected resting energy expenditure, measured using DLW [79]. The healthy underweight subjects were metabolically healthier than normal-BMI controls, which suggests low body weight/fat is a more potent driver of metabolic health than higher physical activity. The results extend previous longitudinal findings into a much lower range of BMI and show that markers of metabolic health continue to improve as BMI falls below 18.5 [79].

Declining Metabolic Rate and Rising Obesity

The obesity epidemic is often blamed on declining energy expenditure due to reduced occupational physical activity combined with increased sedentary behavior and screentime. This was examined in 4,800 adults with DLW data obtained between 1987 and 2017. All results were adjusted for age and body composition [80].

Men and women both showed significant declines in total energy expenditure and significantly increased activity energy expenditure, while physical activity increased significantly in men and non-significantly in women. Basal energy expenditure decreased significantly in men and non-significantly in women. Men and women showed declines in total energy expenditure (7.7% and 5.6%) and basal energy expenditure (14.7% and 2%), respectively. In both sexes, the decline in basal energy expenditure was sufficient to explain the reduction in total energy expenditure. There was no evidence that reduced physical activity leading to lowered total energy expenditure contributed to the obesity epidemic [80]. This is counterintuitive, given the established decrease in occupational physical activity and the suggested progressive increase in sedentary behavior. The increased leisure physical activity between 1965 and 1995 (and 1988–2006) may have offset reduced occupational physical activity. Increased time on computers has largely come at the expense of time watching television; with comparable energy costs, this tradeoff would have little effect on overall activity energy expenditure [80,81].

In addition, the reduction in total energy expenditure was linked to a decline in basal energy expenditure. Declining basal energy expenditure is less easily understood, but consistent with data that body temperatures also declined over the same period as decreasing basal metabolic rate. The magnitude of change in basal metabolic rate is consistent with studies showing that basal metabolic rate increases 10% to 25% with every 1°C increase in core temperature [80]. The authors conclude that a declining basal metabolic rate may be contributing to the obesity epidemic. Identifying the cause, and if it can be reversed, is an urgent priority.

OTHER POTENTIAL ETIOLOGICAL FACTORS

Urbanization

During 1985 to 2014 in most countries, the concurrent increases in BMI and the proportion of populations living in cities compared with rural areas led to a widely accepted view that urbanization, and the resultant sedentary lifestyle, is an important contributor to the global rise in obesity [82]. However, an analysis of 2,009 population studies with direct anthropometric measurements in 112 million adults from 1985 to 2017 demonstrated that 55% of the global rise in adiposity (and >80% in some low- and middle-income regions) is explained by increased adiposity in rural areas [83].

Social Contagion

There is substantial clustering of obesity within social and geographic networks. Whether this results from causal pathways (e.g., social contagion, shared environments) or self-selection is unclear and was studied in 1,519 military families from 38 military installations around the United States who relocated to counties with obesity rates of 21% to 38% [84]. Exposure to communities with higher obesity prevalence was associated with higher BMI and overweight/obesity in parents and children. Specifically, a 1% higher county obesity rate was associated with 5% higher odds of obesity in parents and 4% higher odds of overweight/obesity in children [84].

All associations were strengthened by duration (i.e., >24 months at their current installation) and proximity (living off-base) of exposure and were unchanged after controlling for the shared built environment in the county and neighborhood of residence. There was no evidence to support self-selection or shared environment as explanations, which may suggest the presence of social contagion in obesity [84]. Although data on the previous county obesity rate was unavailable, exposure to communities with higher obesity rates may increase individuals' BMI via the presence of social contagion, possibly by common social norms associated with obesity [85].

Medication-Induced Weight Gain

In 2017–2018, 20.3% of U.S. adults used an obesogenic medication (compared with 13.2% in 1999–2000) [86]. Many widely used drugs cause weight gain that may lead to obesity in susceptible individuals. Weight gain is consistently associated with many older antidiabetic agents, atypical antipsychotics, antidepressants, and antiepileptic drugs [87].

Dietary Sugar and Sugar-Sweetened Beverages

A study that pooled three population-based prospective cohorts of Finnish adults to examine diet and weight gain over seven years found no associations between total carbohydrate, dietary fiber, sugar, or sucrose intake and ≥5% increase in weight or waist circumference. However, the authors state that low sugar-sweetened beverage consumption in Finland compared with the United States may partially explain the lack of association between carbohydrate intake and weight gain [88].

In the United States from 1965 to 2002, daily sugar-sweetened beverage caloric consumption increased 306% per capita and 86% among consumers of sugar-sweetened beverages only. However, from 1999 to 2010, total daily caloric intake from sugar-sweetened beverages among youth (2 to 19 years of age) and adults (≥20 years of age) decreased 31% and 21%, respectively [57].

Evidence for the mainstream view that high sugar consumption leads to obesity and related metabolic diseases is inconsistent, and high sugar intake from s ugar-sweetened beverages may differ from sugar-containing foods (i.e., solid sugars) in BMI/metabolic impact [89].

In a review of prospective evidence, most studies linking high sugar intake to adverse health outcomes examined sugar-sweetened beverages, while studies of solid sugar intake mostly reported null findings. High sugar-sweetened beverage consumption was dose dependently associated with increased risks of cardiovascular disease morbidity and mortality through weight gain; solid sugar sources (e.g., ice cream) were not [89,90].

Sugar-sweetened beverages may be more likely to induce metabolic syndrome. The faster gastric emptying time of sugar-sweetened beverages and higher absorption of its fructose component may lead to fatty accumulation in the liver. Compared with solid sugars, sugar-sweetened beverages induce less satiety and may subsequent cause overeating. The gut can convert low-concentration fructose to glucose, but transports high-concentration fructose (e.g., in sugar-sweetened beverages) to the liver [89].

Increased lipogenesis and circulating triglycerides, very-low-density cholesterol, and uric acid associated with high sugar-sweetened beverage intake may induce hyperglycemia, glucose intolerance and dyslipidemia to increase risks of type 2 diabetes and cardiovascular disease. High intake of fructose-sweetened beverages may disrupt the production of appetite control hormones (decreasing leptin and insulin, increasing ghrelin), suggesting different effects on metabolic and endocrine health of liquid versus solid sugars [89].

Individuals who ingest high dietary sugar often have other unhealthy behaviors that may contribute to the pathogenesis of obesity and related disorders, complicating causal inferences. Although definitive evidence is needed, and reducing sugar remains a general recommendation, there is evidence of greater health risks with sugar-sweetened beverages that might not be comparable to those with sugar in food [89,91].

SUMMARY

That the obesity epidemic lacks a clear explanation is a striking and poorly appreciated fact. The widely accepted causes of ever-increasing caloric intake and progressively declining physical activity are largely unsupported [16,17]. Genetic, developmental, and environmental factors are thought to interact to cause cumulative positive energy balances resulting in weight gain and obesity [92]. Numerous factors have been associated with increased risk of obesity—but a risk factor is not necessarily a cause, and risk factors are not direct causes of disease. Associations in the obesity literature often reflect information bias, reverse causality, erroneous causal inferences, or confounding from other social and behavioral factors [54]. Although spurious, some persist to mislead science, practice, and the public [59].

Provocative evidence demonstrates that the obesity epidemic has expanded beyond humans. Mammals inhabiting human-influenced environments have also exhibited pronounced increases in weight and obesity over the past several decades, including mammals in research labs, feral rats, and domestic dogs and cats [93]. The laboratory animals include four different species of primates in National Primate Research Centers, as well as rats and mice, all living in environments where their diets are strictly controlled [17,93]. In 2015, canine and feline obesity rates had reached pandemic proportions similar to humans [94]. An international multidisciplinary congress, Animal Obesity, was launched in 2016 [95].

A reasonable inference is that something has changed in the shared environment that is inducing weight gain, and exposure to unidentified obesity-promoting factors may be affecting all these populations in concert. There is some evidence pointing to endocrine-disrupting chemicals [17,48,77,93,96].

Endocrine-disrupting chemicals interfere with hormone action to dysregulate endocrine function, insulin signaling, and/or adipocyte function. Adipose tissue is a true endocrine organ and is therefore highly susceptible to disturbance by endocrine-disrupting chemicals. Obesogenic endocrine-disrupting chemicals promote adiposity by altering programming of fat cell development, increasing energy storage in fat tissue, and interfering with neuroendocrine control of appetite and satiety [17,18,48,77,96,97].

Endocrine-disrupting chemicals have become ubiquitous in our environment. Exposure occurs throughout life, but development is the most sensitive period for endocrine-disrupting chemicals to impact future weight gain across the lifespan and generations, and endocrine-disrupting chemicals can act via epigenetic mechanisms. There is an urgent need to understand how exposures to certain endocrine-disrupting chemicals may predispose the population to obesity [48,77,96,98,99].

Note that researchers in some studies have concluded that some unknown factor may be altering normal energy metabolism, as increased caloric intake and/or decreased activity could not adequately explain rising BMI and obesity. A 2023 review suggests that exposure to some yet-to-be-identified factor(s) is promoting obesity by generating false and misleading information about energy status [100].

Most importantly, uncertainty over the obesity epidemic's cause has little bearing on the effectiveness of medical interventions [16]. In fact, pharmacotherapy of obesity with novel approved and investigational agents shows weight loss efficacy and remission of comorbid disorders previously unattainable without bariatric surgery. Bariatric surgery itself can result in dramatic weight loss (≥30%) and remission of obesity-related metabolic disorders persisting for years if not decades. Newer and emerging minimally invasive bariatric procedures are showing promising results while reducing the risks of surgery.

5. THE REGULATION OF BODY WEIGHT

ENERGY BALANCE

When body-fat levels become established, complex biological mechanisms defend the established body mass against persistent pressures that would induce weight loss. This can be understood from an evolutionary perspective. With food scarcity during most of human evolution, evolutionary pressures on the human genetic blueprint selected for genetic variants that favored the storage and conservation of energy to ensure survival and reproduction. The underlying process that defends energy storage and conservation is called energy balance [101,102].

The purpose of energy balance is to maintain adenosine triphosphate (ATP) availability for cells. ATP is required by all cells to sustain and maintain life. Eating acquires the oxidizable fuels that cells use to maintain ATP availability [101,102,103].

Energy balance is regulated by homeostatic processes. Homeostasis maintains interdependent bodily constituents within a controlled stable range. Regulation is the ability to maintain a variable within a narrow range. Control mechanisms are those that maintain the narrow range of the regulated variable. The regulated variable in energy homeostasis is ATP availability [103,104]. Control processes that maintain ATP availability (i.e., energy homeostasis) include energy intake, energy storage, and energy expenditure. Thus, ATP availability is the apex regulated variable and pivot point for energy balance; the dynamic relationships between energy intake, storage, and expenditure are all directed toward this end [103].

Energy Intake and Storage

Glucose and free fatty acids are monomers, the oxidizable fuels for ATP production that cells require. Monomers are the breakdown products of macronutrients, released by digestion and distributed into oxidizable fuels or storage by energy partitioning, depending on current energy balance status [70,102,103].

Excess energy is stored as fat in adipose depots, carbohydrate (as glycogen) in liver, or protein in muscle. The energy density of adipose tissue is nearly 10-fold greater than liver (glycogen) or muscle (protein). The small storage capacity for carbohydrate can cover overnight energy needs during sleep. The larger energy stores of fat are mobilized to cover longer-term energy shortages [70,102,103].

However, as a substrate for energy metabolism, fat is last in the hierarchy that determines fuel selection; it is mostly stored before oxidation and is less likely to be oxidized than carbohydrate or protein. Body-fat mass and oxidation of dietary fat are inversely related—higher fat mass lowers the oxidation rate of dietary fat [70,102,103]. Energy expenditure is the sum of ATP generated by oxidizing monomers to drive physiological processes.

Three States of Energy Balance

Oxidizable fuels from food can fail to meet (negative), equal (balanced), or exceed (positive) requirements to maintain ATP availability within its narrow range. These are the three states of energy balance [70,102,103]:

- Negative: When oxidizable fuel supplies are challenged by prolonged calorie deficit, control mechanisms increase catabolism (breakdown) of fuel stores and reduce energy expenditure to maintain ATP production. During starvation, these mechanisms maintain cell function to an extent that compromises organ and systemic function. The collective outcome of processes that control blood glucose, adiposity, heat production, and eating behaviors, are directed toward maintaining ATP availability within a narrow range.

- Balanced: The rate of anabolic and catabolic processes is equal (a state of energy balance).

- Positive: Energy balance favors anabolism, which increases fuel stores.

Unlike fuels, ATP cannot be stored. An animal can survive for days or weeks without food, but its survival time is measured in seconds if a toxin shuts down oxidative phosphorylation and ATP production. Lacking ATP storage capacity, daily ATP turnover in humans is dramatic [103].

DEFENSE OF BODY WEIGHT

Positive energy balance from increased energy intake, decreased energy expenditure, or both, is considered the proximate cause of weight gain and excess fat storage leading to obesity [66,102,105,106,107].

Obesity is usually the result of small, cumulative positive energy imbalances over an extended period. The homeostatic system continually retunes itself during the upward drift in weight. At some point, for most people, these biological adaptations re-establish a balance at a higher, steady-state weight [108].

Persons with obesity may lose 7% to 10% of initial weight with a 16- to 26-week comprehensive caloric restriction, physical activity, and behavioral intervention [9]. However, it is the maintenance of weight loss that makes long-term control of obesity so difficult [7,8].

In contrast to its subtle, permissive role in the development of obesity, biology plays a prominent, causal role in weight regain [108]. Energy-restricted weight loss mobilizes powerful biological forces that lead to increased hunger, enhanced neural responses to food cues, and heightened drive to consume energy-dense foods [11].

Because both sides of the energy balance equation are affected after weight loss, the biological pressure to gain weight is a consequence of both increased appetite and suppressed energy expenditure as the body attempts to restore energy homeostasis [15,108]. Termed metabolic adaptation, this defense of established adiposity against weight loss recapitulates a physiological response that signals potential starvation [69,104].

Metabolic adaptation has been understood for more than five decades but is missing in public health statements that healthier lifestyle choices are the solution to obesity [6,109,110,111,112,113,114]. As a consequence, patients are often blamed for obesity treatment failure [3,6].

6. OVERVIEW OF CLINICAL MANAGEMENT

Obesity involves dysfunction of the tightly regulated energy homeostasis system and its underlying central, peripheral, and reward mechanisms (Appendix) [115,116]. Powerful compensatory mechanisms drive weight regain following weight loss in obesity by altering appetite, food reward, and energy intake and expenditure. Peripheral changes, including reduced anorectic hormones and increased orexigenic hormones, stimulate food intake. Pressure to overeat combines with central mechanisms that drive food pleasure and reward. Metabolic adaptation reduces resting energy expenditure [117]. These dysregulated mechanisms are the targets of FDA-approved and investigational antiobesity medications and of bariatric surgery.

Knowledge of obesity pathophysiology, and clinical management based on the understanding of obesity as a chronic, progressive cardiometabolic disease, has rapidly evolved over the past decade. Consequently, some clinical practice guidelines on obesity from authoritative bodies have become outdated. For example, the most recent guideline by the AHA, American College of Cardiology, and The Obesity Society (AHA/ACC/TOS) was published in 2014 [118]. The paradigm of long-term management in this guideline is largely obsolete. A 2015 clinical practice guideline from the Endocrine Society and a 2016 guideline from the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) advanced the paradigm to the current standard of care, but available antiobesity medication options addressed in the guideline are non-recent [119,120,121]. Scientific statements by the Endocrine Society and clinical practice guidelines by the OMA, the American Gastroenterological Association (AGA), and the American Society for Metabolic and Bariatric Surgery (ASMBS) reflect current advances in obesity science, antiobesity medication options and their rational clinical use and bariatric surgical and noninvasive options [4,7,30,122,123,124,125,126].

THE FOUR PILLARS OF OBESITY MANAGEMENT

The OMA states that obesity is a serious and multifactorial disease that requires patient access to comprehensive care, including the four pillars of healthful nutrition, physical activity, behavior modification, and medical management with antiobesity medications and surgical interventions. Comprehensive care of obesity is not only about reducing weight but also about improving the health of patients [122].

Initial comprehensive care includes medical history, review of systems, personal history (e.g., family, socioeconomic, culture, nutrition, physical activity, behavioral, and eating disorder history), evaluation for primary and secondary causes of obesity, routine preventive care, physical exam, and laboratory testing [122]. Common metabolic complications of obesity include type 2 diabetes, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and the fat mass complication of sleep apnea. "Treat obesity first" represents a standard of care for patients with obesity-related complications that can slow the progression of metabolic complications and reduce premature mortality [122].

Healthful Nutrition

The OMA recommends that patients with obesity have access to safe, effective, personalized, and evidence-based healthful nutritional intervention. Patients should optimally have access to nutrition therapy via a registered dietitian or via nutritional counseling from obesity medicine clinicians trained in nutritional counseling. Approaches to overcome barriers to nutritional intervention engagement include individual or group videoconferencing, personalized artificial intelligence (AI)-mediated interventions applicable to precision medicine, incorporation of cultural norms, and awareness of the impact of social determinants of health [122].

Physical Activity

The OMA recommends patients with obesity be treated with a safe and effective personalized physical activity plan (i.e., physical activity prescription) based on the patient's underlying health and mobility. To achieve physically active objectives, the OMA recommends that patients with obesity learn the benefits of non-exercise activity thermogenesis, target dynamic goals (e.g., steps per day), and safely incorporate resistance training. The intent is to improve body composition, support weight loss maintenance, improve balance and flexibility, and reduce the risk of injury from falls or joint stress. Improving or maintaining mobility can be achieved via training to promote activities of daily living (e.g., self-dressing, -meal preparation, -bathing, -laundry). Physical activity and exercise training may occur individually or in groups, via live classes/instruction, video format, or AI educational interactions, and may be especially important in patients with sarcopenic obesity [122].

Behavior Modification

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians offer or refer patients with a BMI of 30 or greater intensive, multicomponent behavioral interventions.

https://jamanetwork.com/journals/jama/fullarticle/2702878

Last Accessed: November 28, 2023

Strength of Recommendation: B (The USPSTF strongly recommends that clinicians routinely screen eligible patients. The USPSTF found good evidence that obesity screening improves important health outcomes and concludes that benefits substantially outweigh harms.)

The OMA recommends patients with obesity be treated with evidence-based behavior modification. Important aspects include personalized tracking and regular clinician encounters. Optimizing social support at home and in the community may be helpful. Patients often benefit from behavior modification provided by a knowledgeable physician, nurse practitioner, physician assistant, nurse, or dietitian, or via a psychologist/psychiatrist, health coach, or another appropriate counselor. For patients for which record keeping and accountability metrics may improve health outcomes, other potential interventions include fitness trackers, smartwatches, and use of social media. Behavior modification may also be delivered through AI chatbots [122].

Medical Management

Antiobesity Medications

Medical treatment with antiobesity medication and/or bariatric procedures is the fourth pillar of obesity management. Evidence-based treatment of obesity, including pharmacotherapy, represents a standard of care for patients with obesity [122].

Obesity is associated with $174 billion in excess healthcare costs annually. To mitigate such expenditures, obesity should be treated early and effectively before its complications arise. In patients without acute complications of obesity, a "treat obesity first" approach through antiobesity medications may reduce or eliminate the need (and cost) for antidiabetic medications, antihypertension medications, lipid medications, pain medications, and possibly other medications (e.g., antidepressants) or other treatments (e.g., continuous positive airway pressure devices) [122].

When appropriate for the patient, use of lower-cost antiobesity medications may improve the cost effectiveness of medication. The forthcoming generic status of some current agents and market entry of new antiobesity medications may drive competition and lower costs [122]. However, the OMA stresses the importance of a patient-centered, personalized approach to pharmacotherapy for obesity and that such an approach may depart from the recommended prescribing information [122].

Bariatric Procedures

The OMA recommends that patients with obesity should have access to evidence-based bariatric procedures, when appropriate, as an adjunct to healthful nutrition, physical activity, behavior modification, and pharmacotherapy. Currently, less than 1% of eligible patients receive bariatric surgery, despite extensive evidence of its cost-effectiveness. Importantly, bariatric surgery is associated with reductions in overall mortality, cardiovascular events, risk of cancer, cardiovascular risk factors (e.g., type 2 diabetes, hypertension, dyslipidemia), and improvements in osteoarthritis, skin disorders, and possibly depression [116,122,127,128,129,130].

