WVLPN26 • West Virginia LPNs 2025-2026

Table of Contents

WVLPN26 • West Virginia LPNs 2025-2026

How to Receive Credit

NetCE 4 Hour Course #93010 • Maternal Health Disparities

93010 • Maternal Health Disparities

1. INTRODUCTION

2. EPIDEMIOLOGY

3. EXPLICIT AND IMPLICIT BIAS

4. INTERCULTURAL COMPETENCE AND CULTURAL IDENTITY

5. INTERVENTIONS TO REDUCE IMPLICIT BIAS AND RELATED MATERNAL HEALTH DISPARITIES

6. RESOURCES

7. CONCLUSION

8. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

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 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

WVLPN26 • West Virginia LPNs 2025-2026

Mary Franks, MSN, APRN, FNP-C

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

WVLPN26 • West Virginia LPNs 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.

93010 • Maternal Health Disparities

Mary Franks, MSN, APRN, FNP-C

www.netce.com

Copyright © 2023 NetCE, All rights reserved.

There is no question that maternal health disparities are a significant problem in the United States. Inequalities have been noted associated with many factors, including education level, literacy, and socioeconomic status. However, the greatest disparities have been noted among racial/ethnic minority women and have been linked to explicit and implicit biases in healthcare providers and systems. It is of the utmost importance that those working in health care and caring for patients in the peripartum and postpartum period are committed on lowering the morbidity and mortality rates of all mothers of color. Promoting equity and cultural competence, effectively addressing modifiable risk factors, improving communication and monitoring, and engaging in regular training are needed to improve these maternal health disparities.

Table of Contents

93010 • Maternal Health Disparities

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Individual State Behavioral Health 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. EPIDEMIOLOGY

WORLDWIDE

UNITED STATES

NEW JERSEY

3. EXPLICIT AND IMPLICIT BIAS

POWER DYNAMICS

ORGANIZATIONAL FACTORS

STRATEGIES TO PROMOTE AWARENESS

IMPACT OF BIAS ON THE DELIVERY OF PERINATAL CARE

4. INTERCULTURAL COMPETENCE AND CULTURAL IDENTITY

BLACK PATIENTS

ASIAN PATIENTS

LATINO/A/X OR HISPANIC PATIENTS

NATIVE AMERICAN PATIENTS

WHITE AMERICAN PATIENTS

BARRIERS TO INCLUSION

CULTURALLY RESPONSIVE COMMUNICATION

RACIAL AND REPRODUCTIVE JUSTICE

5. INTERVENTIONS TO REDUCE IMPLICIT BIAS AND RELATED MATERNAL HEALTH DISPARITIES

PERSPECTIVE TAKING

EMPATHY INTERVENTIONS

INDIVIDUATION

MINDFULNESS

COUNTER-STEREOTYPICAL IMAGING

CHIEF EQUITY OFFICERS

6. RESOURCES

7. CONCLUSION

8. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

93010 • Maternal Health Disparities

Education Category. Women's Health - Maternal / Child

Release Date. 11/01/2023

Expiration Date. 10/31/2026

Course Overview

There is no question that maternal health disparities are a significant problem in the United States. Inequalities have been noted associated with many factors, including education level, literacy, and socioeconomic status. However, the greatest disparities have been noted among racial/ethnic minority women and have been linked to explicit and implicit biases in healthcare providers and systems. It is of the utmost importance that those working in health care and caring for patients in the peripartum and postpartum period are committed on lowering the morbidity and mortality rates of all mothers of color. Promoting equity and cultural competence, effectively addressing modifiable risk factors, improving communication and monitoring, and engaging in regular training are needed to improve these maternal health disparities.

Audience

This course is designed for all healthcare providers who may intervene to improve peripartum and postpartum health care and reduce health disparities.

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 has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6361. Programs that do not qualify for NBCC credit are clearly identified. NetCE is solely responsible for all aspects of the programs. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. 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 4 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 4 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 4 ANCC contact hour(s). NetCE designates this continuing education activity for 4.8 hours for Alabama nurses. NetCE designates this continuing education activity for 1 NBCC clock hour(s). Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 4 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. Social workers participating in this intermediate to advanced course will receive 4 Clinical continuing education clock hours. 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 4 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. 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 0.4 CEU(s) for this program. AACN Synergy CERP Category B.

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.