OBESOGENIC MEDICATIONS

Obesity may result from an identifiable primary cause. Some endocrine disorders, including hypothalamic disorders, insulinoma, hypothyroidism, and hypercortisolism, are strongly associated with obesity or its onset [24]. A common culprit are drugs that promote weight gain, and a central task for clinicians caring for patients with obesity involves reviewing their use of obesogenic medications (Table 6) [131].

Table 6: OBESOGENIC MEDICATIONS AND WEIGHT-NEUTRAL OR -REDUCING ALTERNATIVES

Clinical Condition or Drug Class

Weight-Promoting

Weight Neutral

Weight-Reducing

Type 2 diabetes with obesity

Pioglitazone

Sulfonylureas

Insulin

DPP-4 inhibitors

Metformin

SGLT2 inhibitors

GLP-1R agonists

Antidepressants

Paroxetine

Amitriptyline

Mirtazapine

—

Bupropion

Fluoxetine

Atypical antipsychotics

Olanzapine

Quetiapine

Risperidone

Ziprasidone

—

Anticonvulsants and mood stabilizers

Divalproex

Carbamazepine

Gabapentin

Lithium

Lamotrigine

Zonisamide

Topiramate

Inflammatory rheumatic diseases

Corticosteroids

DMARDs

NSAIDs

—

DMARDs = disease-modifying antirheumatic drugs, DPP-4 = dipeptidyl peptidase-4, NSAIDs = nonsteroidal anti-inflammatory drugs, SGLT2 = sodium-glucose cotransporter-2.

Source: [131]

In chronic disease management, the weight-gain potential is often overlooked when choosing pharmacotherapy options. However, many commonly used medications associated with weight gain have alternatives with weight-neutral or weight-losing effects. Shifting medication choices from weight-positive to weight-neutral or -negative choices can be an effective means of facilitating weight loss [122].

Common medication classes associated with weight gain include steroids, antipsychotics, antiepileptics, glucocorticoids, and gabapentinoids. When these or other prescribed medication classes induce significant weight gain, especially to an extent that may exceed the positive treatment effects, switching patients to alternative medications that are weight-neutral or weight-loss-promoting should be considered within a shared decision-making process including the patient and prescribing provider (e.g., psychiatry, neurology, other specialists) [131].

For patients with type 2 diabetes and obesity requiring insulin therapy, adding metformin or GLP-1R agonists can reduce or nullify (with GLP-1R agonists) insulin-associated weight gain. Clinicians should add one of these agents when starting a patient with type 2 diabetes on insulin therapy. Among insulin therapies, basal insulin is associated with less weight gain than biphasic or prandial short-acting insulin and should be the first-line option [131].

Obesity and inflammatory rheumatic diseases commonly co-occur, with a hypothesized causal role due to the proinflammatory nature of adipose tissue. Patients with obesity have higher disease scores and poorer treatment response to disease-modifying antirheumatic drugs (DMARDs). Minimize or avoid corticosteroids, which tend to promote weight gain, in favor of nonsteroidal anti-inflammatory drugs (NSAIDs) and DMARDs [131].

PRIORITIZATION FOR PATIENTS WITH OBESITY AND CARDIOMETABOLIC DISEASE

Patients with acute metabolic abnormalities (e.g., marked hyperglycemia, uncontrolled hypertension, severe hypertriglyceridemia, cardiovascular disease, cancer) should have these illnesses urgently assessed and treated, preferably with concomitant interventions that may also improve obesity [128]. For most patients without acute illness, treatment of obesity is the priority, especially if the therapies chosen for treatment of the obesity are also expected to improve the complications of obesity [128]. In weight-loss pharmacotherapy, the initial priority should be to safely achieve maximal weight reduction, followed by sustained antiobesity medication and lifestyle therapy that may require less supervision to maintain the reduced body weight [132].

TREATING TO TARGET WITH ANTIOBESITY MEDICATIONS

Obesity is a chronic disease that involves more than excessive body fat. The fat mass leads to biomechanical complications, such as obstructive sleep apnea and osteoarthritis. The pathogenic adipose tissue promotes cardiometabolic disease, which begins with subclinical insulin resistance that eventually produces metabolic syndrome, prediabetes, hypertension, dyslipidemia, and hepatic steatosis. These conditions indicate risk for progression to the end-stage manifestations of cardiometabolic disease, namely type 2 diabetes, NASH, and cardiovascular disease. The development of obesity exacerbates insulin resistance and impels progression of cardiometabolic disease toward these ultimate outcomes. As with other chronic diseases, the complications of obesity impair health and confer morbidity and mortality [3].

In treating obesity as a chronic disease, the essential goal of weight-loss therapy is not the quantity of weight loss per se, but rather the prevention and treatment of complications to enhance health and mitigate morbidity and mortality. This paradigm of care is the basis of the complications-centric AACE/ACE obesity guideline and the diagnostic term adiposity-based chronic disease (ABCD) [3].

The degree of efficacy and safety with second-generation antiobesity medications (e.g., semaglutide) and better understanding of obesity as a chronic disease has made possible a treating-to-target paradigm using percent total weight loss as a biomarker that can actively be managed within a range associated with optimal outcomes [123].

A treat-to-target approach has abundant precedent in medicine. In diabetes, clinicians treat the biomarker HbA1c to a target of ≤7.0% or ≤6.5%, because this will minimize micro- and macrovascular complications. Hypertension involves control of blood pressure levels to prevent cardiovascular and renal complications. To prevent and treat cardiovascular disease, LDL-C serves as a biomarker that is managed to a level based on patient risk estimates. In each instance, treatment to target for each biomarker (HbA1c, blood pressure, and LDL-C) is individualized based on an individual patient's overall risk, other comorbid conditions, and natural history of the disease [3].

Similarly, percent total weight loss is a more appropriate biomarker than body weight or BMI. Second-generation antiobesity medications allow clinicians to reach targets of weight loss that will predictably treat or prevent a broad spectrum of complications in ABCD [3]. Weight reductions of ≥10%, ≥15%, or 20% or more may be required for improvement in certain weight-related complications and are often more desired therapeutic goals in clinical practice [133]. Depending on the complication profile, the target for percent total weight loss can be individualized [3].

The estimated weight reduction required to improve morbidity and mortality outcomes are [3]:

- 5% to 10% weight reduction: Improved physical and biomechanical function, type 2 diabetes prevention

- 10% to 15% weight reduction: Cardiovascular disease risk reduction and remission/reduction in obstructive sleep apnea, hypertension, type 2 diabetes hyperglycemia

- ≥16% weight reduction: Type 2 diabetes remission, NASH improvement

These figures are mostly relevant to noninvasive obesity interventions. The long-term reduction and remission of metabolic disorders attainable with bariatric surgery has led to their renaming as metabolic and bariatric surgery [126].

7. ANTIOBESITY MEDICATIONS

Lifestyle modification is considered the primary treatment of obesity. A meta-analysis of 31 randomized controlled trials assessing lifestyle versus control interventions showed an average 3.6-kg weight loss at one year and 2.5-kg at three years [134]. Unfortunately, most people cannot achieve sufficient weight loss or maintain it long-term without pharmacotherapy or surgery [135].

However, effective pharmacological interventions for obesity have historically been challenging to achieve. The reasons are complex and include both behavioral and biological factors, which are difficult to separate from each other. Physiologically, metabolic adaptations in response to energy deficits and weight reduction defend against sustained fat mass loss. In the CNS, redundant pathways favor a state of anabolic and orexigenic activity. Thus, efforts to develop pharmaceutical agents that can overcome these strong neurobiological defenses, while limiting adverse effects, has proven to be somewhat elusive [123].

In 1937, during clinical trials evaluating amphetamine (Benzedrine) for the treatment of depression and narcolepsy, it was noted that subjects lost weight. Amphetamines became widely used weight-loss drugs during the 1940s and 1950s but were associated with numerous side effects [136]. After World War II, researchers discovered that injecting norepinephrine into the CNS of experimental animals reduced food intake and activated thermogenesis, prompting a search for thermogenic drugs that could work through monoaminergic receptors [4]. This resulted in sympathomimetic amines, which modified the molecular structure of amphetamine to mitigate the undesirable side effects, with phentermine, diethylpropion, phendimetrazine, and benzphetamine approved for short-term weight loss and remain available for this indication [3].

The duration required of antiobesity pharmacotherapy was thought to be around 12 weeks, the length of time needed to break a bad habit or learn to ride a bicycle without training wheels [136]. Due to a limited understanding of obesity pathophysiology, it was believed that once weight was lost, ongoing treatment was unnecessary [3]. Obesity was recognized as a disease by the scientific community in 1985, but it was not until 2013 that obesity was acknowledged as a chronic disease by the American Medical Association [136].

Orlistat, which impairs intestinal fat absorption, was approved in 1999 for chronic weight management, but medications were needed for long-term use that could blunt appetite by counteracting abnormalities in the gut-brain axis. Three such medications were approved by the FDA—fenfluramine, sibutramine, and lorcaserin—were prominently serotonergic drugs, but all have been discontinued due to safety concerns [3].

Rimonabant, the first CB-1 receptor antagonist, was approved in Europe, but not by the FDA because of concerns about suicidality. Due to psychiatric side effects, marketing of rimonabant was suspended in Europe in 2008, two years after its approval as an antiobesity medication.

From 2012 to 2014, three centrally acting antiobesity medications were approved for chronic weight management that remain available: phentermine/topiramate extended-release (ER), naltrexone/bupropion ER, and liraglutide. Semaglutide was approved in 2021 [3].

Similar to several other antiobesity medications, GLP-1 receptor agonists (GLP-1 RAs) became used in obesity following observations of weight loss in other clinical populations. Liraglutide, semaglutide, and tirzepatide were approved for the treatment of type 2 diabetes before their efficacy as antiobesity medications was evaluated.

The introduction of semaglutide marks a watershed in the history of nonsurgical obesity treatment. Semaglutide essentially doubled the weight loss observed with existing obesity medications, ushering in the era of second-generation antiobesity medications [3]. Tirzepatide surpasses the weight-loss efficacy of semaglutide.

INDICATIONS FOR USE

Except for setmelanotide and metreleptin, all antiobesity medications are approved as adjuncts to a reduced-calorie diet and increased physical activity for chronic weight management in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related complication, such as hypertension, type 2 diabetes, or dyslipidemia [137]. All antiobesity medications are considered pregnancy risk factor category X drugs and should not be prescribed to a patient who is pregnant, breastfeeding, or trying to conceive [124].

Randomized controlled trials of antiobesity medications mirror the FDA's indications in their inclusion criteria (BMI ≥30 or ≥27 with weight-related complication) and use as adjunct to lifestyle intervention. Whether participants are randomized to placebo or active drug, all receive a standardized lifestyle intervention: healthy meals, a deficit of 500 calories daily, 150 minutes of physical activity weekly, and regular dietitian counseling to help with meals and adherence [133,138]. Infrequent variations are possible and are discussed later in this section.

Evidence Based Practice Recommendation

The Department of Veterans Affairs and the Department of Defense suggest offering prescribed pharmacotherapy (specifically liraglutide, naltrexone/bupropion, orlistat, or phentermine/topiramate) for long-term weight loss in patients with a BMI ≥30 kg/m^2 and for those with a body mass index ≥27 kg/m^2 who also have obesity-associated conditions, in conjunction with a comprehensive lifestyle intervention.

https://www.healthquality.va.gov/guidelines/CD/obesity/VADoDObesityCPGFinal5087242020.pdf

Last Accessed: November 28, 2023

Strength of Recommendation: Weak for

The FDA indications may not adequately reflect current evidence. In 2018, the Endocrine Society endorsed pharmacotherapy as a first-line treatment for weight loss in patients with severe weight-related complications and removed the criteria of failed lifestyle modification [4]. A Korean obesity guideline endorses pharmacotherapy for patients with BMI ≥25, or ≥23 with weight-related complications, which may be applied to Asian populations in the United States [135,139].

Many antiobesity medications were initially evaluated for efficacy in clinical trials of type 2 diabetes. Weight loss is considerably lower in patients with obesity and type 2 diabetes than in those without diabetes. Insulin resistance and chronic hyperglycemia correlate with diminished efficacy of GLP-1 RAs, which also argues for earlier intervention before metabolic organs are irreversibility damaged [132].

Obesity should be considered a chronic condition requiring long-term treatment, as most patients who stop pharmacotherapy are prone to weight gain. If lifestyle modification and drug therapy fail, bariatric surgery should be considered a sustainable weight loss option [135].

FDA-APPROVED AGENTS

For Monogenic Obesity Syndromes

Setmelanotide (Imcivree)

Setmelanotide is the first antiobesity medication approved specifically for the treatment of rare genetic conditions associated with obesity. The drug binds to melanocortin-4 receptor (MC4R) in the hypothalamus, downstream of the leptin signaling pathway [135]. Setmelanotide re-establishes the activity of the MC4R pathway, thus reducing hunger and promoting body weight loss by lowering caloric intake and increasing energy expenditure [140].

Setmelanotide is indicated for patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin-leptin receptor (LEPR) deficiency. The condition must be confirmed by genetic testing demonstrating pathogenic variants in POMC , PCSK1 , or LEPR genes [30]. Setmelanotide is contraindicated for patients with other causes of obesity, polygenic obesity, or benign variants of the gene mutations. Dosing is subcutaneous 2 mg daily (maximum: 3 mg daily). Adverse effects include hyperpigmentation, vomiting, and nausea [135]. Setmelanotide is not associated with adverse effects on blood pressure observed with other MC4R agonists [141].

Bremelanotide

Bremelanotide is another MC4R agonist that also binds to MC3R and is FDA-approved for treatment of low sexual desire in premenopausal women. Data from two small randomized controlled trials in premenopausal women with obesity showed reduced caloric intake and weight loss with bremelanotide, without adverse effects on blood pressure, suggesting this may be an effective treatment of obesity [141].

Metreleptin

Metreleptin is a synthetic leptin analog approved by the FDA in 2014 for patients with congenital leptin deficiency or congenital/acquired lipodystrophy and is administered subcutaneously once daily. The recommended starting daily dose in adults with body weight ≤40 kg is 0.06 mg/kg (maximum: 0.13 mg/kg daily), while adults with body weight >40 kg are started on 2.5 mg or 5 mg for men or women, respectively (maximum: 10 mg daily). No leptin analog has been approved by the FDA or European Medicines Agency (EMA) as an antiobesity medication for generalized obesity [92].

For Short-Term Use: Sympathomimetic Amines

Phentermine, diethylpropion, phendimetrazine, and benzphetamine were approved for short-term use as antiobesity medications in 1959–1960, before obesity was understood as a chronic disease requiring long-term management. As a consequence, long-term (one year or longer) data on these drugs are limited [3].

All sympathomimetic amines are contraindicated in patients with hyperthyroidism, glaucoma, or in patients taking monoamine oxidase (MAO) inhibitors; all four are DEA Schedule IV controlled substances [131].

Phentermine (Adipex-P, Lomaira)

Phentermine HCl is a centrally acting sympathomimetic, with therapeutic effects mediated through increased levels of norepinephrine in the hypothalamus [123]. It was approved for short-term use in 1959 based on a 36-week trial that showed a mean placebo-subtracted weight loss of 8.2 kg [92]. Two more recent randomized controlled trials in Korea confirmed the short-term efficacy of phentermine, both showing significant weight reduction compared with placebo over 12 weeks [131].

Common adverse effects in clinical trials include dry mouth (55%) and insomnia (34%), without significant differences in systolic or diastolic blood pressure, headache, or palpitations between phentermine and placebo groups [131]. Other common side effects include dizziness, flushing, fatigue, and constipation [92]. Phentermine is not recommended for patients with cardiovascular disease, and uncontrolled hypertension is a relative contraindication. Phentermine is available in 8-mg tablets taken three times daily and in 15-mg, 30-mg, and 37.5-mg capsules taken once daily [131].

Phentermine is the most commonly prescribed antiobesity medication and is discussed further in the section on clinical use of antiobesity medications as a potential low-cost generic option to more recently approved agents.

Diethylpropion (Tenuate)

Diethylpropion and bupropion are very closely related structurally [142]. In contrast to phentermine, diethylpropion has been used infrequently in the United States. This contrasts with Mexico, Brazil, and other countries in which diethylpropion is a preferred antiobesity medication and where recent randomized controlled trials have evaluated its safety and efficacy. Outside the United States, diethylpropion is called amfepramone [143].

In one study, weight loss after 52 weeks was greater in patients randomized to diethylpropion than placebo (10.0 kg vs 3.1 kg), and more participants achieved weight loss ≥5% (71.4% vs 33.3%) [144]. Of 156 patients randomized to diethylpropion (75 mg/daily) or placebo, mean weight loss at three months (4.9 kg vs 0.7 kg) and six months (7.7 kg vs 1.1 kg) showed clinical benefit persisting beyond the short-term. Improvements in triglycerides, heart rate, and systolic and diastolic blood pressure with diethylpropion were non-significant [145].

Potential adverse effects of diethylpropion are dry mouth and somnolence (most common), constipation, anxiety, and irritability, all described as mild and nonpersistent, except dry mouth [143,144,145].

Diethylpropion is available in 25-mg short-acting and 75-mg extended-release tablets that are taken three times or once per day, respectively [136].

Other Medications

In analyses of two small 12-week randomized controlled trials, phendimetrazine (Obezine) appears to have similar weight-loss effects as other noradrenergic drugs [146].

Benzphetamine (Didrex) is the least prescribed among the four noradrenergic antiobesity medications, and there are few data from controlled trials evaluating its safety or efficacy [136].

For Long-Term Use

Gelesis100 Oral Hydrogel (Plenity)

Gelesis100 superabsorbent hydrogel is ingested orally, similar to drugs, but is regulated by the FDA as a class II medical device, because it acts mechanically as a transient, space-occupying device in a swallowed capsule that absorbs water to expand and fill up the stomach to induce satiety. Gelesis100 is FDA approved for patients with BMI 25–40. Recommended dosing is three capsules (2.25 g/dose) with water before both lunch and dinner [30,123].

After 24 weeks, more patients on Gelesis100 than placebo had weight loss >5% (58.3% vs 42.3%) and >10% (27.4% vs 15.0%), but the mean weight loss difference (2.02%) did not meet the pre-determined threshold of 3%. The AGA guideline recommends the use of Gelesis100 be limited to clinical trials due to its uncertain benefit [123].

Orlistat (Xenical, Alli)

Orlistat is a pancreatic and gastric lipase inhibitor that blocks the lipase-catalysed breakdown and absorption of around 30% of dietary fats. Orlistat is the only antiobesity medication that does not exert action in the brain; its modest weight-loss effect depends mostly on diet [147].

Orlistat is available in 60-mg capsules over the counter and 120-mg capsules by prescription, both taken three times daily [131]. In the four-year XENDOS trial that randomized 3,304 subjects with obesity to orlistat (120 mg three times daily) or placebo, weight loss was significantly higher with orlistat (5.8 kg vs 3.0 kg). The study also showed a reduced progression from prediabetes to diabetes with orlistat. Adverse effects observed in ≥10% of study populations included rectal leakage, abdominal pain, abdominal stress, flatulence with discharge, fecal urgency, steatorrhea, fecal incontinence, and increased defecation [140].

Overall weight loss with orlistat is of a small magnitude (2.78%). In contrast, the adverse effects are considered very bothersome and result in high treatment discontinuation rates. Therefore, the 2022 AGA obesity guideline suggests against the use of orlistat [123].

Phentermine/Topiramate ER (Qsymia)

Topiramate is an antiepileptic drug that was approved for seizures in 1996 and migraine prevention in 2004. The weight loss observed during epilepsy treatment led to clinical trials as a treatment for obesity, but topiramate development as an antiobesity medication was discontinued due to the associated adverse effects. However, clinical observations in private practice indicated that phentermine mitigated topiramate adverse effects and increased weight-loss efficacy when used together. This led to clinical trials to approve the combination as an antiobesity medication [136].

Topiramate is thought to suppress appetite by increasing dopamine release, inhibiting glutamate receptors, and modulating neuropeptide-Y, an orexigenic hormone. Phentermine/topiramate was approved in 2012 at fixed-dose 7.5/46-mg and 15/92-mg tablets, both taken once-daily [131].

Three phase 3 randomized controlled trials assessed the efficacy of phentermine/topiramate on weight loss: EQUIP, CONQUER and SEQUEL. In EQUIP, patients with obesity (mean BMI: 42) were randomized to 3.75/23 mg, 15/92 mg, or placebo. Mean weight loss was 5.1% (low-dose), 10.9% (high-dose), and 1.5% (placebo) at 56 weeks [140].

CONQUER randomized 2,487 adults with overweight or obesity and at least two weight-related complications to placebo, 7.5/46 mg, or 15/92 mg. Mean weight loss (1.4 kg, 8.1 kg, and 10.2 kg, respectively) and patients with ≥5% (21%, 62%, and 70%, respectively) and ≥10% (7%, 37%, and 48%, respectively) weight loss at 56 weeks were significantly greater with both phentermine/topiramate dose levels [131].

SEQUEL was a 52-week extension of CONQUER involving 676 subjects [148]. At week 108, mean weight loss from baseline was 1.8%, 9.3%, and 10.5% with placebo, 7.5/46 mg, and 15/92 mg, respectively. Absolute weight loss was 2.1 kg, 9.6 kg, and 10.9 kg. Across all levels, weight loss was greater for subjects in the treatment arms than in the placebo group, with more kilograms lost among the higher dosage. After 108 weeks, 50.3% and 53.9% of patients receiving phentermine/topiramate lost at least 10% of their body weight; 9.2% and 15.3% lost 20% or greater. This compares with 11.5% and 2.2%, respectively, of participants in the placebo group. At week 108, mean waist circumference reductions were -3.6 cm for placebo, -9.8 cm for the 7.5/46-mg dose, and -10.6 cm for the 15/92-mg group. The types of adverse events in SEQUEL were similar to those in CONQUER, but the incidence was markedly lower in the second year. Drop-out due to adverse events by week 108 were 3.1%, 4.5%, and 4.4% in placebo, 7.5/46 and 15/92 treatment arms. Both systolic and diastolic blood pressure decreased from baseline by 3–5 mm Hg at 108 weeks in all three treatment arms [148].

As with phentermine monotherapy, phentermine/topiramate ER is not recommended for patients with cardiovascular disease and is contraindicated in patients with hyperthyroidism or glaucoma or in those taking MAO inhibitors [131]. Topiramate is associated with cognitive and neuropsychiatric side effects. A meta-analysis found that, compared with placebo, adverse effects associated with phentermine/topiramate included dysgeusia or altered sense of taste, paresthesia, dry mouth, disturbance in attention, irritability, hypoesthesia, constipation, and dizziness [149]. Abrupt withdrawal of topiramate increases the risk of seizures, and downward titration should be gradual over four to five days [150].

During the two-year SEQUEL trial, the incidence of reported anxiety-related adverse events increased with dose in placebo (3.1%), 7.5/46-mg (6.5%), and 15/92-mg (9.5%) arms. Most were mild in severity, but three subjects in the 15/92-mg group experienced a severe anxiety-related adverse events and one discontinued treatment [148].

Topiramate is teratogenic, posing a risk for orofacial clefts in infants exposed in utero. Women of childbearing age prescribed any topiramate formulation should be counseled to use effective contraception [124].

Naltrexone/Bupropion ER (Contrave)

Bupropion is a norepinephrine and dopamine reuptake inhibitor with FDA-approval for depression and smoking cessation and is the antidepressant least likely to induce weight gain [131]. Bupropion stimulates hypothalamic POMC neurons, releasingα-MSH (which bind MC4R), decreasing food intake, and increasing energy expenditure. Whenα-MSH is released, POMC neurons also releaseβ-endorphin, a μ-opioid receptor (MOR) ligand, which inhibits further release ofα-MSH by activating a negative feedback loop. Naltrexone, an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorder, blocks theβ-endorphin-mediated negative feedback; the subsequent increase in POMC activity may underlie the weight loss effects of naltrexone/bupropion (Contrave) [115].

Each naltrexone/bupropion tablet contains naltrexone 8 mg plus bupropion 90 mg. The target maintenance dose of 4 tablets daily (naltrexone 32 mg/bupropion 360 mg) daily is shortened with the prolonged-release formulation (NB32). The initial dose is 1 tablet daily, increased stepwise to the target of 2 tablets twice daily. Typical weight loss seen in practice is around 5% to 6% with NB32s [131].

The Contrave Obesity Trials (COR) program evaluated NB32 versus placebo over 56 weeks in patients with obesity or overweight and weight-related complication(s) (COR-I, COR-II, and COR-BMOD) and in patients with obesity and type 2 diabetes (COR-DM). Mean weight loss with NB32 compared with placebo in COR-I (6.1% vs 1.3%), COR-II (6.4% vs 1.2%), COR-BMOD (9.3% vs 5.1%), and COR-DM (5.0% vs 1.8%) showed an average 4.35% weight loss advantage over placebo [139].

Common adverse effects of NB32 include nausea (30%), headache (14%), and constipation (15%), without significant differences in depression or suicidality events, insomnia, dizziness, or dry mouth between treatment and placebo groups [131]. NB32 has been shown effective in reducing HbA1c and is safe among subjects with type 2 diabetes taking oral antidiabetic agents [151]. NB32 can increase blood pressure and pulse despite weight loss [139]. While the cardiovascular safety of NB32 was investigated in the LIGHT trial, it was terminated prematurely after the study sponsor publicly released confidential favorable interim results after only 25% of expected vascular events had accrued, making it difficult to interpret the cardiovascular safety of this combination drug [131,139].

Contraindications include pregnancy, uncontrolled hypertension, seizure disorder, eating disorder, severe hepatic dysfunction, and concurrent administration of MAO inhibitors [131]. Naltrexone/bupropion is contraindicated in any patient prescribed opioids for pain control and in any patient receiving medication therapy for alcohol or opioid use disorder.

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs)

Endogenous GLP-1 has a very short half-life due to rapid enzymatic degradation by dipeptidyl peptidase-4 (DPP-4). Synthetic analogs modify the GLP-1 structure to resist DPP-4 by amino acid substitutions in the protein structure or by attachment to large proteins such as albumin or immunoglobulin [147]. Liraglutide shares a 97% amino acid sequence similarity with human GLP-1, while semaglutide has a 94% similarity. Compared with liraglutide, the substantially longer half-life and greater weight loss efficacy of semaglutide may involve differences in the attached fatty acids [139].

Liraglutide and semaglutide are used subcutaneously once-daily and once-weekly, respectively. Liraglutide was approved for type 2 diabetes in 2010 at a dosage of 1.8 mg daily. Subsequently, liraglutide became the first GLP-1 RA approved as antiobesity medication in 2014, and in 2020, its approval was expanded to include adolescents (12 years of age or older) at a dosage of 3.0 mg/day [147]. Liraglutide acts centrally on the arcuate nucleus in the hypothalamus to suppress appetite and potentiate satiety [151].

The SCALE Obesity and Prediabetes and SCALE Diabetes were both 56-week randomized controlled trials examining the effect of daily liraglutide 3.0 mg vs placebo on normoglycemia, prediabetes, and diabetes. Both trials demonstrated significantly greater weight loss with liraglutide. In SCALE Obesity and Prediabetes, weight loss was 8.0% with liraglutide vs 2.6% with placebo; in SCALE Diabetes, weight loss was 6.0% with liraglutide vs 2.0% with placebo. In the former trial, more participants in the liraglutide group achieved weight loss of ≥5% (63.2 vs 27.1%), ≥10% (33.1 vs 10.6%), and ≥15% (14.4 vs 3.5%) [131].

Gastrointestinal adverse effects are common, including nausea (40%), diarrhea (20%), constipation (20%), and vomiting (16%), and were the most common reason for liraglutide drop-out (6.4% vs 0.7% in the placebo group). Potentially serious adverse effects include gallbladder disease (2.5%) and pancreatitis (0.4%) [131]. A 2023 analysis of data including more than 5,000 patients receiving pharmacotherapy for obesity compared the incidence of adverse events associated with GLP-1 RAs with bupropion-naltrexone. Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (hazard ratio: 9.09), bowel obstruction (hazard ratio: 4.22), and gastroparesis (hazard ratio: 3.67) but not biliary disease [152].

Liraglutide is initiated at 0.6 mg daily for one week, with weekly increases in dose (by increments of 0.6 mg) to the recommended 3.0 mg dose [131]. Semaglutide was initially approved for the treatment of type 2 diabetes at a dosage of 1.0 mg weekly in 2017 and at 2.0 mg weekly in 2022. It was subsequently approved at a dosage of 2.4 mg per week for chronic management of obesity in 2021 [147].

Semaglutide directly accesses the hypothalamus, brainstem, and septal nucleus and also induces activation in secondary brain areas without direct GLP-1R interaction, thus having direct and indirect effects on neutral pathways involved in homeostatic (appetite, hunger, satiety) and hedonic (food preference, cravings, control of eating) aspects of food intake and reward-related eating behaviors. Conversely, only a very small percentage of weight loss is explained by delayed gastric emptying and gastrointestinal side effects [151].

The STEP clinical trials program evaluated semaglutide 2.4 mg in patients with obesity or overweight/weight-related complication(s); patients with type 2 diabetes were excluded [30]. At 68 weeks, semaglutide led to greater mean weight loss (14.9%) compared with placebo (2.4%); further, more patients in the semaglutide group experienced weight loss of ≥10% (69.1%), ≥15% (50.5%), and ≥20% (32.0%) than those in the placebo group (12.0%, 4.9%, and 1.7%, respectively).

In an extension of this study, patients in both the treatment and control arms were engaged in intensive behavioral therapy. The therapy consisted of a reduced-calorie diet (1,000–1,200 calories/day for the first seven weeks, followed by 1,200–1,800 calories/day for the remaining study period), 200 minutes exercise per week, and 30 individual therapy sessions with a registered dietitian. The mean weight loss was 16.0% with semaglutide/intense behavioral therapy, compared with 5.7% with placebo and intense behavioral therapy. The authors concluded that intense behavioral therapy plus eight-week low-calorie diet ultimately may not confer significant weight-loss advantages beyond those achieved with semaglutide and less-intensive lifestyle interventions (i.e., 18 behavioral counseling sessions over 68 weeks) [30].

Another extension of the study, referred to as STEP 4, focused on weight-loss maintenance. All patients were initiated on semaglutide and, at week 20, were randomized to either semaglutide continuation or placebo for the remaining 48 weeks (i.e., weeks 20–68). The semaglutide continuation group further lost 8% of weight, for a total 17% weight loss. The placebo group gained 7% of weight during the same period, for a total 5% weight loss.

STEP 5 also examined the durability of weight reduction over two years. At week 104, mean weight loss from baseline was 15.2% with semaglutide compared with 2.6% with placebo (treatment difference: 12.6%).

Finally, STEP 8 was a head-to-head comparison of semaglutide 2.4 mg per week and liraglutide 3.0 mg per day over 68 weeks. Mean weight loss was 6.4% with liraglutide and 15.8% with semaglutide, a 9.4% advantage over liraglutide. While gastrointestinal adverse events were similarly common with semaglutide (84.1%) and liraglutide (82.7%), the drop-out rate due to adverse events was significantly higher with liraglutide than semaglutide (12.6% vs 3.5%) [140].

As of 2023, oral semaglutide is the only oral GLP-1 RA approved for the treatment of type 2 diabetes, at a dosage of 14 mg per day (Rybelsus). Higher doses are being investigated for weight effects in obesity without type 2 diabetes in the OASIS trials [147]. The phase 3 OASIS 1 trial assessed oral, once-daily semaglutide 50 mg in 667 adults with obesity without type 2 diabetes. After 68 weeks, participants on semaglutide had greater mean weight loss (15.1% vs 2.4%), weight loss ≥10% (69% vs 12%), ≥15% (54% vs 6%), and ≥20% (34% vs 3%) compared with placebo. Adverse effects (mostly mild-to-moderate gastrointestinal symptoms) occurred in 80% on semaglutide and 46% on placebo. These outcomes mirror those of semaglutide 2.4 mg subcutaneous [153]. Phase 3 trials have completed, and submission for FDA approval is expected in 2024. Of note, there are currently no registered clinical trials comparing oral with subcutaneous semaglutide for obesity [92].

The liraglutide, semaglutide, and tirzepatide labels carry a boxed warning regarding the risk of thyroid C-cell tumors. All three antiobesity medications are known to cause dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in rodents [20,137]. It is unknown whether semaglutide for obesity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. However, semaglutide for obesity is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2) [20,137]. All patients should be counseled regarding the potential risk of MTC and symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

In addition, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists [20,137]. These agents have not been studied in patients with a history of pancreatitis; if used as an antidiabetic agent, clinicians should consider an alternate option in such patients.

Data are lacking on use in pregnant women. However, reproduction studies in animals have shown teratogenic effects. There is no published research linking semaglutide to decreased oral contraceptive efficacy. However, any medication associated with delayed gastric emptying could theoretically impact the absorption of oral contraceptive agents.

A meta-analysis of treatment with GLP-1 RAs found liraglutide or dulaglutide associated with increased risk for gallbladder or biliary diseases; subcutaneous semaglutide and exenatide associated with non-significant increased risk; and higher-dose subcutaneous semaglutide associated with increased gallbladder or biliary diseases. Oral semaglutide, lixisenatide, and albiglutide are not associated with these increased risks [154].

GLP-1 RAs may be associated with increased risk of gallbladder or biliary diseases because GLP-1 inhibits gallbladder motility and delays gallbladder emptying by suppressing cholecystokinin secretion. The risk of gallbladder or biliary diseases was higher in trials for weight loss than diabetes control, which may relate to the greater weight loss, GLP-1 RA dose, or treatment duration [154]. When assessing potential risk to patients, prescribers should consider the denominator for essential context, when possible. The overall absolute risk increase, an additional 27 cases per 10,000 persons treated per year, was small and should be weighed against the demonstrated benefits of obesity treatment with GLP-1 RAs [154].

Tirzepatide

Tirzepatide was approved for type 2 diabetes treatment by the FDA (as Mounjaro) and the European Medicines Agency in 2022 [147]. In 2023, the FDA approved the agent for chronic weight management [155].

Tirzepatide acts as a dual incretin agonist of GLP-1R and glucose-dependent insulinotropic polypeptide (GIP) receptor and is dubbed the "twincretin" [135]. Tirzepatide has five-fold greater potency at GIPR than GLP-1R [132].

GIP was the first incretin hormone identified, but its therapeutic potential was disregarded because chronic hyperglycemia in type 2 diabetes down-regulates GIPR expression inβ-cells, blunting response to GIP. Normalizing blood glucose can restore GIPR sensitivity to GIP [139,147]. With a GIP/GLP-1 receptor agonist, GLP-1 quells the potential glucagon-stimulatory effects of GIP and (re)sensitizesβ-cells to GIP's incretin effects, while potentially enhancing GIP's beneficial effects on weight regulation mechanisms [147].

GIPR agonism may have effects on adipocytes that include increasing lipoprotein lipase, promoting lipogenesis, enhancing fatty acid and glucose uptake, and inhibiting lipolysis mediated by glucagon and adrenergic receptors [139]. However, the relative contributions of GLP-1R vs GIPR agonist effects to weight loss have yet to be clearly defined [156].

SURPASS-1 compared tirzepatide (5 mg, 10 mg, or 15 mg) to placebo for 40 weeks, finding significant mean reductions in hemoglobin A1C (-1.87%, -1.89%, -2.07%) and body weight (- 7.9%, -9.3%, -11.0%) for all tirzepatide doses versus placebo [131]. SURPASS-2 compared tirzepatide (5 mg, 10 mg, or 15 mg) with semaglutide 1.0 mg weekly, finding more effective and dose-dependent reductions in body weight, blood pressure, and hemoglobin A1C with tirzepatide [131]. (Note that semaglutide 1.0 mg is a subtherapeutic dose for weight-loss efficacy.)

SURMOUNT-2 randomized 1,514 adults to tirzepatide or placebo. At week 72, mean weight loss with tirzepatide 10 mg or 15 mg or placebo was 12.8%, 14.7%, and 3.2%, respectively. This translated to mean differences vs placebo of 9.6% and 11.6% for 10 mg and 15 mg. More participants had weight loss ≥5% with tirzepatide (79% to 83%) than placebo (32%). The most frequent adverse effects with tirzepatide were gastrointestinal-related, including nausea, diarrhea, and vomiting, mostly mild to moderate in severity, and few led to drop-out (<5%). Serious adverse events were reported by 7% of participants overall [157].

In the phase 3 SURMOUNT-1 trial, 2,539 patients with obesity without type 2 diabetes were randomized to weekly tirzepatide (5 mg, 10 mg, or 15 mg) or placebo [133]. Mean weight loss at week 72 was unprecedented (Table 7) [131]. Notably, 50% and 57% of participants in the 10- and 15-mg groups had weight loss ≥20% [131]. For the first time ever, weight loss with a medication approached levels that had only been possible with bariatric surgery.

Table 7: SURMOUNT-1 WEIGHT-LOSS OUTCOMES AT 72 WEEKS

Weight Loss Parameter

Tirzepatide

Placebo

5 mg

10 mg

15 mg

Mean weight loss

15.0%

19.5%

20.9%

3.1%

≥5% weight loss

85.1%

88.9%

90.9%

34.5%

≥10% weight loss

68.5%

78.1%

83.5%

18.8%

≥15% weight loss

48.0%

66.6%

70.6%

8.8%

≥20% weight loss

30.0%

50.1%

56.7%

3.1%

≥25% weight loss

15.3%

32.3%

36.2%

1.5%

Mean reduction in waist circumference

14.0 cm

17.7 cm

18.5 cm

4.0 cm

Source: [133]

Drop-out from adverse effects was 4.3%, 7.1%, and 6.2% with 5 mg, 10 mg, and 15 mg tirzepatide, respectively, and 2.6% with placebo. The incidence of adverse effects was similar in 10- and 15-mg groups, while the proportion of ≥10%, ≥15%, and ≥20% weight-loss was higher with 15 mg. This suggests the 15-mg dose may confer additional benefits in some patients without added safety concerns [133].

Participants treated with tirzepatide had a percent reduction in fat mass approximately three times greater than the reduction in lean mass, resulting in an overall improvement in body composition. The ratio of fat-mass loss to lean-mass loss is similar to lifestyle and surgical treatments for obesity [133].

Nearly all participants (>95%) with prediabetes initiated on tirzepatide converted to normoglycemia by 72 weeks (compared with 62% with placebo plus lifestyle changes). These improvements may translate to reduced risk of cardiovascular disease, chronic kidney disease, NAFLD, and type 2 diabetes, among other outcomes. Studies of this are still in progress [133].

The safety profile of tirzepatide was consistent with previous findings in the SURPASS trials in patients with type 2 diabetes and similar to other incretin-based therapies for the treatment of obesity. Cholecystitis was observed more frequently with tirzepatide, but the low incidence (≤0.6%) made causal conclusions difficult. Gallbladder-related events have been reported to increase in persons with considerable weight reduction and are also observed with other obesity therapies, such as bariatric surgery and treatment with GLP-1 receptor agonists [133].

Meta-analyses have variously examined the effectiveness and safety of tirzepatide compared with semaglutide in obesity. Head-to-head comparative trials have not been conducted, so indirect comparisons were used. One analysis found greater weight loss with tirzepatide 10 mg and 15 mg than semaglutide 2.4 mg [158]. Another found no significant difference from semaglutide in gastrointestinal adverse effects [159]. Together, these trials show promise for tirzepatide as an effective and safe medication for both weight reduction and glycemic control in patients with obesity with or without type 2 diabetes. Typical adverse effects are similar to GLP-1 agonists and include nausea, vomiting, and diarrhea. No clinically significant hypoglycemia was reported in any trial [131].

GLP-1 RAs provide substantial benefits in glycemic control and weight loss while improving health-related quality of life among individuals with type 2 diabetes. GLP-1 RAs have also been shown to significantly decrease the risk of cardiovascular and all-cause mortality in type 2 diabetes, producing a significant reduction in the risk for non-fatal myocardial infarction and non-fatal stroke. However, their impact on heart failure-related outcomes is nil [160].

Compared with semaglutide in subjects with type 2 diabetes, tirzepatide produced significantly more improvements in total insulin secretion and insulin sensitivity, reflecting a significant improvement in pancreaticβ-cell function. Similar effects were also documented in another trial comparing tirzepatide with the GLP-1 RA dulaglutide, suggesting that dual receptor agonism might be responsible for improving insulin sensitivity, especially since the observed effect was only partially attributable to weight loss [160].

The question that inevitably arises is whether tirzepatide is more efficacious and equally safe compared with GLP-1 RAs. When tirzepatide was compared with GLP-1 RAs, it was not associated with a significant increase in the odds of nausea, vomiting, or diarrhea, except for tirzepatide 10 mg, which correlated with 51% greater odds for diarrhea compared with GLP-1 RA treatment. Tirzepatide use in subjects with type 2 diabetes did not significantly impact the incidence of any serious adverse effects compared with placebo, basal insulin, or GLP-1 RAs [160].