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190;

Special Approvals

This course is designed to meet the New Jersey requirement for implicit and explicit bias education for those healthcare professionals who provide perinatal treatment and care to pregnant persons. This course fulfills the Maryland requirement for 3 hours of anti-oppressive content, including cultural humility, social justice, racial equity, implicit bias, or anti-racism practices. NetCE is approved as a provider of continuing education by the California Consortium of Addiction Programs and Professionals. Provider Number 5-08-151-0626. NetCE is approved as a provider of continuing education by the California Association of DUI Treatment Programs (CADTP). Provider Number 185. This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency. NetCE designates this continuing education activity for 4 continuing education hours for addiction professionals.

Course Objective

The purpose of this course is to provide healthcare professionals with the knowledge and skills necessary to improve maternal outcomes in all races, ethnicities, and marginalized groups.

Learning Objectives

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

1. Outline the epidemiology of maternal morbidity and mortality.

2. Discuss how explicit and implicit bias may contribute to pregnancy-related deaths and maternal and infant health outcomes.

3. Identify cultural identity across racial, ethnic, and other marginalized groups, including historical and contemporary exclusion and oppression.

4. Identify environmental, personal, interpersonal, institutional, and cultural barriers to inclusion.

5. Discover communicating more effectively across racial, ethnic, religious, and gender identities.

6. Review information about racial and reproductive justice.

7. Identify measures to decrease explicit and implicit bias at the interpersonal and institutional levels.

Faculty

Mary Franks, MSN, APRN, FNP-C, is a board-certified Family Nurse Practitioner and NetCE Nurse Planner. She works as a Nurse Division Planner for NetCE and a per diem nurse practitioner in urgent care in Central Illinois. Mary graduated with her Associate’s degree in nursing from Carl Sandburg College, her BSN from OSF Saint Francis Medical Center College of Nursing in 2013, and her MSN with a focus on nursing education from Chamberlain University in 2017. She received a second master's degree in nursing as a Family Nurse Practitioner from Chamberlain University in 2019. She is an adjunct faculty member for a local university in Central Illinois in the MSN FNP program. Her previous nursing experience includes emergency/trauma nursing, critical care nursing, surgery, pediatrics, and urgent care. As a nurse practitioner, she has practiced as a primary care provider for long-term care facilities and school-based health services. She enjoys caring for minor illnesses and injuries, prevention of disease processes, health, and wellness. In her spare time, she stays busy with her two children and husband, coaching baseball, staying active with her own personal fitness journey, and cooking. She is a member of the American Association of Nurse Practitioners and the Illinois Society of Advanced Practice Nursing, for which she is a member of the bylaws committee.

Faculty Disclosure

Contributing faculty, Mary Franks, MSN, APRN, FNP-C, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Margo A. Halm, RN, PhD, NEA-BC, FAAN

Alice Yick Flanagan, PhD, MSW

Margaret Donohue, PhD

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

Substantial differences in maternal morbidity and mortality among racial and ethnic groups exist in the United States. Black women are more than twice as likely to die related to maternal complications compared with White women [1]. The Centers for Disease Control and Prevention (CDC) reports that nearly 20% of surveyed women reported experiences of mistreatment during their pregnancy and/or the delivery of their child/children [2]. However, the reported rates were higher among Black (30%), Hispanic (29%), and multiracial (27%) patients.

Increasingly, research has shown that the quality of health care is an important lever for expanding positive outcomes for racial and ethnic minority women [1]. This course will identify underlying drivers of maternal disparities, review potential contributing factors (with the intention of supporting amelioration), and outline approaches to improve maternal outcomes. This course will also explore supportive measures, particularly in minority populations to reduce explicit and implicit bias in perinatal care.

2. EPIDEMIOLOGY

WORLDWIDE

The United Nations International Children's Emergency Fund (UNICEF) reports an overall global 34% decline in the maternal mortality rate, from 342 maternal deaths per 100,000 live births in 2000 to 223 maternal deaths per 100,000 live births in 2020 [3]. This decrease is consistent with achieving the sustainable development goal of 70 maternal deaths per 100,000 live births by 2030. However, the maternal mortality rates plateaued in Western Europe and North America between 2016 and 2022, and Latin America and the Caribbean noted an increase over the same period. The goal annual reduction rate is 15% for every country [3].