The cardiovascular safety of tirzepatide in type 2 diabetes was demonstrated in a meta-analysis of seven trials and 7,215 subjects randomized to tirzepatide, placebo, or an active comparator. Tirzepatide was associated with a non-significant decrease in the risk for major adverse cardiovascular events (e.g., cardiovascular death, myocardial infarction, stroke, hospitalized unstable angina) and all-cause death [161].

Current evidence suggests that tirzepatide might be more efficacious than GLP-1 RAs in terms of improvements in glycemia, body weight,β-cell function, and insulin sensitivity. Tirzepatide seems at least equally safe as GLP-1 RAs by not increasing the odds for serious adverse events [160].

Results of the ongoing cardiovascular outcome trial (SURPASS-CVOT) are awaited to answer whether tirzepatide exerts cardioprotective effects similar to that observed with GLP-1 RAs. In this trial, tirzepatide is compared with dulaglutide on major cardiovascular events in patients with type 2 diabetes and increased cardiovascular risk. Because dulaglutide has a confirmed cardioprotective effect, this head-to-head study will be particularly informative [160]. The study is expected to conclude in late 2024.

Tirzepatide is known to reduce the efficacy of oral contraceptive medications due to delayed gastric emptying. This delay is largest after the first dose, so patients should switch from oral to nonoral contraceptives for the first four weeks when tirzepatide is initiated [162]. Patients should be counseled regarding the risk of unintended pregnancy and the necessity of other contraceptive methods.

INVESTIGATIONAL ANTIOBESITY MEDICATIONS IN CLINICAL TRIALS

Given the heterogeneity and complex pathogenesis of obesity, combination therapy with multiple pathophysiologic targets is a logical approach to increasing weight-loss response with pharmacotherapy [163]. Peptide engineering, exemplified by tirzepatide, allows the development of multi-receptor agonists [139]. Other antiobesity medications in development include oral GLP-1R mono-agonists. Except where noted, the following agents are administered subcutaneously once weekly.

Cagrilintide

Amylin, a pancreatic hormone released with insulin in response to nutrient intake, acts on:

- Appetitive/energy-regulating hypothalamic neurons impacting food intake

- Dopaminergic neurons in the ventral tegmental area impacting reward and motivation

- Chemoreceptive neurons in the brainstem nucleus tractus solitarius

Pramlintide, the first amylin analog, was approved in 2005 as an adjunct to insulin for type 1 and type 2 diabetes and promotes weight loss in patients with diabetes by substituting three amino acids of human amylin with proline [139,147]. Cagrilintide is an emerging agent that overcomes pramlintide's short half-life and frequent administration as a long-acting amylin analog. Cagrilintide is being developed in combination with semaglutide (CagriSema) to achieve sustained weight loss in persons with obesity. Both cagrilintide and CagriSema have shown promising weight loss and safety in clinical trials that supports their further development [163].

Among 706 individuals with obesity after 26 weeks, mean weight loss with cagrilintide 4.5 mg (10.6%) and 2.4 mg (9.7%) was greater than with liraglutide 3.0 mg (8.4%) and placebo (2.8%). Side effects of cagrilintide include nausea, diarrhea, constipation, fatigue, and injection-site reactions [147].

CagriSema combines cagrilintide with semaglutide to produce an additive effect on appetite reduction and weight loss [163]. In a trial of adults with obesity, mean weight loss at 20 weeks was 17.1% with CagriSema, compared with 9.8% with semaglutide 2.4 mg [147]. Among 92 adults with type 2 diabetes and BMI ≥27 randomized to once-weekly CagriSema, semaglutide, or cagrilintide (all escalated to 2.4 mg), mean weight loss at week 32 with CagriSema (15.6%) was significantly greater than semaglutide (5.1%) or cagrilintide (8.1%). Mild or moderate gastrointestinal adverse effects were common and comparable. No moderate or greater hypoglycemia was reported [164].

Retatrutide (LY3437943)

A triple agonist may provide even more effective glycemic control and weight loss compared to single or dual receptor agonists. Retatrutide is a triple agonist at GCGR, GIPR, and GLP-1R [139]. A phase 2 dose-response study evaluated retatrutide in 338 adults with obesity [165]. At 48 weeks retatrutide 1 mg, 4 mg, 8 mg, and 12 mg led to 8.7%, 17.1%, 22.8%, and 24.2% mean weight loss, compared with a 2.1% reduction with placebo. Among those who received 8 mg or 12 mg retatrutide, 91% and 93% experienced weight loss ≥10% and 75% and 83% experienced weight loss ≥15% (compared with 9% and 2% among those receiving placebo).

Dose-related mild-to-moderate nausea, diarrhea, vomiting, and constipation were the most common retatrutide adverse effects, partially mitigated with a lower starting dose (2 mg vs 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter [165,166].

Survodutide (BI 456906)

Survodutide is a dual GLP-1 and glucagon receptor (GCGR) agonist developed for obesity and NASH treatment. As glucagon release from pancreatic a-cells increases blood glucose, antagonism was initially pursued as a type 2 diabetes treatment. More recent studies have localized GCGR to adipose tissue, brain, and liver and have shown that GCGR activation increased energy expenditure via thermogenesis [139,147]. An agent combining selectively increased energy expenditure with appetite suppression is a reasonable strategy for effective weight loss or weight maintenance [139]. Hepatocytes express GCGR, but not GLP-1R, and drugs like survodutide that target GCGR may have greater benefit in improving liver fibrosis or NASH than GLP-1RAs [139].

In Phase 1 studies of survodutide, maximum placebo-corrected weight loss was 13.8% after 16 weeks, including 12.37% in Japanese men with no unexpected tolerability concerns [167,168]. Common survodutide adverse effects included nausea, dyspepsia, vomiting, diarrhea, abdominal pain, and headache [167].

AMG-133

Co-agonism is not the only possible strategy for a unimolecular antiobesity medication. AMG-133 is a GCGR antagonist and GLP-1R agonist [25]. In one study, individuals with obesity averaged 14.3% weight loss after 12 weeks on higher-dose AMG-133. AMG-133 was associated with adverse gastrointestinal effects, but its once-monthly subcutaneous use may be advantageous to weekly tirzepatide [141]. If replicated, the rapidity and extent of this weight loss provokes questions regarding the drug's mode of action and the role of GIP and GLP-1 in physiologic weight regulation [25]. As of 2023, peer-reviewed publication of the full trial results is awaited [141].

Bimagrumab (BYM338)

Bimagrumab is a human monoclonal antibody that binds to the activin type II receptor (ActRII). Antibody blockade of ActRII signaling stimulates skeletal muscle growth, and previous studies suggest that ActRII inhibition with bimagrumab also promotes excess adipose tissue loss and improves insulin resistance [169]. A single intravenous dose of bimagrumab increased lean mass, reduced total body fat mass (by 7.9%), and ameliorated insulin sensitivity in insulin-resistant individuals during the 10-week study [92].

A phase 2 trial randomized adults with obesity and type 2 diabetes to IV bimagrumab (10 mg/kg up to 1,200 mg) or placebo every 4 weeks for 48 weeks. Body composition changes used dual x-ray absorptiometry (DEXA) and magnetic resonance imaging. At week 48, mean changes with bimagrumab vs placebo were noted in fat mass (-20.5% vs -0.5%), lean mass (3.6% vs -0.8%), waist circumference (-9.0 cm vs 0.5 cm), and body weight (-6.5% vs - 0.8%) [169]. Muscle spasms and mild diarrhea were the most common adverse effects with bimagrumab. Further studies on the efficacy and safety of bimagrumab are ongoing [92].

Orforglipron (LY3502970)

Orforglipron, an oral once-daily nonpeptide GLP-1 RA, was evaluated in 272 adults randomized to orforglipron (12 mg, 24 mg, 36 mg, or 45 mg) or placebo for 36 weeks [170]. Mean weight loss with orforglipron was 9.4% to 14.7%, compared with 2.3% with placebo. In those taking orforglipron, weight loss ≥10% was noted in 46% to 75%, compared with 9% of patients taking placebo. Orforglipron led to improvement in all prespecified weight-related and cardiometabolic endpoints [170].

The most common orforglipron adverse effects were mild-to-moderate gastrointestinal events, primarily during dose escalation, and led to discontinuation of orforglipron in 10% to 17% of participants across dose cohorts. The safety profile was consistent with GLP-1RAs [170]. This trial mirrored the safety and weight reduction findings of a smaller oral orforglipron trial in patients with type 2 diabetes [171].

Danuglipron

Danuglipron is another oral GLP-1 RA under development for type 2 diabetes and obesity and is taken twice-daily with food [147]. A phase 2b trial randomized 411 adults with type 2 diabetes to placebo or danuglipron. At week 16, mean weight loss difference vs placebo was –2.04 kg and –4.17 kg with danuglipron 80 mg and 120 mg, respectively. The most common adverse effects were nausea, diarrhea, and vomiting. Only 77% of patients completed the trial [172]. In a 12-week, dose-escalation study of adults with type 2 diabetes, discontinuation from danuglipron due to adverse effects ranged from 27.3% to 72.7% [173]. In December 2023, Pfizer halted its trial of twice-daily danuglipron in response to high drop-out rates related to unacceptable side effects; the once-daily trial continued [309].

Ecnoglutide

Ecnoglutide is a novel, long-acting GLP-1 analog being explored for patients with diabetes and obesity. In laboratory tests, ecnoglutide was effective at stimulating the production of cAMP, a key signaling molecule involved in glucose control and body weight regulation. In a phase 1 clinical trial, ecnoglutide was found safe and well-tolerated, with pharmacokinetic properties that support once-weekly subcutaneous injections [174].

In a phase 2 trial of 206 participants with obesity and diabetes, weekly ecnoglutide 1.2 mg, 1.8 mg, or 2.4 mg led to weight loss of 11.5%, 11.2%, and 14.7%, respectively, vs 8.8% with daily liraglutide 3.0 mg [175]. A phase 3 dose comparison trial was initiated in early 2023 [176].

Mazdutide

Mazdutide is a novel once-weekly GLP-1 and glucagon receptor dual agonist. As an oxyntomodulin analogue, mazdutide may also increase energy expenditure and improve hepatic fat metabolism through the activation of glucagon receptor. In a phase 2 trial in China, mazdutide 9 mg led to a mean weight loss of 15.4%, a weight change vs placebo of -14.7 kg, and weight loss ≥20% in 21.7% of participants (vs 0% with placebo) after 24 weeks [177].

APH-012

APHD-012 is a novel approach to address metabolic disease through the delivery of dextrose to the lower small intestines via an oral bead formulation. In the 1960s, researchers found that glucose delivered directly distal to the jejunum better stimulated insulin release and secretion of GLP-1 and GIP compared with glucose delivered higher up the tract. This agent builds on such research [178].

As of 2023, a Phase 2 trial involving 150 adult obese participants with or without endocrine/metabolic conditions is underway [179].

ARD-101

ARD-101 is a potential bitter taste receptor (TAS2R) agonist that stimulates the release of the body's natural CCK, but primarily targets vagal nerve afferents located near the gut; this in turn induces positive effects on hunger, metabolism, and inflammation through gut-brain signaling. Three phase 2 trials were initiated in 2022 to assess efficacy and safety in adults with general obesity, adults with refractory post-bariatric weight gain, and those with Prader-Willi Syndrome, a rare genetic disorder characterized by persistent hyperphagia [180].

In the general obesity trial, patients treated with ARD-101 experienced a 2.51-fold greater reduction in hunger rating vs placebo [181]. Nausea or diarrhea common among available GLP-1 drugs were not noted in the ARD-101 group.

HU6

HU6 has demonstrated inhibition of phosphodiesterase 9A in mice linked to reduced body (and myocardial) fat and stimulated mitochondrial activity, without altered activity levels or food intake [182]. In this trial, positive weight loss effects were exclusively observed in male and ovariectomized female mice, suggesting a strong sexual dimorphism in treatment response. A phase 2 trial initiated in 2023 enrolled 250 participants with type 2 diabetes at risk for NASH and will compare three doses of HU6 on weight loss and hepatic function effects [183].

Nabilone

The endocannabinoid system is involved in the regulation of body weight and metabolism throughout the body. In the CNS, endocannabinoids bind to CB1 receptors in the hypothalamus (which control appetite), gastrointestinal tract, pancreas, and adipose tissue [184]. Elevated endocannabinoid levels can lead to increased hunger and food intake.

However, a meta-analysis of data from the National Epidemiologic Survey on Alcohol and Related Conditions and the National Comorbidity Survey-Replication found a decreased prevalence of obesity among current users of cannabis (≥3 days per week) of 14.3% and 17.2%, respectively [185]. Given this decreased likelihood of obesity in current cannabis users, research has begun to explore how the endocannabinoid system can be manipulated to promote weight loss and improve metabolic health.

Nabilone is an oral synthetic Δ9 –THC analog and partial CB1 agonist approved for the treatment of cancer and HIV cachexia for increasing appetite and body weight. A randomized controlled trial of cannabis-naive adults with obesity is underway to examine safety and feasibility, weight-loss effectiveness, changes in gut microbiome, and metabolic markers [186]. The results are expected in 2024–2025.

NNC9204-1177

NNC9204-1177 is a glucagon/GLP-1 receptor co-agonist that underwent three phase 1 trials. After 12 weeks, mean weight loss was 12.6% at the higher dose level. However, dose-dependent increases in heart rate (5–22 beats per minute) and decrease in reticulocyte count, increased markers of inflammation, hepatic disturbances, and impaired glucose tolerance halted further clinical development [187].

CLINICAL USE OF ANTIOBESITY MEDICATIONS

If permanent weight loss could be achieved solely with behavioral reductions in food intake and increases in energy expenditure, antiobesity medications would not be needed [120]. Unfortunately, this is not commonly the case. Thus, antiobesity medication pharmacotherapy is indicated as an adjunct to caloric restriction and physical activity in adults with obesity or overweight with weight-related complications [131].

Antiobesity medication approvals have been based on efficacy as adjunctive treatment, including 1960s phentermine trials with 1,000 calorie/day diets for both drug and placebo groups; none have been shown to be effective on their own, because such studies have not been conducted [120,131,188]. Patients should be educated that the addition of antiobesity medications to a lifestyle program enhances weight loss, as clinical trials have demonstrated [131]. For example, 224 adults were initiated on sibutramine (discontinued in 2020) and randomized to brief lifestyle counseling or to a comprehensive diet, exercise, and behavior therapy program. At 12 months, mean weight loss with sibutramine plus brief counseling was 4.6% compared with 11.2% among those who received sibutramine plus comprehensive intervention [189].

As of 2023, few professional organizations have independently produced practice recommendations for current antiobesity medication options. In adults for whom antiobesity medications are indicated (per FDA), the 2022 AGA guideline states that long-term pharmacologic therapy is recommended, with multiple effective and safe treatment options that include semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, naltrexone-bupropion ER, phentermine, and diethylpropion [123].

Explicit first-choice recommendations have also been made. Data show that greater weight loss (≥10%) leads to greater clinical improvements in weight-related complications, including greater relative risk reduction for cardiovascular events, improvements in NASH histology, decreased disease activity in inflammatory rheumatic disease, and improvements in osteoarthritis, obstructive sleep apnea, and cancer risk [131].

Given the significantly greater weight loss with semaglutide (15%) than other currently approved antiobesity medications (6% to 10%) and with 69% and 50% of subjects attaining weight loss ≥10% and >15%, respectively, semaglutide 2.4 mg weekly is recommended as the first-line antiobesity medication for obesity management [131]. Weight-loss goals for most individuals with obesity should be at least 10% or more, which is now achievable with current antiobesity medications.

After initiating any antiobesity medication, the weight lost by 12 weeks is considered an indicator of treatment response. If adherence can be ensured and 5% weight loss is not achieved after three months, the drug can be given at an increased dose, combined with another drug, stopped altogether, or replaced with a new drug [135].

Nonetheless, long-term pharmacotherapy is still challenged by some who question whether obesity itself constitutes a disease worthy of chronic drug therapy. Lifelong pharmacologic management of chronic diseases such as hypertension might offer a relevant template for obesity treatment strategies. In these diseases, it is common practice to target multiple mechanisms to achieve optimal disease management. It seems inevitable, and with good precedent, that such a conceptual approach to lowering body weight will eventually prevail [132].

Practical Tips for Success with GLP-1 Agonists

When starting GLP-1 agonists, several strategies can promote success and decrease risk of discontinuation. Strategies to minimize adverse effects include slow dose escalation, counseling on expected adverse effects and their duration, and using a multidisciplinary team approach (including the primary care provider, pharmacists, nurses, and medical assistants) to provide regular follow-up and guidance as patients initiate the medication. It is particularly important to discuss gastrointestinal adverse effects, as patients who are not expecting these adverse effects may prematurely discontinue the medication [131].

Routine follow-up can come in many forms, including virtual visits, phone calls, pharmacist check-ins, or even portal messages at routine intervals. This type of follow-up can increase communication with the patient, normalizing expected adverse effects and allowing tighter dose titration, while also reducing the number of clinical visits a patient has to make, thereby reducing primary care provider burden and overall healthcare costs. Other strategies include a dose escalation period, with one-week dose pause when adverse effects are encountered, which may minimize nausea/vomiting. Gastrointestinal adverse effects may also be reduced by avoiding high-fat foods and focusing on small meals [131].

Demand and Supply Problems

Interest in GLP-1 RAs has expanded beyond clinicians and patients struggling to lose excessive body-fat mass. Formulations of semaglutide approved for type 2 diabetes (Wegovy and Ozempic) have gained attention as celebrities and social media influencers have described taking thee agents to lose weight in short timeframes [190]. Many people have described in the media how taking semaglutide for obesity fundamentally changed their experience of hunger and appetite [191]. Consumer demand has led to widespread supply shortages of both products and concerns that people will associate them with "vanity," not as critical medications for patients with diabetes with or without obesity [190].

Additionally, news reports have commented on the possible misuse of semaglutide and other GLP-1 analogs. The issue is facilitated by the acquisition of medications from rogue websites. Pharmacists have reported forged prescriptions and use for weight loss in patients without diabetes. Social media influencers' semaglutide promotion for weight-loss, and the associated increase in demand, have contributed to an ongoing worldwide shortage of the drug in 2023 [192].

Off-Label Prescribing of Antiobesity Medications

If all antiobesity medications could be prescribed based on individualized patient need without affordability concerns, discussion of off-label use would not be needed. Unfortunately, medication cost and insurance coverage are the primary drivers in selecting antiobesity medications for an individual patient. In a 2018 review of 136 marketplace health insurance plans, only 11% had coverage for antiobesity medications [193]. Medicare excludes drug therapy for obesity, and only 11 state Medicaid programs have full antiobesity medication coverage (California, Kansas, Minnesota, Wisconsin, Michigan, Pennsylvania, Virginia, Delaware, Rhode Island, Connecticut, and New Hampshire); a limited number of other states may offer partial coverage [131]. Even for patients with insurance, cost can be a barrier due to the lack of antiobesity medication coverage under the diagnosis of obesity [124].

In this context, off-label prescribing includes prescribing an antiobesity medication for longer than its labeled duration [194]. Phentermine as a long-term option is obviously attractive given its low cost (Table 8), and there are several considerations to weigh.

Table 8: FDA-APPROVED ANTIOBESITY MEDICATIONS AND RETAIL COST, 2023

Agent

Typical Maintenance Dose

Average Retail Price, 30-Day Supply

Phentermine

8–37.5 mg daily

$11.31

Diethylpropion

75 mg daily

$48.73

Orlistat

60 mg TID (OTC)

120 mg TID (Rx)

~ $45.00 (Alli)

$808.06 (Xenical)

Naltrexone/bupropion ER

16/180 mg BID

$308.00

Phentermine/topiramate ER

7.5–15/46–92 mg daily

$231.07

Liraglutide 3.0 mg

Once daily

$1,064.86

Semaglutide 2.4 mg

Once weekly

$1,576.73

Tirzepatide (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg)

Once weekly

$1,059.87

BID = twice daily, OTC = over the counter, Rx = prescription, TID = three times daily.

Source: [131]

The original 90-day label has not been updated since 1959, despite phentermine approval for long-term treatment of obesity when combined with topiramate as Qsymia [124]. Its short-term indication is in conflict with what is now known about the nature of obesity necessitating long-term treatment [195]. When a patient shows good therapeutic response and tolerability with phentermine, the Endocrine Society states this presents a conundrum for clinicians because it is clear that weight regain will likely occur once the medication is stopped [120].

Phentermine has long been the most commonly prescribed antiobesity medication due in large measure to its low potential for CNS stimulation and abuse, its low price as a generic drug, and clinician familiarity [136]. A large proportion has been for off-label doses and durations to sustain a positive clinical response [195].

Authors of the Endocrine Society practice guideline acknowledged little evidence of any serious side effects with long-term phentermine monotherapy and concluded it was reasonable to prescribe it long-term for patients who:

- Lack serious cardiovascular disease and/or serious psychiatric or substance use disorder

- Have been informed about FDA-approved antiobesity medications shown safe and effective for long-term use while phentermine has not

- Do not show clinically significant increases in pulse or blood pressure

- Show significant weight loss on phentermine

These aspects of care should be documented in the patient's medical record, and the off-label nature of the prescribing documented at each visit [120].

Subsequent to this clinical practice guideline, an observational study of 13,972 adults with obesity, including those with hypertension (21%) and type 2 diabetes (12%), initiated on phentermine found no increase in cardiovascular risk with long-term use up to 36 months versus use 3 months of less [196].

An obesity medicine specialty clinic also examined the abuse liability of phentermine treatment in 269 patients administered validated, structured addiction medicine interviews. No evidence was found of compulsive use, cravings, unsanctioned dose escalation, or withdrawal symptoms on abrupt cessation, including at doses much higher than commonly recommended and after treatment durations of up to 21 years [197].

The AGA and the ASMBS recommend phentermine as a long-term antiobesity medication option. The OMA convened a roundtable discussion of phentermine by expert clinicians, who suggested that, while not required by the prescribing label, prescribers may obtain an electrocardiogram (ECG) before starting phentermine. In addition to finding troubling wave patterns or cardiac dysrhythmias, a baseline ECG helps bring piece-of-mind to patient and clinician. Some clinicians perform ECGs on all patients before any intensive weight loss program or antiobesity medication [198]. In addition, the experts state that phentermine can be combined with GLP-1 RAs or other antidiabetic drug classes for further weight reduction, especially in patients with a high burden of obesity. Phentermine should not be used in patients with active cardiovascular disease nor as first-line antiobesity medication with advanced age or cardiovascular disease risk factors. Patients with a history of methamphetamine use are best treated with DEA unscheduled, non-stimulant antiobesity medications or bariatric procedures [198].

It is important to pick the right drug for the right patient. A patient who tends to skip meals all day and eat large volumes late at night might not be a good match for morning phentermine, which would mainly reduce daytime hunger. If phentermine is prescribed, patients should be advised that they may have trouble sleeping for two to three nights after initiating phentermine [198].

Canagliflozin is an SGLT2 inhibitor approved for type 2 diabetes. In a randomized controlled trial of 335 subjects without type 2 diabetes (mean BMI: 37.3), the weight loss effects of once-daily canagliflozin 300 mg (Cana), phentermine 15 mg (Phen), or combined Cana/Phen were compared after 26 weeks [199]. Mean weight loss with placebo, Cana, Phen, and Cana/Phen was 1.1%, 2.6%, 4.6%, and 8.1%, respectively. Weight loss with Cana/Phen continued through week 26, with no apparent plateau. The Cana/Phen group also had greater improvements in blood pressure and heart rate. This study demonstrated the complementary renal effects with canagliflozin and CNS activity with phentermine on weight loss [199].

In commenting about the cost barrier of phentermine/topiramate ER, some have suggested prescribing phentermine and generic topiramate separately at monotherapy dosages that match Qsymia to lower the cost, noting that topiramate is not approved as an antiobesity medication but has shown benefits against weight regain following bariatric surgery [150].

Low-cost, off-label prescribing has focused on phentermine due to its extensive familiarity to obesity specialists, but diethylpropion also has low cost, comparable benefit and safety as monotherapy, and is likewise endorsed as a long-term antiobesity medication option by the AGA [123].

8. BARIATRIC SURGICAL PROCEDURES AND DEVICES

Bariatric approaches encompass invasive laparoscopic surgical procedures, minimally invasive endoscopic therapies that remodel the stomach using suturing/plication devices or that insert space-occupying devices to reduce gastric volume, and endoscopically placed vagal stimulation devices [125].

As discussed, the hazards of obesity are many, including a shortened life span, type 2 diabetes, cardiovascular disease, some cancers, kidney disease, obstructive sleep apnea, gout, osteoarthritis, and hepatobiliary disease, among others. Weight loss reduces all of these diseases in a dose-related manner—the more weight lost, the better the outcome [4]. Bariatric surgery is the most effective treatment for severe obesity and obesity with metabolic disease. In the majority of appropriately selected cases, substantial weight loss is sustained for years if not decades [200].

The ASMBS, the largest professional organization and recognized authority and resource on metabolic and bariatric surgery, has endorsed six surgical approaches for obesity (Table 9) [201]. None involve devices.

Table 9: ASMBS-ENDORSED SURGICAL APPROACHES

Procedure

Optimally Suited For

Percent Excess Weight Lossa

At 2 years

At 10 years

Roux-en-Y gastric bypass (RYGB)

Higher BMI, GERD, diabetes

55% to 75%

52% to 69%

Sleeve gastrectomy

Metabolic disease

50% to 70%

67% to 71%

Laparoscopic adjustable gastric banding (LAGB)

Lower BMI, no metabolic disease

30% to 50%

38% to 47%

Biliopancreatic diversion with duodenal switch (BPD/DS)

Super-obesity (BMI ≥50), diabetes

63% to 80+%

68%

Single anastomosis duodenal-ileal bypass with sleeve (SADI-S)

Super-obesity

74%

NA

One-anastomosis gastric bypass (OAGB)

Higher BMI, diabetes

68% to 80%

73%

BMI = body mass index, GERD = gastroesophageal reflux disease, NA = not available.

aMean average

Source: [127,135,202,203]

Bariatric operations increased from 158,000 in 2011 to 263,000 in 2021, including sleeve gastrectomy (153,000), Roux-en-Y gastric bypass (RYGB) (56,500), revisional (31,000), biliopancreatic diversion with duodenal switch (BPD/DS) (5,525), gastric balloon (4,100), endoscopic sleeve gastroplasty (ESG) (2,200), one-anastomosis gastric bypass (OAGB) (1,149), and single anastomosis duodenal-ileal bypass with sleeve (SADI-S) (1,025) [201].

RYGB is the prototypical bariatric surgery in use for many decades. Restrictive procedures (e.g., LAGB, vertical banded gastroplasty [VGB]) were widely used in the 1980s and 1990s as simpler alternatives to RYGB with fewer complications [204]. With malabsorption thought necessary for effective weight loss, BPD/DS was introduced as a two-stage procedure, initiated with sleeve gastrectomy. Large weight loss during sleeve gastrectomy led to its stand-alone use after 2008 and progressive replacement of VGB and LAGB [204; 205]. LAGB fell from 56,000 procedures in 2011 to just 1,121 in 2021 [201].

TERMINOLOGY

Some terminology in the bariatric literature differs from or seldom appears in the antiobesity medication literature. This includes [4,119]:

- Metabolic and bariatric surgery (MBS): This is often preferred to the term "bariatric surgery," because these procedures are superior to intensive medical treatment for controlling and inducing remission of type 2 diabetes.

- Obesity-related complications: Replaces the term "weight-related complications," because patients with BMI <30 have not traditionally been considered MBS candidates.

- Pre-operative: The preferred term (rather than baseline) when referring to condition prior to MBS. May be notated with a p prefix (e.g., pBMI, pT2DM).

In discussion of MBS outcomes, those occurring in the 1 to 2 years following the procedure are considered short-term; medium-term outcomes are seen after 3 to 10 years, and those seen more than 10 years after surgery are considered long-term [206].

Percent excess weight loss is a more common measure of impact than percent weight loss. Excess weight is total weight above an ideal reference standard, usually BMI 25. Percent excess BMI loss uses the same concept in units of BMI. For example, in a study of 846 patients (average pBMI: 50.0) treated with RYGB, the outcomes (mean) after one year [207]:

- BMI: 33

- BMI units lost: 17

- Percent excess BMI loss: 68%

- Post-RYGB weight: 204 pounds

- Absolute weight lost: 106 pounds

- Percent weight loss: 34%

- Percent excess weight loss: 72%

Thus, for the same amount of weight loss in the same patients, percent of excess weight loss was about twice that of overall weight loss [127].

PROPOSED MECHANISMS

Considering that similar weight loss via caloric restriction provokes powerful adaptive and counter-regulatory responses (e.g., increased hunger, reduced metabolism), the sustained weight loss effects and diminished adaptive responses after MBS have sought explanation [200]. More recently, the long-term metabolic improvements have attracted investigation.

MBS is traditionally classified as restrictive, malabsorptive, or restrictive plus malabsorptive (e.g., BPD/DS) [208]. Historically, macronutrient malabsorption and restriction were considered necessary for efficacy [200,209]. However, RYGB and sleeve gastrectomy produce large and sustained weight loss despite lower malabsorption. The weight-loss efficacy of both likely involve normal physiological mechanisms affecting energy intake, expenditure, and metabolic regulation, significantly mediated by increased GLP-1 signaling and also by melanocortin signaling pathways, which clearly go beyond mechanical restriction and malabsorption [200].

Bypassing the duodenum via RYGB is thought to uniquely benefit metabolic parameters, independent of weight loss [210]. However, an 18% weight loss with RYGB or caloric restriction showed similar metabolic benefits due to the weight loss itself in patients with obesity and type 2 diabetes [211]. Patients attained similar type 2 diabetes remission rates after RYGB (72%) and sleeve gastrectomy (70%) in a study that established a weight-loss threshold of ≥20% for type 2 diabetes remission [212].

Thus, type 2 diabetes mitigation is dependent on weight loss and appears independent of MBS approach, although the literature is inconsistent and the underlying mechanisms of efficacy remain unclear [209]. Some inconsistency stems from retrospective versus prospective data and short-term versus long-term follow-up.

More broadly, greater clinician and patient acceptance of MBS is believed to hinge on more rigorous evidence of weight loss durability and obesity-related complication amelioration from prospective, long-term data. This includes ≥80% patient follow-up [206,213]. However, the history of MBS shows frequent innovations, technical progress, and implementation of new approaches. The longer the timeframe of patient accrual or follow-up, the greater the odds that the procedure has been modified or replaced [214].

INDICATIONS FOR BARIATRIC SURGERY

The universally applied threshold for bariatric surgery (i.e., BMI >40 or BMI >35 with comorbidities) was set in 1991 by the National Institutes of Health. With significant advances in obesity science and safer, more effective bariatric approaches supported by three decades of evidence, this indication no longer reflects best practice and was replaced with new practice guidelines by the ASMBS in 2022 [126]. According to the ASMBS, MBS is recommended for [126]:

- Patients with BMI ≥35, regardless of presence, absence, or severity of obesity-related complication

- Patients with type 2 diabetes and BMI ≥30

Evidence Based Practice Recommendation

The American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders assert that metabolic and bariatric surgery is recommended for individuals with a BMI >35 kg/m^2, regardless of presence, absence, or severity of comorbidities.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834364

Last Accessed: November 28, 2023

Level of Evidence: Expert Opinion/Consensus Statement

MBS should also be considered in patients with BMI 30–35 who do not achieve substantial or durable weight loss or obesity-related complication improvement nonsurgically [126].

The BMI thresholds should be adjusted in Asian populations [126]. A BMI >25 suggests clinical obesity in these patients, and those with BMI >27.5 should be offered MBS.

The ABMS asserts that there is no upper age limit to MBS [126]. Older patients who could benefit from MBS should be considered after careful assessment of comorbidities and frailty.

MBS is also an effective treatment of clinically severe obesity in patients who need other specialty surgery, such as joint arthroplasty, abdominal wall hernia repair, or organ transplantation. Severe obesity is a chronic disease requiring long-term management after primary MBS, which may include revisional surgery or adjuvant antiobesity medication to achieve or sustain desired treatment effects [126].

PRE- AND POSTPROCEDURE RECOMMENDATIONS

Although safety is a concern with MBS, perioperative mortality rates (0.03% to 0.2%) have substantially improved from the early 2000s [215]. Studies consistently report that surgeon and surgical center experience are predictors of safety [4].

The OMA recommends that MBS procedures be performed at surgery centers with accreditation for quality standardization, such as the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) administered by the ASMBS and the American College of Surgeons [127]. A multidisciplinary team can help manage the patient's modifiable risk factors to reduce perioperative complications and improve long-term outcomes [126].

Preprocedure Evaluation and Medical Clearance for Bariatric Procedures

Before undergoing bariatric surgery, a preoperative medical evaluation is optimally conducted by an obesity specialist. A bariatric surgery specialist consultation should also be performed, as well as cardiology, pulmonary, gastroenterology, and/or other specialists, as clinically indicated [127].

Potential MBS candidates should undergo a formal mental health evaluation by a qualified licensed professional to assess environmental, familial, and behavioral factors, including trauma history, suicide risk, coping mechanisms, and underlying eating, mood, and substance use disorders. Patients should receive education regarding the potential for increased suicide risk and addiction postprocedure. After RYGB and sleeve gastrectomy, high-risk groups should stop drinking due to postoperative impaired alcohol metabolism and increased risk of alcohol use disorder [125,127].

Patients should undergo nutritional assessments by registered dietitians with expertise in MBS, who can help obtain a comprehensive weight history, identify maladaptive eating behaviors or patterns, and correct any micronutrient deficiencies prior to surgery. A registered dietitian can also provide preoperative nutrition education and prepare the patient for expected dietary changes after MBS, which include an understanding that even with bariatric surgery, lifelong adherence to healthful nutrition, physical activity, and favorable behavior modification facilitates the best chance for long-term success [127].

Other preoperative evaluations include proactive medication adjustment. While individual instructions will vary depending on the individual patient, several weeks prior to the bariatric surgery, the medical and surgical team often work together in management of medications that may increase surgical risk, such as increased bleeding risk with antiplatelet therapies (e.g., clopidogrel), anticoagulants (e.g., warfarin), and increased thrombotic risk with sex hormone pharmacotherapies (e.g., estrogens). All herbal and over-the-counter supplements should be discontinued [127].

NSAIDs should be avoided before and after MBS, because they are implicated in the development of anastomotic ulcerations, perforations, and leaks. Alternative pain medication should be identified before the surgery [125].

Tobacco use, and cigarette smoking in particular, must be avoided at all times by all patients. Patients who smoke cigarettes should stop as early as possible, preferably one year but at the very least six weeks before MBS. In addition, tobacco use must be avoided post-MBS given the increased risk of poor wound healing, anastomotic ulcer, and overall impaired health. Structured intensive smoking cessation programs are preferable to general advice and should be implemented [125].

Postoperative Nutritional Considerations

Nutrient deficiencies are common after bariatric surgery and are carefully monitored for optimal patient health and recovery. Lower levels of vitamin D are common in patients with obesity and may worsen postoperatively without adequate supplementation. High-quality bariatric-specific multivitamin/mineral/ trace element supplements are routinely recommended after MBS, with vitamin supplements often containing higher amounts of vitamin B12, iron, vitamin C (to assist with iron absorption), vitamin D, and calcium [127]. Registered dietitians can also assist postoperative patients experiencing food intolerances, malabsorption issues, micronutrient deficiencies, or weight regain [126].

Procedure Selection

Selection should be based on individualized goals of therapy (e.g., weight-loss target, improvements in specific obesity-related complication), available local/regional expertise (e.g., obesity specialists, bariatric surgeon, institution), patient preferences, and personalized risk stratification that prioritizes safety. Laparoscopic should be preferred over open procedures [125]. The decision about MBS approach should be driven primarily by informed patient preferences, but the ultimate decision for surgical readiness will be determined by the surgeon [126,215].

Other Issues

Preoperative Predictors of Outcome

Because weight loss after surgery is heterogeneous and not entirely predictable, particularly in the long-term, there is considerable interest in identifying individuals more or less likely to benefit from MBS based on preoperative factors [208]. Although age, gender, anthropometrics, obesity-related complications, eating behavior, genetic background, circulating biomarkers (e.g., microRNAs, metabolites, hormones), and psychological and socioeconomic factors could potentially impact post-MBS weight loss, none have shown predictive utility [216].

A study of 2,022 patients with average three-year weight loss of 31% with RYGB and 16% with LAGB concluded that preoperative factors have limited predictive value for a patient's chance of a successful weight loss outcome following MBS [217]. However, surgical volume at the clinic (more than 100 per year), surgeon experience, surgery in a tertiary care center, female sex, age 55 years or older, and respiratory status all correlated with lower complications risk [208].

As genetic variants in the leptin-melanocortin pathway are associated with obesity, their effect on long-term bariatric outcomes was examined. The weight regain pattern in these patients after RYGB and sleeve gastrectomy highlights the need for proactive lifelong management to prevent relapse and careful expectation management [218]. Additionally, genotyping patients with significant weight regain after RYGB could help individualize weight-loss interventions to improve weight maintenance after surgery [219].

Preoperative Denials or Delays of Approval for Insurance Coverage

Insurance-mandated preoperative weight loss is discriminatory, arbitrary, scientifically unfounded, and contributes to patient attrition, or worse [126]. In a large study of patients medically cleared for a bariatric procedure and for whom insurance approval was requested, 22% were denied insurance coverage. For these patients, the mortality rate increased threefold during follow-up [220]. This practice by insurers leads to unnecessary delay of life-saving treatment and progression of life-threatening comorbid conditions [126].

Postoperative Esthetic Concerns

Bariatric surgery (and possibly antiobesity medication in hyper-responders) can lead to massive weight loss, resulting in excess skin and tissue that impairs hygiene, causes discomfort, and is disfiguring. Excess skin can lead to stigma due to appearance and pronounced physical and psychological impairments, but it can be mitigated by body-contouring surgery [221]. Body-contouring surgery is best pursued after weight loss has stabilized (typically 12 to 18 months after bariatric surgery) [125]. Smoking cessation is an absolute requirement before any type of body-contouring surgery [221].

Abdominoplasty can improve mobility, reduce skin fold complications, and improve psychosocial functioning. Patients who underwent body-contouring surgery after bariatric surgery had significantly better long-term weight loss than a matched cohort of patients [222]. A subsequent meta-analysis confirmed the added long-term benefits of body-contouring surgery for selected patients after massive weight loss and recommended a multidisciplinary team involving a bariatric surgeon, a plastic surgeon, nutritionists, and psychologists for the management of patients [223].

SURGICAL APPROACHES

There are several measures of procedure success. Nadir weight loss is defined as the lowest weight post-MBS, while weight recurrence is the weight regained after nadir. A case is categorized a nonresponse if the nadir excess weight loss is <50% of pre-MBS excess weight. Interventions for nonresponse and weight recurrence include revision or conversion (to another MBS type), corrective (to resolve a complication), and antiobesity medication augmentation [125,224].

Weight-loss success with MBS has often been defined as ≥50% excess weight loss and/or ≥25% total weight loss [212]. In the first validation of success criteria for MBS, ≥25% total weight loss exceeded 90% [225]. The quality of evidence for surgical bariatric approaches continues improving, with more prospective and longer-duration results, comparisons between MBS, and systematic reviews and meta-analyses.

Roux-en-Y Gastric Bypass (RYGB)

RYGB is the criterion-standard MBS with the longest-term safety and efficacy data [226]. In this procedure, the stomach is divided; a small gastric pouch is anastomosed (cross-connected) to a severed "roux" limb of small bowel jejunum through which food passes, bypassing the larger gastric remnant, duodenum, and proximal jejunum [227]. This approach has been found to dramatically improve type 2 diabetes and is part of the treatment algorithm for uncontrolled type 2 diabetes in patients with BMI ≥35. It is also associated with modestly greater weight loss and improvements in metabolic disease compared with sleeve gastrectomy. It also improves GERD [127,135].

However, it is associated with more malabsorptive complications than sleeve gastrectomy, though fewer than duodenal switch. The bypassed portion of stomach cannot be viewed by conventional gastroscopy; if cancer occurs after surgery, early diagnosis is almost impossible [228]. RYGB is also not recommended for patients with Crohn disease. Potential adverse effects include marginal ulcers, internal hernia, small bowel obstruction, and vitamin and mineral deficiencies.

Efficacy

A prospective study followed 486 patients after RYGB. Average total weight loss at 2 years (36%) and 15 years (28%) showed good durability. Rates of improved or resolved obesity-related complication after one year for type 2 diabetes (99%), obstructive sleep apnea (97%), hypertension (95%), and GERD (97%) remained high through ≥10 years [226].