The location with the largest number of maternal deaths is sub-Saharan Africa, where the rate is 545 maternal deaths per 100,000 live births. Countries with the lowest rates of maternal mortality include Australia and New Zealand (with 4 maternal deaths per 100,000 live births) [3]. Among regions, women in sub-Saharan Africa face the highest lifetime risk of maternal death (1 in 41), which is approximately 268 times higher than in Western Europe (1 in 11,000), the lowest-risk region [3].

UNITED STATES

In the United States, maternal deaths represent the largest disparity among all populations within perinatal health measures. The maternal mortality rate in the United States is unacceptably high and rising. In 2021, 1,205 women died of maternal causes in the United States, compared with 861 in 2020 and 754 in 2019 [4]. The maternal mortality rate for 2021 was 32.9 deaths per 100,000 live births, compared with a rate of 23.8 in 2020 and 20.1 in 2019. More than 80% of all pregnancy-related deaths that occur in the United States are considered preventable [5].

Maternal mortality rates in the United States are higher among American Indian, Alaskan Native, Pacific Islander/Native Hawaiian, and Black women than among Asian, Hispanic, or White populations [6]. In 1933, the first time all states reported maternal deaths, the maternal mortality rate for Black women (1,000 deaths per 100,000 births) was 1.8 times greater than the rate for White women (564 deaths per 100,000 births). As of 2021, maternal death rates among Black women (69.9 per 100,000 births) had risen to 2.6 times higher than the rate noted for White women (26.6 per 100,000 births) [7].

Increases in maternal mortality rates are significantly greater among women 40 years of age and older. In this group, the mortality rate was 138.5 deaths per 100,000 live births in 2021 [7]. This represents an 83.4% increase compared with 2019. Data reported by the U.S. Government Accountability Office between 2020 and 2021 indicate the COVID-19 pandemic is a contributing factor to the increasing maternal mortality rate. This was believed to be linked to the chronic physiological stress present during pregnancy paired with severe illness from COVID-19 [8].

Evidence Based Practice Recommendation

The American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine recommend using two criteria to screen for severe maternal morbidity: transfusion of 4 or more units of blood and admission of a pregnant or postpartum patient to an intensive care unit.

https://www.acog.org/clinical/clinical-guidance/obstetric-care-consensus/articles/2016/09/severe-maternal-morbidity-screening-and-review

Last Accessed: October 16, 2023

Strength of Recommendation: Expert Opinion/Consensus Statement

The CDC considers the following diagnoses/procedures as indicators of delivery hospitalizations with severe maternal mortality [9]:

- Acute myocardial infarction

- Aneurysm

- Acute renal failure

- Acute respiratory distress syndrome (ARDS)

- Amniotic fluid embolism

- Cardiac arrest/ventricular fibrillation

- Conversion of cardiac rhythm

- Disseminated intravascular coagulation

- Eclampsia

- Heart failure/arrest during surgery or procedure

- Puerperal cerebrovascular disorders

- Pulmonary edema/acute heart failure

- Severe anesthesia complications

- Sepsis

- Shock

- Sickle cell disease with crisis

- Air and thrombotic embolism

- Hysterectomy

- Temporary tracheostomy

- Ventilation

Blood transfusion is not included on this list but is considered separately as a potential indicator.

In addition to mortality, obstetric morbidity is also associated with increased risk in the minority populations, particularly for non-Hispanic Black women. For every reported maternal death, 100 women experience a severe obstetric disease or life-threatening diagnosis during their hospitalization for delivery. Analysis of 2012–2015 data indicates that the incidence of severe maternal morbidity was significantly higher among deliveries to women in every racial and ethnic minority category compared with deliveries among non-Hispanic White women [10]. Severe maternal morbidity occurred at a rate of 231.1 per 10,000 delivery hospitalizations for non-Hispanic Black patients; the rate was 139.2 per 10,000 delivery hospitalizations among non-Hispanic White women. Racial and ethnic minority women have higher rates on most major morbidity indicators than White patients [1,9].

NEW JERSEY

In 2018, the New Jersey legislature enacted P.L. 2018, c.82, which requires the New Jersey Department of Health to issue a report on hospital maternity care. This report (often referred to as the maternal health report card for the state of New Jersey) gives insights into the evolution of the maternal population as well as trends in serious maternal morbidity and mortality [10]. Over time, the maternal population in New Jersey has become more diverse. In 2020, 54% of mothers identified as a race/ethnicity other than White, compared with 46% in 2000 [10]. There has also been a trend away from hospital births, with a 2% decrease in hospital deliveries between 2019 and 2020 [10].

The report assesses five measures to track maternal morbidities and delivery complications in the state: third- and fourth-degree perineal laceration, episiotomy, obstetric hemorrhage, post-admission infections, and severe maternal morbidity (a surrogate for other complications) [10]. In 2020, non-Hispanic Black mothers in New Jersey were noted to have the highest rate of obstetric hemorrhage, defined as cumulative blood loss greater than 1,000 mL regardless of the method of delivery (i.e., vaginal or cesarean birth) or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process. Risk factors for obstetric hemorrhage were Non-Hispanic Black or Hispanic race, cesarean delivery, placental or uterine disorders, nulliparity, premature gestational age, infection, pre-existing anemia, ICU admission, and pre-pregnancy overweight or obesity [10].

Non-Hispanic Black mothers in New Jersey also had the highest rate of severe maternal morbidity with need for blood transfusion, at a rate of 36.5 cases per 1,000 delivery hospitalizations. This represented a slight increase from the 2019 rate (35.6 cases per 1,000 delivery hospitalizations) [10]. Hispanic patients had the second highest rate (25.2 cases per 1,000 delivery hospitalizations). Non-Hispanic White mothers had the lowest documented transfusion rate (15.7 cases per 1,000 delivery hospitalizations)—a rate less than half that of Black mothers [10].

Asian mothers were identified to have the highest risk of third- and fourth-degree perineal tears without instrumentation (3.4 cases per 100 delivery hospitalizations). Hispanic and non-Hispanic Black mothers had the lowest rate of this complication (0.9 cases per 100 delivery hospitalizations) [10].

Asian mothers were also the most likely to experience episiotomies (11.6 cases per 100 delivery hospitalizations). The rate among this population is almost triple the next most likely group, Hispanic patients (4.3 cases per 100 delivery hospitalizations). Non-Hispanic Black mothers had the lowest episiotomy rate, at 2.8 cases per 100 delivery hospitalizations [10].

Postadmission infections were also most likely among Asian patients, who had a reported rate of 25.4 cases per 1,000 delivery hospitalizations. Hispanic mothers followed closely, with a rate of 21.8 per 1,000 delivery hospitalizations. The lowest rate occurred among non-Hispanic White mothers, who had a postadmission infection rate of 12.7 cases per 1,000 delivery hospitalizations (half the rate among Asian patients) [10].

Between 2016 and 2018, a total of 125 deaths with a temporal relationship to pregnancy (within 365 days) were reported in New Jersey [11]. Of these deaths, 44 (35%) were determined to be pregnancy-related, 74 (59%) were pregnancy-associated but not related, and 7 (6%) were unable to be determined. As in the rest of the country, the maternal mortality outcomes for non-Hispanic Black women continue to be largely disparate when compared to White women. The maternal mortality rate for Black women in New Jersey (39.2 deaths per 100,000 live births) is 6.6 times higher than the rate for White women (5.9 per 100,000 live births). The rate for Hispanic women (20.6 per 100,000 live births) is 3.5 times higher than the rate for White women [11].

3. EXPLICIT AND IMPLICIT BIAS

Bias plays a pivotal role in health care, especially patient care. Therefore, it is important to define the term. In a sociocultural context, biases are generally defined as negative evaluations of a particular social group relative to another group. Explicit biases are conscious, whereby an individual is fully aware of his/her attitudes and there may be intentional behaviors related to these attitudes [13]. For example, an individual may openly endorse a belief that women are weak, and men are strong. This bias is fully conscious and is made explicitly known. Implicit bias refers to the unconscious attitudes and evaluations held by individuals. These individuals do not necessarily endorse the bias, but the embedded beliefs/attitudes can negatively affect their behaviors [14,15,16,17]. Some have asserted that the cognitive processes that dictate implicit and explicit biases are separate and independent [17].