After RYGB, 418 patients were prospectively studied (with >90% follow-up) at 12-years. Mean total weight loss was 28.0% at 6 years and 26.9% at 12 years. Approximately 70% and 40% of patients maintained ≥20% and ≥30% total weight loss. Type 2 diabetes remission at 2, 6, and 12 years was 75%, 62%, and 51%, respectively; prevention of new-onset type 2 diabetes was 98% [229]. Evidence suggests that RYGB provides stable weight loss of more than 25% beyond 12 to 15 years that corresponds with sustainable resolution of obesity-related complications.

Sleeve Gastrectomy

Sleeve gastrectomy, also referred to as laparoscopic sleeve gastrectomy or LSG, consists of the majority of the stomach being vertically resected; a tube-shaped remnant, or "gastric sleeve," is left along the lesser curvature [227]. This procedure improves metabolic disease while maintaining small intestinal anatomy. Due to its effectiveness, relative simplicity, and low rates of margin bleeding (1.0%), leakage (1.1%), and postoperative stenosis (0.4%), sleeve gastrectomy has become the most popular MBS [228]. Micronutrient deficiencies not as frequent with sleeve gastrectomy as with some other bariatric surgeries. If necessary, these patients can be converted to RYGB at a later stage.

Despite the benefits, rates of GERD and dysphagia are high. In some cases, these effects may be severe, requiring conversion to RYGB and/or chronic medical therapy (e.g., with proton pump inhibitors) [127,135]. Lack of bypass makes sleeve gastrectomy suboptimal for improving obesity-related complications in superobesity; other drawbacks include weight recurrence and poor diabetes control [228]. Chronic obstructive symptoms and potential strictures are additional concerns.

Efficacy

There has been concern that the popularity of sleeve gastrectomy has outpaced its long-term evidence support, especially in superseding RYGB. A systematic reviews and meta-analyses of ≥10-year sleeve gastrectomy results found 24.4% total weight loss and good remission of type 2 diabetes (45.6%) and hypertension (41.4%). However, high de novo GERD (32.3%) and 0% diabetes remission were noted in two of the reviewed studies [230].

In a randomized trial involving 240 patients with 85% follow-up at 10 years, sleeve gastrectomy led to 43.5% excess weight loss (vs 51% with RYGB), <5% weight loss in 5% of participants (vs 3% with RYGB), and similar remission of type 2 diabetes (26% vs 33%), dyslipidemia (19% vs 35%), and obstructive sleep apnea (16% vs 31%). Superior hypertension remission was noted with RYGB (8% vs 24%). The researchers found higher esophagitis rates after sleeve gastrectomy (31% vs 7%) but similar Barrett esophagus (4% vs 4%) and reoperation (15.7% vs 18.5%) rates. Longer preoperative type 2 diabetes duration was associated with lower remission, emphasizing the importance of early surgical treatment [231].

Laparoscopic Adjustable Gastric Banding (LAGB)

In LAGB, an adjustable silicone band is placed around the upper stomach and connected to a port in the subcutaneous tissue, which can be used to restrict the food-holding capacity of the stomach [127,135]. LAGB is the considered safest bariatric surgical procedure, and it is reversible if necessary [203]. Today, LAGB is disfavored due to lack of durable long-term weight loss, limited metabolic benefits, and the risks of device complications and revisional surgery [127,135].

Possible adverse events include band slippage, erosion, bowel obstruction, and dilatation of the esophagus. Band overfilling may underlie some LAGB problems. In one study, among 699 LAGB patients (pBMI: 41.4) with low (≤3 mL) or high (≥4 mL) band filling, low filling led to superior BMI (30.3 vs 35.8) and excess weight loss (49.1% vs 38.2%) at four to six years, and substantially lower rates of vomiting, epigastric pain, reflux, band slippage, migration, removal, and revision compared with high filling. Using low-volume band filling and strict follow-up, the authors suggest that abandonment of LAGB should be reconsidered [232].

Efficacy

Following LAGB, excess weight loss at 10 to 20 years is approximately 47%. However, the distribution of weight loss is heterogeneous. At seven years, 62% of patients have 15% total weight loss, and equal rates have ≥35% (19%) and <5% (19%) total weight loss [233].

Due to late complications, de novo GERD in up to 70% of patients, and comparatively mediocre long-term effectiveness, trends over the past decade indicate that LAGB is managed in patients treated years or decades earlier, rather than initiated as MBS [201,233].

Biliopancreatic Diversion with Duodenal Switch (BPD/DS)

BPD/DS involves sleeve gastrectomy, transection of the duodenum distal to the pylorus, and creation of an alimentary limb 200–250 cm long, thereby reducing anastomotic ulcers and dumping syndrome [228]. This approach is associated with the highest weight loss and metabolic disease resolution of all MBS techniques.

Technical complexity and risk of long-term nutritional deficiencies limits the acceptance of BPD/DS, which is reserved for super-obese (BMI ≥50) patients or those with nonresponse after sleeve gastrectomy without GERD, with nadir excess weight loss of 70% to 80% after two years [200,228,234]. Patient unwillingness or inability to follow/afford long-term nutritional recommendations, which can lead to life-threatening micronutrient deficiencies, is considered an absolute contraindication to this approach [127,135]. Other possible adverse effects include protein malnutrition, anemia, diarrhea, stomach ulceration, duodenal dissection, and internal hernias.

Efficacy

As RYGB can lead to insufficient weight loss in patients with super-obesity (BMI >50), some surgeons advocate BPD/DS in this group [132]. In a study involving 47 patients (pBMI: 54.5) randomized to BPD/DS or RYGB (81% with 15-year follow-up), 1-, 3-, and 15-year BMI was superior with BPD/DS (28, 31, 34) compared with patients who had undergone RYGB (33, 39, 41), reflecting 20.4 vs 12.4 BMI loss and 37.5% vs 23% total weight loss [132].

Unfortunately, BPD/DS also led to greater adverse events (2.7 vs 0.9 per patient), GERD (22.2% vs 0%), and severe adverse effects (0.9 vs 0.3 per patient), including malnutrition and bowel perforation. Long-term mortality did not differ. The trial was not powered for significant differences in obesity-related complication remission.

That half of patients with RYGB remained severely obese is greatly concerning, as BMI >40 reduces life expectancy by 8 to 10 years. The benefits of BPD/DS should be weighed against the increased risk of complications, which may be severe, and the need for rigorous follow-up. However, weight and comorbidity recurrences are problematic, creating health consequences and reducing life expectancy [132].

Single-Anastomosis Duodenal-Ileal Bypass with Sleeve Gastrectomy (SADI-S)

SADI-S creates a single, end-to-side anastomosis between the created gastric sleeve pouch with preserved pylorus and distal ileum, with the division at the level of the duodenum [135]. This approach was introduced in 2010 as a simplified version of BPD/DS and is characterized by strong metabolic effects. Short-term outcomes appear similar to BPD/DS in measure of excess weight loss (BPD/DS: 81%; SADI-S: 75%), improvement of obesity-related conditions, malnutrition, and complications [228]. Potential drawbacks include micronutrient deficiencies and duodenal dissection.

Efficacy

In one study, 121 patients (pBMI: 52) had BMI ≤29, excess weight loss 80%, and total weight loss 57% after 31 months. Post-30-day adverse events (3.3%) were malnutrition or chronic diarrhea [235]. A SADI-S review noted little weight regain after 24 months, resolution of type 2 diabetes (73%), dyslipidemia (77%), and hypertension (59%) [236].

In another study, three-year total weight loss was superior with SADI-S (39%) compared with RYGB (29%). Weight loss with RYGB (30%), SADI-S (35.5%), and BPD/DS (35%) was similar in obesity with type 2 diabetes. Diabetes improved comparably with SADI-S and BPD/DS and better than RYGB [234]. For unclear reasons, longer-duration data on SADI-S are lacking.

One-Anastomosis Gastric Bypass (OAGB)

OAGB was introduced as a simplified version of RYGB, with a significantly reduced difficulty, learning curve, and operation time [228]. It consists of a single gastrojejunal anastomosis between a long gastric pouch and a jejunal omega loop [228]. It may be simpler and safer than BPD/DS, with strong metabolic effects. It may also have less micronutrient deficiencies than BPD/DS.

OAGB is suitable in patients who are elderly, with low BMI (30–35) and obesity-related complications, and high BMI (>50) as one-stage procedure. It may also be suitable for patients with large/concurrent hiatal hernia [202].

This procedure is not reversible and is not recommended for patients with GERD or esophagitis [125]. Potential adverse effects include abdominal pain, nausea, liver abscess, micronutrient deficiencies, and duodenal dissection.

Efficacy

OAGB showed substantial, durable weight loss in a trial involving 1,200 patients (pBMI: 46), with 6-, 9-, and 12-year BMI (28.5, 29.6, 29.9), excess BMI loss (83%, 78%, 76%), and excess weight loss (77%, 72%, 70%) all showing improvement. Approximately 70% of patients had data at 12 years [237]. Patients showed remission of presurgery type 2 diabetes (94%), insulin resistance (100%), hypertension (94%), hyperlipidemia (96%), GERD (92%), obstructive sleep apnea (90%), respiratory insufficiency (100%), and fatty liver (100%). In addition, improvement/remission was noted in osteoarthritis (82%/18%) and urinary incontinence (78%/22%). All affected patients experienced improvement in polycystic ovarian disease. Complications included early severe events (2.7%), late severe events (1%), and bile reflux symptoms (2%). No followed patient required conversion for weight regain [237].

ENDOSCOPIC BARIATRIC TECHNIQUES

Endoscopic bariatric therapies have emerged as minimally invasive alternatives for patients who are not surgical candidates or who do not want to undergo surgical intervention. These approaches are expected to eventually fill the gap between conservative treatment and surgical bariatric procedures [228]. However, long-term data are needed to determine the durability of safety and efficacy.

Endoscopic Sleeve Gastroplasty (ESG)

ESG reduces gastric volume by 70% to 80%, creating a narrowed luminal sleeve—similar to sleeve gastrectomy, but without incisions or laparoscopy—using an endoscopic suturing device (OverStitch, Apollo Endosurgery, Austin, TX, USA) [238,239]. It is approved by the FDA for patients with BMI 30–50 [238]. It acts via gastric remodeling that increases PYY and GLP-1 by decreasing leptin and preventing rising ghrelin release, which increases fullness, decreases hunger, and promotes greater weight loss [238].

ESG is associated with fewer adverse effects than other bariatric procedures, with no obvious disadvantages [239]. The most common possible adverse effects include postprocedure nausea, vomiting, and epigastric pain. Severe adverse effects are rare (0% to 2%) [228,238].

In one study, 6-month weight loss robustly predicted 24-month weight loss, allowing early prediction of nonresponse and initiation of adjunctive therapies [238]. The MERIT trial randomized 209 participants to lifestyle modification with or without ESG. At 52 weeks, ESG showed superior excess weight loss (49% compared with 3%) and weight loss (14% compared with 0.8%) to controls. At 104 weeks, 68% of patients with ESG maintained ≥25% excess weight loss. No deaths, surgical interventions, or intensive care stays occurred [240].

In the longest prospective outcomes, weight loss at three and five years was 15% and 16%, respectively [228]. In 404 adults (pBMI: ≥40) after three years, weight loss was 20.3% and excess weight loss was 47% [62]. A meta-analysis of studies assessing efficacy of ESG found short-term and medium-term weight loss of 16.2% and 15.4%, respectively, and resolution of type 2 diabetes (55%), hypertension (63%), dyslipidemia (56%), and obstructive sleep apnea (52%) in patients with moderate obesity [241].

A study of ESG in 189 overweight patients (pBMI: 28) showed weight loss at 12, 24, and 36 months of 15%, 15.3%, and 15%, respectively. At 12 and 24 months, 76% and 86% of participants achieved normal BMI, with mean BMI reductions of 4.1 and 4.3. ESG was safe and effective in treating overweight patients, with high BMI normalization rates that could halt progression to obesity [242].

Overall, ESG looks promising as a minimally invasive bariatric procedure but needs longer-term data.

Laparoscopic Gastric Plication

Laparoscopic gastric plication is also referred to as a primary obesity surgery endoluminal (POSE) procedure. This incision-less procedure creates full-thickness plications in the gastric fundus and body using anchors that effectively reduce gastric capacity. Whereas endoscopic suturing is somewhat reversible, laparoscopic gastric plication places polypropylene anchors with baskets cinched on either end of tissue folds and is designed for permanent gastric remodeling. To accomplish this, it uses the incisionless operating platform, a medical device. As with ESG, laparoscopic gastric plication is associated with fewer adverse events compared with other bariatric procedures. The most common complaints are abdominal pain, nausea, and vomiting [127,135,239].

In a meta-analysis of the original laparoscopic gastric plication procedure, excess weight loss was 49% and weight loss 13% at 12 to 15 months. Severe adverse events occurred in 3% of cases and included bleeding, hepatic abscess, severe pain, nausea, and vomiting [243].

Laparoscopic gastric plication outcomes after five or more years are scarce. Among 88 patients at two and six years, weight loss was 21% and 12% and excess weight loss was 60% and 32%. The six-year weight regain of 58% led to a high revision rate (23.5%) [244].

Intragastric Balloon Devices

Intragastric balloon devices are filled with liquid or gas to reduce the effective volume of the stomach, thereby lowering the satiety threshold of meals, stimulating gut chemo-motor receptors, regulating ghrelin and other peptide hormone levels, reducing food intake, and delaying stomach emptying to achieve weight loss [228].

Three intragastric balloon devices are ASMBS-endorsed and FDA-approved for six-month dwell-time. The Orbera and Reshape balloons are both filled with methylene blue and saline. A leak or rupture releases the dye, which turns the urine blue to rapidly reveal the problem [135,228].

Contraindications to intragastric balloon devices use include prior abdominal or weight-reduction surgery, inflammatory bowel disease, obstructive disorders, GI ulcers, severe reflux, prior GI bleeding, severe liver disease, coagulopathy, ongoing alcohol use disorder, or intestinal varices, stricture, or stenosis [239,245].

Orbera Balloon Device

Orbera, the most widely and longest used intragastric balloon device, is an endoscopically inserted single gastric balloon filled with 400–750 mL of fluid [245]. In a meta-analysis of 1,683 patients, weight loss at 6 and 12 months was 13.2% and 11.3%, respectively. Common adverse events were pain (34%), nausea (29%), GERD (18%), gastric mucosal erosion (12%), and balloon removal due to intolerability (7.5%). Severe events included gastric ulcers (2.0%), balloon displacement (1.4%), small bowel obstruction (0.3%), perforation (0.1%), and death (0.08%). All perforations occurred in patients with prior gastric surgery; all deaths were secondary to perforation or aspiration. Thus, individualized, detailed risk assessment is necessary for patients planning to undergo intragastric balloon device placement [228]. Orbera early removal is also associated with use of selective serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) [125].

Obalon Balloon System

Obalon uses up to three deflated balloons, swallowed as capsules. Gas is then injected into the balloons under x-ray observation. Weight loss typically is about 6.6%. In a registry of 1,343 patients, weight loss was 10.0% in the indicated BMI category (BMI 30–40), 10.3% in BMI 25–30, and 9.3% in BMI >40. Adverse event (14%) and severe adverse event (0.15%) rates included seven balloon deflations, none of which resulted in obstruction [246].

Common adverse effects are mainly nausea and mild abdominal pain, and serious events are rare. However, leaking occurs more easily with gas-filled than liquid-filled balloons, and leaking balloons must be removed by gastroscopy, a disadvantage with Obalon [228,245].

ReShape Duo Balloon

With the ReShape Duo balloon device, two balloons are connected by a soft silicone rod. Each balloon is filled with 450 mL of fluid. The two-balloon design is intended to prevent premature failure, better conform to the stomach curvature, and improve patient tolerability. The ReShape device significantly reduces severe adverse effects rates compared with Orbera, but postoperative adverse event rates remain relatively high [228]. Average weight loss is approximately 6.8% [135].

AspireAssist

AspireAssist was a form of aspiration therapy via modified percutaneous endoscopic gastrostomy. In 2022, the maker of AspireAssist terminated production of this FDA-approved product [247].

OTHER OPTIONS

The TransPyloric Shuttle (TPS)

In 2019, the FDA approved the TransPyloric Shuttle (TPS) to promote weight loss in patients with BMIs 30–40 for a dwell time of 12 months. TPS provides a mechanism similar to intragastric balloon devices, with easy reversibility. The device contains a space-occupying balloon and a flexible silicone catheter that connects to a smaller bulb designed to intermittently advance through the pylorus to induce gastric outlet obstruction [239].

The initial TPS feasibility study in 22 patients demonstrated 14% weight loss at six months. The pivotal TPS trial randomized 302 patients to TPS or sham device. Weight loss at 12 months was superior with TPS (9.8 vs 2.8%). The few adverse events included esophageal rupture and gastric impaction [239].

Vagal Nerve Blocking Therapy (Vbloc)

With vagal nerve blocking therapy, a pacemaker-like implantable device is surgically placed under the skin, with lead wires placed laparoscopically around the vagus nerve just above the stomach. Activation of the device causes intermittent vagal blockade to induce a sense of satiety. It is FDA approved for weight management in patients with BMI >40 or BMI >35 with weight-related complications [127,135]. Contraindications include cirrhosis, portal hypertension, hiatal hernia, and other implanted devices (e.g., pacemakers, defibrillators) [127,135].

In one study, weight loss ≥10% and ≥15% at 12 months (39% and 22%) and 24 months (34% and 21%) was similar among all 123 patients. Adverse events included nausea, reflux, and pain at regulator site. No new adverse effects were noted in the second year of the two-year trial [248]. Weight loss is superior to sham-treated controls but lower than conventional MBS. Despite good safety, the modest efficacy may limit the desirability of intermittent vagal blockade [4].

Liposuction

While not a bariatric procedure, liposuction is a common esthetic procedure that can remove significant amounts of subcutaneous adipose tissue without affecting visceral adipose tissue. In a small 12-week study, women with and without diabetes had 9.1–10.5 kg body fat loss and reduced waist circumference but no improvement in blood pressure, inflammatory markers, or insulin sensitivity [4]. Removal of subcutaneous adipose tissue without reducing ectopic fat depots has little influence on the risk factors related to overweight or obesity [4].

IMPACT ON OBESITY-RELATED CARDIOMETABOLIC ENDPOINTS

MBS effects on major adverse cardiovascular events (a composite of coronary artery events, cerebrovascular events, heart failure, or cardiovascular death), major adverse liver outcomes (progression to cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related death), and obesity-related cancer is of considerable interest [249]. Addressing this are meta-analyses and matched-cohort studies comparing the long-term outcomes of MBS to usual obesity care (controls). Most of these data are retrospective. A noteworthy exception generating many studies is the Swedish Obese Subjects (SOS) project, which has prospectively followed 4,000 bariatric and control patients and a random population reference group of 1,135 over more than 20 years with >98% patient follow-up [250].

In cardiovascular disease outcomes, MBS has been associated with a significantly reduced risk of cardiovascular mortality and incidence of heart failure, myocardial infarction, and stroke [129]. In a 2020 SOS study, patients who had undergone MBS were 30% less likely to die from any cardiovascular disease than controls, including myocardial infarction, heart failure, and stroke, and were 23% less likely to die from cancer. Median life expectancy of MBS patients was 3.0 years longer than controls but 5.5 years shorter than the general population [250].

A 2021 systematic review and meta-analysis found increased median life expectancy of bariatric patients of 9.3 years in those with pretreatment diabetes and 5.1 years among those with no pretreatment diabetes compared with controls. The authors responded to the shorter life expectancy gain from MBS in the 2020 SOS study by citing residual confounding and outdated procedures [251].

In a 2023 SOS study, MBS increased life expectancy by 2.1 and 1.6 years in patients with and without diabetes at a median 26-year follow-up. These authors criticized the 2021 systematic review and meta-analysis for reliance on relatively short-term retrospective data and control patients captured from registers with limited information on health status. MBS benefit in pretreatment type 2 diabetes partly depends on irreversible organ damage (more common with long diabetes duration) and whether short-term or durable remission is achieved (also affected by the severity and duration of diabetes) [252].

Among obese adults with NASH and liver fibrosis, 10-year cumulative incidence of major adverse liver outcomes was 2.3% in those who underwent MBS, compared with 9.6% in controls; major adverse cardiovascular events occurred in 8.5% of MBS participants, compared with 15.7% among controls. For patients with NASH and obesity, MBS was associated with a significantly lower risk of incident major adverse liver outcomes and major adverse cardiovascular events than nonsurgical management [249].