Implicit biases can start as early as 3 years of age. As children age, they may begin to become more egalitarian in what they explicitly endorse, but their implicit biases may not necessarily change in accordance with these outward expressions [18]. Because implicit biases occur on the subconscious or unconscious level, particular social attributes (e.g., skin color) can quietly and insidiously affect perceptions and behaviors [19]. According to Georgetown University's National Center on Cultural Competency, social characteristics that can trigger implicit biases include [20]:

- Age

- Disability

- Education

- English language proficiency and fluency

- Ethnicity

- Health status

- Disease/diagnosis (e.g., HIV/AIDS)

- Insurance

- Obesity

- Race

- Socioeconomic status

- Sexual orientation, gender identity, or gender expression

- Skin tone

- Substance use

An alternative way of conceptualizing implicit bias is that an unconscious evaluation is only negative if it has further adverse consequences on a group that is already disadvantaged or produces inequities [21,22]. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages [21].

Implicit bias has been linked to a variety of health disparities [23]. Health disparities are differences in health status or disease that systematically and adversely affect less advantaged groups [24]. These inequities are often linked to historical and current unequal distribution of resources due to poverty, structural inequities, insufficient access to health care, and/or environmental barriers and threats [25]. As illustrated, health disparities have been clearly documented in maternal and perinatal care among racial/ethnic groups.

In an ideal situation, health professionals would be explicitly and implicitly objective, and clinical decisions would be completely free of bias. However, healthcare providers have implicit (and explicit) biases at a rate comparable to that of the general population [22,26]. It is possible that these implicit biases shape healthcare professionals' behaviors, communications, and interactions, which may produce differences in help seeking, diagnoses, and ultimately treatments and interventions [26]. They 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 [15].

POWER DYNAMICS

Power dynamics are inevitable in many situations, including throughout the healthcare system, when two or more individuals are attempting to balance the power among themselves. These dynamics may look different in various situations. Seven types of power dynamics have been identified: coercive, expert, reward, informational, formal, referent, and connection [27]. When power is exerted differently between the parties, inequity can result. In practice, healthcare professionals may use power to protect their autonomy and exert their expertise. This can lead to problems in interprofessional collaboration and in a failure to focus on the patient's role in making healthcare decisions, advocating for their needs and preferences, and being an empowered member of the care team. Communication, competence, and role perceptions are common factors that influence power dynamics [28].

ORGANIZATIONAL FACTORS

Larger organizational, institutional, societal, and cultural forces contribute, perpetuate, and reinforce implicit and explicit biases, racism, and discrimination. Psychological and neuroscientific approaches ultimately decontextualize racism [17,29]. Sources of bias in organizations include internal politics, culture, leadership, organizational history, and team-specific structures. Organizational bias reaches far beyond individuals themselves; the language used or tasks identified influence how the organization functions daily [30]. Bias within an organization can detour patients from visiting if they feel they are being viewed or cared for as a "lesser" patient. One of the primary roles and responsibilities of health professionals is to analyze how institutional and organizational factors promote racism and implicit bias and how these factors contribute to health disparities. This analysis should extend to include one's own position in this structure.

STRATEGIES TO PROMOTE AWARENESS

It is important to promote awareness of bias—both explicit and implicit biases and at personal, organizational, and professional levels. Education and training are powerful tools to identify and address issues related to bias. Reflection exercises and role play can be used, as hands-on skills are necessary in order to apply theories to practice. Creating safe environments and using skill-building exercises are key components of any program designed to reduce biases and related health disparities [31].

Harvard University sponsors Project Implicit, a research project which monitors implicit biases. Project Implicit houses the Implicit Association Test (IAT), which can be used as a metric to assess professionals' level of implicit bias on a variety of subjects, and this presupposes that implicit bias is a discrete phenomenon that can be measured quantitatively [32]. When providers are aware that implicit biases exist, discussion and education can be implemented to help reduce them and/or their impact. The IAT is available at https://implicit.harvard.edu/implicit, and anyone may complete an assessment.

Another way of facilitating awareness of providers' implicit bias is to ask self-reflective questions about each interaction with patients. Some have suggested using SOAP (or subjective, objective, assessment, and plan) notes to assist practitioners in identifying implicit biases in day-to-day interactions with patients [33]. Integrating the following questions into charts and notes can stimulate reflection about implicit bias globally and for each specific patient interaction:

- Did I think about any socioeconomic and/or environmental factors that may contribute to the health and access of this patient?

- How was my communication and interaction with this patient? Did it change from my customary pattern?

- How could my implicit biases influence care for this patient?

When reviewing the SOAP notes, providers can look for recurring themes of stereotypical perceptions, biased communication patterns, and/or types of treatment/interventions proposed and assess whether these themes could be influenced by biases related to race, ethnicity, age, gender, sexuality, or other social characteristics. A review of empirical studies conducted on the effectiveness of interventions promoting implicit bias awareness found mixed results. At times, after a peer discussion of IAT scores, participants appeared less interested in learning and employing implicit bias reduction interventions. However, other studies have found that receiving feedback along with IAT scores resulted in a reduction in implicit bias. Any feedback, education, and discussions should be structured to minimize participant defensiveness [34].

IMPACT OF BIAS ON THE DELIVERY OF PERINATAL CARE

Worldwide, the maternal mortality has decreased 43% since 1993. However, the United States is the only developed country in which maternal mortality has increased [35]. As of 2023, the United States reports the highest maternal mortality of all developed countries. The rate in New Jersey (25.7 maternal deaths per 100,000 live births) is higher than the national average (23.5 deaths per 100,000 live births). The greatest rates tend to occur in the South [36].

What is further troubling is that most maternal deaths and cases of severe morbidity are preventable [35]. This then leads to the necessary question: Why are these deaths occurring? A review of maternal deaths across nine states found that the deaths were most commonly related to "clinician, facility, and system factors, such as inadequate training, missed or delayed diagnosis of complications, poor communication, and lack of coordination between clinicians" [37]. Improvements in clinician knowledge, skill, interprofessional collaboration, and bias could make inroads to improving maternal health care in the United States.

In a survey of 2,402 women regarding their maternal care, the following mistreatments were most commonly reported [2]:

- Receiving no response to requests for help

- Being shouted at or scolded

- Not having their physical privacy protected

- Being threatened with withholding treatment or made to accept unwanted treatment

About 30% of Black, Hispanic, and multiracial women reported mistreatment, with lower rates or reported mistreatment among White (19%), Native American/Alaska Native/Native Hawaiian/Pacific Islander (18%), and Asian (15%) patients. Mistreatment was most commonly reported by those with no insurance (28%) or public insurance (26%); only 16% of those with private insurance reported mistreatment. Patients most commonly reported discrimination and/or mistreatment during prenatal care related to age, weight, income, and race/ethnicity [2]. About 29% of women experienced discrimination, with the highest rates among Black (40%), multiracial (39%), and Hispanic (37%) women [2]. While satisfaction with maternity care overall was high (90%), satisfaction among those who reported mistreatment was considerably lower (75%). Mistreatment and discrimination impact experiences of care.

Social determinants of health are the conditions in the environments where people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks. These circumstances are shaped by the distribution of money, power, and resources at global, national, and local levels. For example, historical economic stresses and restrictions on housing, jobs, and education have resulted in health inequalities for racial and ethnic minority groups. Healthy People 2030 groups social determinants of health into five categories [38]:

- Economic stability

- Education access and quality

- Health care access and quality

- Social and community context

- Neighborhood and built environment

These factors have a major impact on people's health, well-being, and quality of life. Social determinants contribute to maternal outcomes; however, they do not fully explain the large number of women of racial and ethnic backgrounds having higher than average maternal morbidity and mortality rates [37].

Implicit biases have been directly linked with lesser quality of care for certain patients, particularly those of minority groups. In some cases, this lower quality of care is triggered by stressful circumstances [35]. One explanation is that implicit biases are a heuristic, or a cognitive or mental shortcut. Heuristics offer individuals general rules to apply to situations in which there is limited, conflicting, or unclear information. Use of a heuristic results in a quick judgment based on fragments of memory and knowledge, and therefore, the decisions made may be erroneous. If the thinking patterns are flawed, negative attitudes can reinforce stereotypes [39].

Negative stereotyping can be a contributing factor to maternal health disparities. For example, healthcare providers may neglect to recognize the pain of non-Hispanic Black women or feel that this group's expressions of pain are more disproportionate than their actual experiences. One study found that a Black woman in New York City with a college education is nearly three times more likely to endure severe maternal morbidities compared with a White woman of similar age with less than a high school education [37]. In one study of patients following cesarean delivery, Black and Hispanic women were evaluated for pain less frequently, had higher pain scores, and received less pain medication than White women, even after controlling for other clinical factors, suggesting that these inequities are the result of different approaches to care delivery [40]. These implicit racial beliefs also have the potential to affect the way a patient is counseled about treatment options [35].