Ten-year outcomes significantly favored MBS in obesity-related cancer incidence (2.9% vs 4.9%) and mortality (0.8% vs 1.4%). Comparable RYGB and sleeve gastrectomy outcomes suggest the primary mechanism is weight loss itself, not procedure-specific physiological alteration. Among MBS patients, cancer incidence was highest in those with weight loss less than 24%. Dose-dependent reduction in cancer risk required substantial weight loss, and the separation of survival curves only appeared six years after the index date [130].

POSTBARIATRIC INTERVENTIONS

Greater comprehension of obesity as a chronic disease requiring long-term management has highlighted the importance of intervention in patients with primary or secondary MBS nonresponse [214]. Nonresponse has been defined as <50% excess weight loss over one to two years following intervention, and weight recurrence is defined as regaining ≥20% of nadir weight loss after MBS [224,253]. Weight recurrence refers to secondary nonresponse [214]. Estimated rates of nonresponse (11% to 22%) and weight recurrence (16% to 37%) vary by definition used [224,254].

Causes of weight recurrence include increased caloric intake due to increased appetite and maladaptive or dysregulated eating, inadequate physical activity, and psychosocial stresses. Weight recurrence can promote recurrence of previously controlled type 2 diabetes and other obesity-related complications, with diminished quality of life and poor emotional health. Preventing weight recurrence is a primary goal [224].

Surprisingly, nutritional, cognitive-behavioral, supportive, and other psychological and lifestyle interventions, started perioperatively or up to two years postoperatively, have not demonstrated a significant effect on overall weight loss. Systematic reviews and meta-analyses of these interventions have concluded their efficacy in preventing or reversing weight recurrence is marginal or null [224].

Intervention for patients experiencing nonresponse or weight recurrence entails revisional surgery or adjuvant antiobesity medication [126]. Because most revisional procedures carry higher morbidity than primary procedures, nonsurgical interventions should be tried first [224,255].

Antiobesity Medication

Antiobesity medications may work synergistically with MBS, and treating patients with obesity via a multimodal approach has the potential to increase and possibly enhance MBS efficacy and durability. The ASMBS supports preoperative use of antiobesity medications for reducing perioperative risk and increasing postsurgery attainment of weight-loss goals and comorbidity resolution as well as post-MBS for ameliorating weight recurrence [124].

Phentermine is one of the most commonly used antiobesity medications in MBS patients. Pairing phentermine with topiramate may be advantageous in weight-loss efficacy through combinatory mechanisms and cost considerations in post-MBS patients. GLP-1 agonists offer high efficacy, few drug interactions, and few side effects, but cost can be a deterrent [124].

In most patients, MBS results in supraphysiological levels of circulating GLP-1. However, patients with poor postsurgery weight loss demonstrate an unfavorable postoperative gut hormone profile, including lower circulating GLP-1 levels. As such, GLP-1 analogs may benefit these patients [256].

In the BARI-OPTIMISE randomized placebo-controlled trial, patients with poor weight loss (≤20%) and suboptimal nutrient-stimulated GLP-1 response one or more years following sleeve gastrectomy or RYGB received liraglutide 3.0 mg or placebo. After 26 weeks, mean total weight loss with liraglutide was 8.82%, compared with 0.54% with placebo [256].

Patients receiving liraglutide for late weight recurrence after RYGB were prospectively followed. After 24 months, patients lost >85% of weight recurrence from nadir; hypertension and dyslipidemia also improved [257].

Weight recurrence studies of GLP-1 RAs have largely used liraglutide. However, semaglutide may be superior to liraglutide for weight recurrence, regardless of MBS procedure. In one study, semaglutide was superior on with 12-month weight loss (13% vs 9%) and odds ratio for ≥15% weight loss (2.55) compared with liraglutide [258].

Patients treated with liraglutide or semaglutide for weight recurrence after RYGB lost 67.4% of the weight regain after six months. More patients on semaglutide had total weight loss ≥10% (47.6% vs 31%) and ≥15% (24% vs 3.5%) [254].

The optimal time to initiate antiobesity medication may be at weight plateau, rather than after weight recurrence [259]. Proactive liraglutide may significantly augment ESG efficacy. Initiated five months after ESG and assessed seven months later, liraglutide/ESG showed greater reductions in weight (25% vs 20.5%) and body fat (10.5% vs 8%) compared with ESG alone at one year postprocedure [260].

Revisions/Conversions

The choice of conversion depends on the type of primary operation and the indication for conversion [125]. Patients may require reoperation (to correct/adjust) or conversion following any primary MBS, but some evidence suggests that more "restrictive" procedures (e.g., LAGB, sleeve gastrectomy) lead to higher rates of reoperation or conversion.

Conversions are the third most common MBS procedure. Of 57,683 performed between 2015 and 2017, most involved gastric band (LAGB) conversion to sleeve gastrectomy (15,433), to RYGB (10,485), or removal (14,715). It is projected that sleeve gastrectomy to RYGB conversions (8,491) will likely surpass LAGB conversions with time [261].

Weight recurrence within several years of sleeve gastrectomy is described as an emerging problem. After seven years, 28% to 30% of patients had weight recurrence and 20% had revisions, mostly due to weight recurrence (13%) and GERD (3%) [262,263]. However, over 5 to 12 years after RYGB, up to 25% of patients experience <20% weight loss due to nonresponse/weight recurrence [256].

The ASMBS has made several suggestions concerning revisions/conversions, stating that in addition to improving weight loss, type 2 diabetes improvement and remission rates also increase [125]. It is important to consider behavioral factors, such as binge-eating, may be responsible for poor weight outcomes after LAGB reoperation. If necessary, conversions to RYGB or sleeve gastrectomy after LAGB can be performed in one or two stages. If conversion is required due to GERD, the preferred procedure is RYGB. Conversion of sleeve gastrectomy for additional weight loss can be RYGB or duodenal switch, which results in greater weight loss than RYGB but higher risk of long-term nutritional deficiencies [125].

For weight recurrence after sleeve gastrectomy, SADI-S led to greater total weight loss (30% vs 19%) and remission of type 2 diabetes and hypertension, fewer complications and reoperations after five years when compared with OAGB [264]. In one trial, OAGB for 1,075 patients with weight recurrence after various MBS led to two- and five-year excess weight loss of 68.5% and 71.6%, respectively. Adverse events included leak (1.5%), marginal ulcer (2.4%), anemia (2%), and mortality (0.3%) [265].

9. CONCLUSION

During 1980–2000, obesity prevalence increased roughly 100% as adults consumed less fat and sugar, became more active, and initiated more frequent weight loss attempts with diet and exercise. The obesity epidemic is unexplained by worsening diet and physical inactivity.

Today, it is acknowledged that obesity is a chronic, relapsing disease with cardiometabolic complications (e.g., insulin resistance, hypertension, type 2 diabetes, NAFLD, cardiovascular diseases) arising from adipose mass due to shared pathophysiology. The goal of obesity treatment—long-term weight loss sufficient to ameliorate cardiometabolic morbidity and premature mortality—usually requires antiobesity medications, bariatric surgery, or both.

Recently approved and emerging antiobesity medications are revolutionizing obesity treatment by achieving long-term weight loss previously unattainable without surgical intervention. Reversing the low utilization of medication and surgical treatment begins with ending the stigmatization of patients with obesity.

10. APPENDIX: PHYSIOLOGY AND PATHOPHYSIOLOGY

As explored throughout this course, knowledge of the mechanisms underlying obesity and advances in the understanding of how and why adiposity persists are essential in the development of new approaches in the treatment of patients with obesity. Healthcare professionals involved in the care of these patients benefit from a clear understanding of the physiology and pathophysiology involved.

NEUROHORMONAL REGULATION OF ENERGY BALANCE AND BODY WEIGHT

The biological system that regulates energy balance and body weight is dominated by a bidirectional feedback loop between the brain and periphery, sometimes called the gut-brain axis [108]. Peripheral tissue (gut, pancreas, adipose tissue) releases hormones, metabolites, and peptides to communicate information about long-term energy stores and short-term nutrient availability to the brain. Because these molecular messengers provide homeostatic feedback of energy availability and status to the brain, they are called signals (of satiety, hunger, adiposity) [266].

These signals of energy balance reach the hypothalamus via the bloodstream and/or the brainstem via afferent vagal pathways that terminate in the nucleus tractus solitarius (nTS) [103,267]. Brain circuits respond to this input by adjusting metabolism and behavior to acute and long-term needs and modifying energy intake and expenditure to match energy demands. Over time, this homeostatic regulation of energy balance establishes a metabolic set-point [101,102].

Peripheral signals can be anorexigenic (appetite-suppressing) or orexigenic (appetite-stimulating) and long- or short-term. Long-term signals of energy balance circulate in proportion to fat mass to inform the brain about long-term energy storage in adipose tissue (i.e., adiposity signals) and are always (leptin) or often (insulin) anorexigenic. Short-term signals of nutrient and meal-derived energy availability (i.e., satiety and hunger signals) are gut-released and include [101,150,267]:

- Glucagon-like peptide-1 (GLP-1), peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), and oxyntomodulin (OXM), which are all anorexigenic

- Ghrelin, which is orexigenic and known as the "hunger hormone"

In obesity, this system is dysfunctional and generates and sustains excessive adipose tissue mass. Abnormal interaction between peripheral hormones and brain centers of energy homeostasis is a core feature of obesity pathophysiology [3].

The Hypothalamus

The hypothalamus, as the superordinate regulator of energy homeostasis, receives input via the bloodstream, ascending neurons from the brainstem, and descending neurons from cortical areas. It then coordinates energy balance and other homeostatic systems, integrates reciprocal orexigenic and anorexigenic responses, and governs metabolic adaptation [102,103,268].

The arcuate nucleus (ARC) of the hypothalamus is adjacent to the median eminence, a circumventricular organ outside the blood brain barrier, giving ARC neurons direct bloodstream access to detect circulating hormones and metabolites. Arcuate neurons are thus 'first-order' neurons, since circulating peripheral signals act directly on them [101,102,269].

First-order ARC neurons project to second-order neurons in the paraventricular (PVH), ventromedial, dorsomedial, and lateral hypothalamus. Second-order hypothalamic neurons project to brainstem circuits and midbrain areas [101,102,115,269]. Brainstem circuits respond rapidly to gut signals to control meal size and termination. Brainstem neurons project to hypothalamic areas and communicate to the gut via parasympathetic signals. Many antiobesity medications work by activating receptors on both hypothalamic and brainstem neurons [102,115].

The hypothalamic integrative capacity is enhanced by crosstalk with corticolimbic systems that process external sensory information, cognitive and emotional control, and reward-based decision making and mediate emotional, cognitive, and executive aspects of ingestive behavior [8].

A salience network in the frontal cortex, ventral and dorsal striatum, and amygdala, associated with motivation, desire, and craving for palatable high-energy food, is more active in obese than lean subjects. An inhibitory network in the dorsolateral prefrontal cortex is activated in subjects instructed to resist craving. This cognitive control ability is greater in patients with the highest weight loss after bariatric surgery. Connectivity between the salience and inhibitory networks (hedonic control) and the hypothalamus (homeostatic control) differs in lean versus obese subjects. The former homeostatic/ hedonic ingestive dichotomy has given way to a more unified and integrative control system [8].

The Arcuate Nucleus and the Melanocortin System

In the ARC, the melanocortin system is a critical and conserved pathway of body weight homeostasis and essential to the regulatory function of the hypothalamus in energy balance and homeostasis. The melanocortin system consists of two distinct, functionally antagonistic neuron populations [150,268,270,271,272]:

Anorexigenic melanocortin neurons (POMC), which release melanocortin peptides (α- andβ-MSH) that bind and stimulate melanocortin receptors (MC3R and MC4R) expressed on second-order neurons. Brain-derived neurotrophic factor, corticotropin-releasing hormone, and thyrotropin-releasing hormone mediate the downstream effects of MC4R activation on suppressing food intake.

Orexigenic agouti-related protein (AgRP) neurons, which antagonize melanocortin neurons and receptors by releasing AgRP, gamma-aminobutyric acid (GABA), and neuropeptide Y (NPY). AgRP antagonizes MC3/4R to prevent the anorexigenic effects ofα- andβ-MSH binding. GABA directly inhibits POMC neurons in the ARC. NPY is the most potent known short-term orexigenic stimulus.

The brainstem has a smaller number of POMC neurons. AgRP neurons solely exist in ARC and send long-distance projections throughout the hypothalamus and brainstem. AgRP neuron expression is negatively correlated with BMI [273].

POMC and AgRP neurons are tightly linked, exert opposite functions in the reciprocal regulation of downstream MC3/4R neurons, and are themselves reciprocally regulated by circulating hormones and neural inputs [274,275].

Energy Balance and Melanocortin Activity

POMC and AgRP neurons detect and respond to circulating metabolic and hormone signals of short- and long-term deficit or surplus in energy availability [8]. Circulating hormones (e.g., leptin, insulin, ghrelin, GLP-1) bind to their respective receptors (LepR, InsR, GHSR, GLP-1R) on POMC and AgRP neurons [141]. Energy surplus stimulates POMC neurons. Heightened energy demand activates AgRP neurons [3,276].

The PVH is a major output nucleus for the ARC and receives afferent inputs from POMC and AgRP neurons [102]. It has the highest number of MC4R-expressing neurons in the CNS [271].

POMC neurons are stimulated by positive energy balance, elevated leptin, and insulin. In contrast, AgRP neurons are inhibited by leptin and insulin deficit and activated by negative energy balance and ghrelin.

POMC and AgRP neuron projections both converge on MC4R neurons in the PVH, which anorexigenic melanocortin peptides activate to suppress food intake and enhance energy expenditure, and orexigenic AgRP neuropeptides inhibit to increase food intake [141,277]. Also, circulating ghrelin binds its receptor on AgRP neurons, which then release NPY [3].

Negative energy balance and prolonged caloric restriction activate AgRP neurons in part by reducing plasma levels of leptin and insulin that inhibit AgRP neurons. Inactivating this inhibitory input activates AgRP neurons and increases the drive to eat, which promotes positive energy balance and recovery of lost weight [7].

Circulating levels of leptin, insulin, and other hormones serve the hypothalamus with feedback about the availability of energy. When circulating levels of these energy signals decrease during prolonged caloric deficit, increased AgRP neuron excitation recapitulates many behaviors and physiological effects associated with starvation, such as enhanced rewarding properties of food, as well as stimulating food intake [277]. Disruption of this fine-tuned control in the arcuate circuitry leads to dysregulation of energy balance and metabolism [8,266].

Hypothalamic Regulation of Adiposity and Energy Expenditure

White adipose tissue, the dominant body fat, is comprised of fat cells (adipocytes), stores energy in the form of triglycerides, and can increase fat reserves (lipogenesis) or utilize fat as energy (lipolysis) [278]. Melanocortin signaling regulates lipid metabolism and adiposity via the sympathetic nervous system (SNS) activity; disruption promotes lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue [150,275].

The SNS innervates white adipose tissue, and sympathetic terminals are adjacent to more than 90% of adipocytes. The brain releases norepinephrine from sympathetic terminals, which activateα- andβ-adrenergic receptors on adipocytes. This sympathetic outflow is the principal initiator of lipolysis, mediated in part by MC3/4R activity on sympathetic cholinergic neurons [271,276].

A common frustration for individuals trying to lose weight is the marked compensatory reduction in energy expenditure associated with caloric restriction [277]. AgRP neurons, activated by negative energy balance, shift metabolism toward energy conservation by promoting lipid storage and adipogeneses, elevating carbohydrate fuel use, reducing lipolysis, and thus decreasing energy expenditure in adipose tissue, in part, by suppressing sympathetic outflow to white adipose tissue. NPY release increases food intake and decreases energy expenditure via NPY1R-mediated reduction in downstream sympathetic output to adipose tissue [268]. SNS neurons also produce NPY, which induces vasoconstriction and fat tissue expansion [150].

A key point is that through extensive bidirectional communication, adipose tissue importantly influences energy balance, while CNS and hypothalamus play an essential role in controlling systemic metabolism [279].

Hypothalamic POMC Neurons and Cannabinoids

Cannabis use represents a "wildcard" in appetite mediation by the melanocortin system. By activation of cannabinoid receptor 1 (CB1R), cannabis-induced eating is a hallmark of cannabis use [280].

POMC neurons also produceβ-endorphin, an opioid peptide that binds the μ-opioid receptor (MOR). CB1R activation selectively increasesβ-endorphin, but notα-MSH, release by POMC neurons. Beta-endorphin inhibits AgRP neuron activity, and acute CB1R-induced eating is blocked by naloxone, a MOR antagonist [280].

Thus, cannabis stimulates a switch fromα-MSH toβ-endorphin release by POMC neurons and subsequently increases appetite and food intake (i.e., "the munchies"). This interesting and paradoxical finding argues against an exclusively anorexigenic role of POMC neurons [266].

Brainstem Circuits

The gut communicates information about food ingestion to the brain via vagal afferent fibers in the NTS. Most of these signals act rapidly to promote meal termination, with less impact on energy expenditure or long-term food intake [150,281]. The NTS receives and integrates the afferent vagal information and communicates this information to other brain regions it innervates [141,282].

POMC neurons are also expressed in the NTS, where they project to and receive inputs from brain regions that both overlap and are distinct from connections of arcuate POMC neurons [269]. NTS POMC neurons respond to, among other things, gut-secreted CCK and adipocyte-derived leptin [271].

Some NTS neurons project to the parabrachial nucleus, a central node in this ascending pathway. An anorexigenic circuit implicated in satiety and meal termination arises from calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus. Activation of CGRP neurons by gastric distention, CCK, and GLP-1 decreases appetite, while inhibition increases meal size [7,266].

Arcuate nucleus signaling strongly influences CGRP neuron activity [7,266,274]. In the ARC, glutamate-releasing/oxytocin-receptor expressing (Vglut2/OxtR) neurons convey an excitatory, fast-acting satiety mechanism. Projections from these neurons converge with GABAergic AgRP projections on MC4R neurons in PVH, a critical second-order node in the regulation of feeding. In the PVH, MC4R neurons release glutamate and excite downstream CGRP neuron targets in the parabrachial nucleus. Thus, the parabrachial nucleus serves as a third-order node in feeding regulation. In addition, AgRP neurons project to the parabrachial nucleus; activation of AgRP neurons stimulate feeding and delays satiation by inhibiting CGRP [7].

Of note, the substantial complexity inherent in food intake regulation cannot be reduced to a small set of interacting neurocircuits, and much remains to be learned [7].

Peripheral Signals of Energy Status

As will be discussed later in this course, many novel and emerging antiobesity medications act through the hypothalamic receptors of peripherally released hormones and peptides.Table 10 summarizes the effects of endogenous and pharmacological ligand-binding of these receptors.

Table 10: HORMONE, METABOLIC, AND PEPTIDE SIGNALS OF SATIETY, HUNGER AND ADIPOSITY, BY PERIPHERAL TISSUE ORIGIN

Hormone

Receptor Locations in CNS

Effects on Energy Balance and Obesity

Adipocyte origin

Adiponectin

Hypothalamus

↓Body weight, plasma lipids

Leptin

ARC

↓Food intake, body weight

Pancreatic cell origin

Amylin

ARC, AP, VTA, striatum

↑Satiety

↓Gastric emptying, food intake

Glucagon (GCG)

ARC, NTS

↑Satiety, glycogenolysis, gluconeogenesis

Insulin

ARC

↓Food intake, body weight

Pancreatic polypeptide (PP)

Hypothalamus, NTS

↑Satiety

↓Gastric emptying

Enteroendocrine cell origin

Cholecystokinin (CCK)

Hypothalamus, NTS

↑Satiety

↓Gastric emptying/motility

Ghrelin

ARC

↑Food consumption and reward

GIP

ARC, PVH, DMH

↓Food intake

↑LPL, postprandial insulin

Glucagon-like peptide-1 (GLP-1)

ARC, NTS, AP, striatum

↑Satiety, postprandial insulin

↓Gastric emptying/motility, food reward

Oxyntomodulin (OXM)

Hypothalamus

↑Satiety

↓Gastric emptying, food intake

Peptide tyrosine tyrosine (PYY)

ARC, NTS

↑Satiety

↓Gastric emptying/motility

AP = area postrema, ARC = arcuate nucleus of the hypothalamus, CNS = central nervous system, DMH = dorsomedial hypothalamus, GHSR, growth hormone secretagogue receptor, GIP, glucose-dependent insulinotropic polypeptide, NTS = nucleus tractus solitarius, PVH = paraventricular nucleus of the hypothalamus, VTA = ventral tegmental area.