Evidence Based Practice Recommendation

In order to reduce Black maternal mortality, the Centers for Disease Control and Prevention recommends that healthcare providers:

- Ask questions to better understand their patient and things that may be affecting their lives.

- Help patients, and those accompanying them, understand the urgent maternal warning signs and when to seek medical attention right away.

- Help patients manage chronic conditions or conditions that may arise during pregnancy, like hypertension, diabetes, or depression.

- Recognize and work to eliminate unconscious bias in themselves and in their office on an ongoing basis.

- Respond to any concerns patients may have.

- Provide all patients with respectful quality care.

https://www.cdc.gov/healthequity/features/maternal-mortality

Last Accessed: October 16, 2023

Strength of Recommendation: Expert Opinion/Consensus Statement

Serious maternal complications, including hemorrhage, embolism, eclampsia, and stroke, occur in all racial and age groups; however, there is a clearly documented increased risk for racial or ethnic minority women. Failure to recognize these complications could be related to the high-stress environments in which they occur, but they may also be related to stereotypical unconscious thoughts related to minority groups [38].

Preconception counseling and care is critical to optimizing maternal health. This includes management of chronic diseases, maternal and fetal screenings, and lifestyle changes. Racial and/or ethnic minority women tend to have less accessibility to preconception and antenatal care [37]. Closing these access and engagement gaps could help address some of the disparities in birth complications.

Postnatal care is less emphasized but is a significantly important aspect of maternal care. During the eight weeks following delivery, the physical and emotional needs of the mothers should be assessed, including chronic health issues or complications that developed during the gestational period (e.g., gestational diabetes, hypertension, anemia, peripartum anxiety, peripartum depression). Unfortunately, it is reported that 16% to 36% of women do not attend a six-week follow-up visit following birth [36]. Furthermore, those who do attend the six-week visit report insufficient care and postnatal guidance, indicating a need to improve both adherence and provision of care during this period.

Healthcare professionals have a responsibility to repair biased systems that perpetuate racial health disparities. The American College of Obstetricians and Gynecologists has released a statement on racism in obstetrics and gynecology that reads, in part, [41]:

Racial and ethnic inequities in obstetrics and gynecology cannot be reversed without addressing all aspects of racism and racial bias, including sociopolitical forces that perpetuate racism. The actualization of an equitable health care system which serves all people can only occur through acknowledgment of the historical context from which modern health inequities grew, including reproductive injustices.

4. INTERCULTURAL COMPETENCE AND CULTURAL IDENTITY

Cultural identity is defined as the "shared characteristics of a group of people, which encompasses place of birth, religion, language, cuisine, social behaviors, art, literature, and music" [42]. Cultural identity is important as it influences how we respond to different situations. In health care, cultural identity can influence the behaviors one exhibits, the barriers upheld, and professional decisions, interactions, and performance. Cultural identity can evolve, and even if one does not consider their culture consciously, it is exhibited subconsciously [43]. It is important to remember that one's cultural identity should not impede the care provided to patients. For example, religion can influence one's practice but it should not determine how one practices or the type or quality of care given.

Providing culturally responsive care can help to avoid practice that is influenced by explicit or implicit biases. The U.S. Department of Health and Human Services has outlined steps important to incorporate in evaluation and treatment planning processes to ensure culturally competent clinical and programmatic decisions and skills [44]. The first step is to engage patients. When engaging in any patient teaching, remember that individuals may be new to the specific language or jargon and expectations of the diagnosis and care process. Patients should be encouraged to collaborate in every step of their care. Practitioners should also work to identify screening and assessment tools that have been translated into or adapted for other languages and have been validated for their particular population group(s). Typically, culturally responsive care establishes holistic treatment goals that include objectives to improve physical health and spiritual strength; utilizes strengths-based strategies that fortify cultural heritage, identity, and resiliency; and recognizes that treatment planning is a dynamic process that evolves along with an understanding of patient history and treatment needs.

As part of the cultural competence process and as a reflection of cultural humility, practitioners should strive to learn as much as possible about the specific racial/ethnic populations they serve. However, considerable diversity exists within any specific culture, race, or ethnicity [45]. Cultural beliefs, traditions, and practices change over time, both through generations and within an individual's lifetime. It is also possible for the differences between two members of the same racial/ethnic group to be greater than the differences between two people from different racial/ethnic groups. Within-group variations in how people interact with their environments and specific social contexts are also often present.