Source: [115,147,267]

Adipose Tissue and Pancreatic Hormones

Some peripheral signals of energy balance are released by adipocytes (leptin, adiponectin), and pancreaticαcells (GCG),βcells (insulin, amylin), and F cells (pancreatic polypeptide) [150,282].

Leptin, the canonical signal of adipose tissue mass, is produced by white adipose tissue in approximate proportion to triglyceride stores. Adequate leptin action via its receptor (LepR) on arcuate neurons indicates sufficient energy stores; reduced leptin signaling indicates an energy deficit, promoting hunger and increasing energy intake [281]. LepR activation also decreases body weight by increasing lipolysis and energy expenditure [277]. CCK potentiates leptin effects to decrease food intake and body weight [267].

Normal body-weight maintenance requires intact leptin-regulated neurocircuits. An association of obesity with leptin resistance has been suggested, but some obese individuals may simply require more leptin to fully engage relevant neurocircuits. The primary role of leptin-responsive neurocircuits may relate more to preventing loss of body fat (by decreased leptin signaling to CNS) than defending against its increase (by increased leptin levels) [7].

Adiponectin is an adipocyte-derived protein that decreases body weight and plasma lipid levels and enhances insulin suppression of hepatic glucose production. Adiponectin levels increase following weight loss interventions in obesity, and patients with obesity show an inverse correlation between plasma adiponectin and insulin resistance [115].

Insulin and leptin both circulate in proportion to fat mass. Insulin activates its receptor (IR) expressed in the melanocortin system, which mediates its central anorexigenic effects, decreasing food intake and body weight [115]. Insulin also acts centrally to decrease hepatic glucose output, in part by inhibiting hypothalamic neurons [102]. Insulin inhibits AgRP neuron firing via IR-dependent signaling. Disruption of IR in the CNS promotes obesity with increases in body fat and leptin levels, insulin resistance, elevated insulin levels, and hypertriglyceridemia [266].

Amylin is co-released with insulin from pancreaticβ-cells in response to high blood glucose levels, reduces the rate of glucose absorption and inhibits glucagon release. Amylin receptor complexes in the area postrema and brainstem NTS mediate its anorectic effects by activating a central satiety pathway. Amylin also affects hedonic eating by inhibiting reward neurocircuits [141,267]. Amylin and leptin act synergistically, in part by amylin acting directly on AgRP neurons that co-express LepR. Amylin's ability to slow post-prandial gastric emptying also contributes to satiety [141].

Glucagon (GCG)is secreted by pancreaticα-cells and binds its receptor (GCGR) in the CNS, pancreas, adipocytes, and liver. Glucagon stimulates energy expenditure, reduces food intake, and decreases body weight through multiple mechanisms, including inducing satiety and lipolysis [147,267]. Hypothalamic GCGR activity inhibits AgRP neuron activity to attenuate orexigenic effects, while central resistance to glucagon-induced hypophagia contributes to the development of obesity [141]. Glucagon's anorectic action seem to be mediated via the liver-vagus-hypothalamus axis [267].

Gut Peptide Hormones

Other signals of energy balance are released by enteroendocrine cells that line the gut, one of the largest hormone-producing organs. Enteroendocrine cells and their respective hormones include L-cells (GLP-1, OXM, PYY), I-cells (CCK), K-cells (GIP), and P/D1 cells (ghrelin). Gut hormones bind their receptors in CNS and on pancreaticβcells (GLP-1, GIP), pancreas (CCK, OXM), and adipocytes (GIP) [147,267,283].

Meal termination involves meal-induced enteroendocrine cells release of peptides (e.g., GLP-1, CCK), which promote satiety by activating vagal afferent neurons that relay GI signals to brainstem areas, including the NST [7]. Glucagon-like peptide 1 (GLP-1) increases in circulation following meals and decreases during fasting, stimulates insulin secretion and regulates energy intake, and is also produced in the NTS. GLP-1 acts on GLP-1R in the gut and brain to delay gastric emptying and decrease food intake through activation of satiety pathways and efferent pathways regulating GI function. GLP-1 also reduces glucagon secretion, inhibiting hepatic glucose production [284].

GLP-1 inhibits eating mainly by activating GLP-1R on hypothalamic and brainstem NTS neurons. GLP-1R agonists also suppress hedonic eating by interacting with the mesolimbic reward system, including the ventral tegmental area and nucleus accumbens [267]. GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP-IV), leading to a circulating half-life of only two minutes for GLP-1 [150].

GIP acts in concert with GLP-1 on the pancreas after meals to regulate blood glucose by stimulating insulin and glucagon release. GIP contributes to lipid metabolism by promoting lipid storage, adipose tissue blood flow, and triglyceride uptake in adipocytes [284]. The GIP receptor (GIPR) is expressed in arcuate, dorsomedial hypothalamus, and PVH neurons; GIPR activation reduces food intake [267].

Ghrelin circulates as an orexigenic signaler, promoting hunger and meal initiation by binding its receptor (GHSR) on AgRP neurons, which stimulates NPY and AgRP release and inhibits POMC neurons by increasing GABAergic signaling. Vagal afferent neurons also have ghrelin receptors [115,267]. Compared with lean controls, individuals with obesity have lower circulating ghrelin levels and are more sensitive to its appetite-stimulating effects [115,267].

Ghrelin and leptin have a reciprocal relationship aimed at increasing or decreasing adiposity. Fasting increases ghrelin and reduces leptin, while high leptin levels suppress gastric ghrelin release and prevent ghrelin-induced NPY neuron activation [141]. Ghrelin and GLP-1 have opposite actions on eating behaviors. Ghrelin reinforces food reward by activating ventral tegmental area dopaminergic neurons; GLP-1 attenuates various palatable food-motivated efforts [267].

Ghrelin remains the only metabolic signal that potently activates orexigenic AgRP neurons. Discovery of an endogenous antagonist of ghrelin, liver-expressed antimicrobial peptide, sparked research interest in it as a possible candidate for obesity treatment [267].

CCK is secreted postprandially and binds CCK1 receptors (CCK1R) expressed in the vagal afferents, brainstem, and hypothalamus to decrease food intake. The satiety signals of CCK are transmitted to the NTS by vagal sensory neurons. CCK activates NTS POMC neurons, and brainstem MC4R signaling is required for CCK-induced appetite suppression [267]. CCK is an acutely acting signal with a very short half-life. Compensatory increases in meal frequency prevent CCK from producing long-term effects on total food intake or body weight [102].

OXM is secreted with GLP-1 and PYY in the postprandial state and exerts its anorectic action primarily via GLP-1R and secondarily via GCGR. The GLP-1R-mediated effects of OXM differ from those of GLP-1. OXM decreases body weight by lowering food intake and increasing energy expenditure and may act via different hypothalamic pathways than those of GLP-1 [267].

PYY is co-secreted with GLP-1 following a meal. Its major circulating form (PYY3-36) binds Y2R expressed on AgRP neurons, inhibiting these neurons and activating POMC neurons. Thus, PYY reduces appetite and body weight by increasing anorexigenic melanocortic activity in the arcuate [267].

PATHOPHYSIOLOGY

Long-term positive energy balance and increased fat mass promote pathogenic adipocyte hypertrophy and adipose tissue accumulation and dysfunction, resulting in immunopathies, endocrinopathies, increased circulating free fatty acids, and lipotoxicity. The OMA uses the term adiposopathy, or "sick fat disease," to describe pathogenic adipose tissue [128].

The consequences of adiposopathy contribute to metabolic diseases including type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, NAFLD, and cancer [18,29]. Obesity-related metabolic and cardiovascular diseases can be termed cardiometabolic disease or metabolic syndrome.

Adiposopathy is analogous to the disease state of other organs, such as myopathy, cardiomyopathy and encephalopathy. In the disease of adiposopathy, pathogenic enlargement of fat cells and the fat organ results in anatomic and functional abnormalities, metabolic and biomechanical morbidities, and increased mortality [18,29].

Adipose Cell and Tissue Function

Part of understanding obesity as a disease is recognizing that adipocytes and adipose tissue have vital functions beyond energy storage alone [128]. Adipose tissue is mostly comprised of adipocytes, regulates multiple body processes critical to energy and metabolic homeostasis, and is functionally classified into two types: white and brown [128,285]. White adipose tissue is an active endocrine and immune organ that includes subcutaneous adipose tissue and visceral (abdominal) adipose tissue and primarily stores energy. However, subcutaneous adipose tissue contains brown-like inducible adipocytes that perform mitochondrial and thermogenic functions and burn fat [286].

Brown adipose tissue, comprising 1% to 2% of body fat, has more mitochondria (thus its brown appearance) and is abundant in neonates but decreases in adults and decreases further in obese adults [286]. Brown adipose tissue produces heat energy, termed thermogenesis, uponβ-adrenergic stimulation [287].

Subcutaneous adipose tissue is the largest fat depot. Visceral adipose tissue is more metabolically active, vascular, and innervated than subcutaneous tissue. Ectopic fat, a third depot, is strictly pathogenic [48].

Fat depots are sexually dimorphic; on average, men have more visceral adipose tissue, and women have larger subcutaneous adipose tissue stores. Given the relative impact of fat depots on metabolic health, this sexual dimorphism may explain sex differences in metabolic disease risk until menopause, when decreased estrogen may increase low-density lipoprotein, triglycerides, visceral fat, morbidity, and mortality in women [48].

Adipocytes, which constitute the largest cell volumes in adipose tissue and are the defining fat cell type, have three important roles: lipid storage, insulin sensitivity, and secretory function. Disruption of any contributes to obesity-related metabolic disease states [288].

Some key players in adipose tissue physiology and obesity pathophysiology include glucose, glycogen, triglycerides, and insulin [289,290]. Glucose is a carbohydrate, one of three macromolecule classes (with fats and proteins); some argue alcohol is a fourth class. Glycogen is the storage form of glucose in liver and muscle. Triglyceride, the storage form of fatty acids, is made of three fatty acids linked to glycerol. The capacity to store carbohydrates (as glycogen) is limited. What cannot be stored as glycogen, or quickly used, gets stored as triglyceride. Insulin, released by pancreaticβ-cells in response to rising blood glucose, aims to store carbohydrate as glycogen or fatty acids.

Lipid Storage

During energy surplus, 60% to 80% of excess calories are stored as triglyceride by adipocytes [291]. Adipocytes can increase fat stores (lipogenesis) or release fatty acids (lipolysis) to supply other tissues with energy [278,285]. Insulin is critically involved in these processes.

For lipogenesis, adipocytes accumulate lipid through free fatty acids from circulating triglyceride and by synthesizing triglyceride from non-lipid metabolite sources, termed de novo lipogenesis [285]. For lipolysis, enzymatic cleavage of triglyceride by lipases generates glycerol and free fatty acids, which are released into circulation for use by organs as fuel (e.g., glycerol for liver gluconeogenesis) [288]. Lipolysis is controlled by sympathetic nervous system input and norepinephrine. In the fasting state, insulin levels drop, releasing norepinephrine, which promotes lipolysis [288].

Because adipose tissue is central to the regulation of systemic lipid metabolism, a balance between lipogenesis and lipolysis within adipocytes is required to maintain insulin sensitivity and energy homeostasis. Nutrient (free fatty acids and glucose) and hormonal cues regulate both processes [288].

Insulin Sensitivity

Insulin sensitivity of adipose tissue is vital to metabolic homeostasis and systemic energy balance [285]. Insulin binds to its receptor in liver, muscle, and adipose tissue to initiate several processes [48,292].

Insulin activates glucose transporter-4 (GLUT4) on cell surfaces, which transport glucose from the bloodstream into cells. On fat cells, insulin accelerates glucose delivery into adipocytes and induces breakdown of glucose into triglycerides for storage.

Insulin upregulates lipoprotein lipase on fat cell surfaces that bring free fatty acids into adipocytes to store them triglycerides. Insulin also increases triglyceride accumulation by inhibiting their breakdown and release as free fatty acids.

The primary source of glucose for all tissues and largest glucose storage site (as glycogen) is the liver. Hepatocytes are critical intermediaries in energy (lipid, carbohydrate) metabolism. Insulin decreases glucose output by the liver, the main target for pancreatic insulin and glucagon [292,293].

During caloric deficit, low insulin disinhibits lipolysis, which mobilizes lipids to meet energy demand. However, elevated insulin during caloric excess stimulates glucose uptake, inhibits lipolysis, and orchestrates de novo lipogenesis. The body goes into "storage" mode of carbohydrates and fat. These normal functions of insulin help protect against the cellular and tissue toxicity caused by high circulating glucose and free fatty acids [285,289].

Endocrine and Immune (Secretory) Function

As an endocrine/immune organ, adipose tissue releases adipokines (via adipocytes) and receives (via receptors) metabolic signals to influence and regulate adipogenesis, lipid metabolism (lipogenesis and lipolysis), appetite and energy balance, inflammatory and immune response, glucose homeostasis (insulin sensitivity), vascular homeostasis (endothelial function), blood pressure, and other processes [128,285,288].

Adipokines are hormones, cytokines, extracellular matrix proteins, and growth factors that transmit information from fat tissue to other metabolic organs. They can act locally (paracrine) and/or systemically (endocrine) [128,285]. Adipocytes express receptors for nuclear and traditional hormones, adipokines, neuropeptides, lipoproteins, prostaglandins, endocannabinoids, and others [128]. Several adipokine hormones, including leptin and adiponectin, are regulators of systemic lipid and glucose homeostasis [285,288,294].

Accordingly, adipose tissue can release pro-inflammatory hormones (leptin), cytokines (e.g., tumor necrosis factor-alpha [TNF-a], interleukin-6 [IL-6], IL-8), acute phase response proteins (e.g., C-reactive protein [CRP]), chemokines (e.g., monocyte chemoattractant protein–1 [MCP-1]), and prostaglandins. In addition, adipose tissue can release anti-inflammatory hormones (adiponectin), interleukins (IL-10), and transforming growth factor beta 1 (TGF-beta) [128; 295; 296].

Pathogenesis of Adiposopathy and Obesity-Related Complications

An immune response appears early during adipose accumulation. With excessive fat mass, local adipose-induced inflammatory processes progress to widespread systemic inflammation that damages distant tissue and induces a host of metabolic disorders and organ tissue complications in obesity [194,297].

Local Pathogenesis

Adipose tissue contains adipocytes, vascular cells, fibroblasts, cells of the innate (e.g., monocytes, macrophages, natural killer cells) and adaptive (e.g., lymphocytes) immune systems, and other cell types essential to its normal physiology that become abnormally altered and interact in the pathophysiology of obesity-related cardiometabolic complications [285,296]. To expand triglyceride storage as obesity develops and fat mass increases further, adipocytes abnormally increase in number (hyperplasia), then in size (hypertrophy) [278,285]. Hypertrophy compromises the function of adipose tissue, degrading the extracellular matrix which promotes a switch toward fibrosis that restricts adipocyte fat storage [295,298].

Triglyceride accumulation promotes hypoxia, apoptosis, and oxidative and mitochondrial stress in adipocytes and release of pro-inflammatory factors [287,296]. As obesity advances, lipid-laden hypertrophied adipocytes undergo necrotic and/or apoptotic cell death, contributing to the recruitment of inflammatory cells and to adipose tissue dysfunction [298].

Adipose tissue macrophages are essential for maintaining adipose tissue energy homeostasis and inflammatory response [291]. The adipose tissue macrophage phenotypic correlates to BMI and adipocyte size [296]. The obesity-induced M1 phenotype is associated with inflammation and tissue destruction; M1 may comprise 50% of all adipose tissue cells (compared with 10% to 15% in lean adults) [298,299].

As adipose tissue expands, angiogenesis lags. The hypoxic state triggers an inflammatory response, which initiates monocyte recruitment and differentiation into M1 adipose tissue macrophages [299]. Circulating macrophages infiltrate adipose tissue, producing MCP-1, which recruits more inflammatory cells to adipose tissue and TNF-a and further promotes MCP-1 production by adipocytes, recruiting yet more immune cells to adipose tissue. The M2 to M1 shift aggravates a vicious cycle of chronic low-grade inflammation [128,285].

Systemic Pathogenesis

The inflammatory adipose tissue microenvironment diffuses systemically and to remote organ sites. MCP-1 recruitment and proliferation into liver, adipose, pancreatic islet, intestine, and muscle tissue induces a pro-inflammatory M1 state [299]. Cytokines (TNF-a, IL-1b, IL-6) and adipokines (leptin) activate systemic and organ-specific inflammatory signaling pathways, impairing β-cell function, suppressing insulin secretion, and promoting accumulation of ectopic fat, insulin resistance and hyperglycemia [287,297,298,300].

Adiposopathic tissue pumps free fatty acids into circulation, leading to ectopic pathogenic deposition of fatty acids into pericardial and perivascular fat depots, within/around the liver, muscle, heart, pancreas, and kidney [128]. Ectopic fat intensifies local inflammatory activity and promotes lipotoxicity [300].

Insulin resistance in adipocytes impedes fat storage, accelerates lipolysis and further increases plasma free fatty acids, promoting insulin resistance in liver and muscle, hepatic steatosis and dyslipidemia, and contributing toβ‐cell failure. Insulin resistance in muscle and fat is marked by impaired glucose transport from circulation due to M1 inhibition of GLUT4, leading to hyperglycemia [301].

Increased ectopic fat deposition, lipotoxicity from excess circulating free fatty acids, glucose toxicity, along withβ‐cell resistance to GLP-1, cause progressive failure ofβ‐cell functioning. Increased glucagon and enhanced liver sensitivity to glucagon lead to excessive hepatic glucose production. Increased renal glucose reabsorption by sodium/glucose co‐transporter 2 (SGLT2) helps maintain hyperglycemia.

Insulin resistance in obesity leads to chronic compensatory hyperinsulinemia, which in turn promotes further weight gain [302]. This is exacerbated by resistance to the anorexigenic effects of insulin, leptin, GLP-1, amylin, and PYY [303].

Insulin resistance, hyperglycemia, and hyperinsulinemia in obesity promote hypertension, dyslipidemia, endothelial dysfunction, and a prothrombotic state, leading to NAFLD and type 2 diabetes [304]. NAFLD increases the risk of liver cirrhosis and hepatocellular carcinoma and is strongly correlated with cardiovascular disease and type 2 diabetes [305].

Type 2 diabetes, the predominant consequence of insulin resistance accounting for more than 90% of all diabetes cases, can lead to disabling and life-threatening microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiovascular disease) complications [304,306].

Biomechanical Consequences of Obesity

Local biomechanical stress due to excessive fat mass and body weight (e.g., on the joints, respiratory tract, blood vessels or within the abdominal compartment) causes and/or exacerbates morbidities common in patients with obesity, such as knee osteoarthritis, back pain, restrictive lung disease, obstructive sleep apnea, gastroesophageal reflux disease (GERD), hernias, and chronic venous insufficiency. These complications are further aggravated by the adverse metabolic profile and chronic inflammatory state in obesity, amplifying the overall burden of the disease and creating a vicious cycle that can be effectively broken only by sustained weight loss [302].

"Metabolically Healthy" Obesity

The concept of metabolically healthy obesity has been described in the literature. In general, it is defined as obesity in the absence of type 2 diabetes, hypertension, and hypercholesterolemia. Some have questioned the cardiovascular disease risk of persons with metabolically healthy obesity, suggesting this as a low-risk phenotype [307]. However, a large cohort demonstrated that obesity is a risk factor for cardiovascular disease regardless of whether the individual remained metabolically healthy over long periods [308]. Furthermore, a study of 270 patients who met strict inclusion criteria for metabolically healthy obesity found that even with strict criteria to eliminate all patients with any metabolic problems, a significant proportion had unsuspected NAFLD (35.5%); some had steatohepatitis (8.2%) and liver fibrosis (4.4%) [305].

Psychiatric Disorders

The neuropathological processes that lead to psychiatric disorders share common brain pathways with those that lead to obesity, metabolic syndrome, and cardiovascular disease risk factors, each of which can influence the risk for the others. Evidence points to a critical role for two major pathways: inflammatory processes that induce alterations of brain functions, and chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis [87].

Psychiatric disorders are often characterized by a chronic HPA axis activation and sustained cortisol elevation, both of which are linked to abdominal obesity, hepatic steatosis, insulin resistance, and cardiovascular disease. Conversely, increased adiposity leads to chronic low-grade activation of inflammatory processes, which plays a potent role in the pathophysiological brain alterations associated with psychiatric disease. Thus, adiposity-driven inflammation may contribute to the growing prevalence of mood disorders [87].

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Evidence-Based Practice Recommendations Citations

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