In addition to these general approaches, specific considerations may be appropriate for specific populations. While discussion of every possible patient subgroup is outside of the scope of this course, some of the most common factors are outlined in the following sections.

BLACK PATIENTS

"Black" or "African American" is a classification that serves as a descriptor; it has sociopolitical and self-identification ramifications. The U.S. Census Bureau defines African Americans or Black Americans as persons "having origins in any of the Black racial groups of Africa" [46].

Historical adversity and institutional racism contribute to health disparities in this group. For the Black population, patient assessment and treatment planning should be framed in a context that recognizes the totality of life experiences faced by patients. In many cases, particularly in the provision of mental health care, equality is sought in the provider-patient relationship, with less distance and more disclosure. Practitioners should assess whether their practices connect with core values of Black culture, such as family, kinship, community, and spirituality. Generalized or Eurocentric treatment approaches may not easily align with these components of the Black community [47]. Providers should also consider the impact of racial discrimination on health and mental health among Black patients. Reports indicate that expressions of emotion by Black patients tend to be negatively misunderstood or dismissed; this reflects implicit or explicit biases.

ASIAN PATIENTS

"Asian" is a single term widely used to describe individuals who have kinship and identity ties to Asia, including the Far East, Southeast Asia, and the Indian subcontinent. This encompasses countries such as China, Japan, Korea, Vietnam, Cambodia, Thailand, India, Pakistan, and the Philippines. Pacific Islander is often combined with Asian American in census data. The Pacific Islands include Hawaii, Guam, Samoa, Fiji, and many others [48]. There are more than 25 Asian/Pacific Islander groups, each with a different migration history and widely varying sociopolitical environments in their homelands [49].

As of 2019, 22.9 million Americans identified as Asian [50]. Between 2000 and 2019, Asians experienced the greatest growth compared with any other racial group at 81% [51,52]. The Chinese group represents the largest Asian subgroup in the United States, and it is projected that this population will grow to 35.7 million between 2015 and 2040 [53,54].

Recommended best practices when caring for Asian American patients include:

- Create an advisory committee using representatives from the community.

- Incorporate cultural knowledge and maintain flexible attitudes.

- Provide services in the patients' primary language.

- Develop culturally specific questionnaires for intake to capture information that may be missed by standard questionnaires.

- Emphasize traditional values and incorporate traditional practices (e.g., acupuncture) into treatment plans, when appropriate and desired.

- Explore patient coping mechanisms that draw upon cultural strengths.

While these approaches have been identified as useful for Asian patients, they may be broadly applicable across racial groups.

LATINO/A/X OR HISPANIC PATIENTS

In 2020, the Hispanic population in the United States numbered 60.6 million, comprising 18.7% of the U.S. population [55]. As such, they are the largest ethnic minority group in the United States. The majority of the Hispanic population in the United States (63.3%) identify themselves as being of Mexican descent [56]. Approximately 27% of the U.S. Hispanic population identify as Puerto Rican, Cuban, Salvadoran, Dominican, Guatemalan, Colombian, Honduran, Ecuadorian, or Peruvian [57].

When involved in the care of Latinx/Hispanic individuals, practitioners should strive to employ personalismo (warm, genuine communication) and recognize the importance of familismo (the centrality of the family). More flexible scheduling strategies may be more successful with this group, if possible, and some patients may benefit from culturally specific treatment and ethnic and gender matching with providers. Aspects of Latino culture can be assets in treatment: strength, perseverance, flexibility, and an ability to survive.

NATIVE AMERICAN PATIENTS

The Native American population is extremely diverse. According to the U.S. Census, the terms "Native American," "American Indian," or "Alaskan Native" refer to individuals who identify themselves with tribal attachment to indigenous groups of North and South America [58]. In the United States, there are 574 federally recognized tribal governments and 324 federally recognized reservations [59].

In 2020, it was reported that there were 7.1 million Native Americans in the United States, which is approximately 2% of the U.S. population. By 2060, this number is projected to increase to 10.1 million, or 2.5% of the total population [59].

Listening is an important aspect of rapport building with Native American patients, and practitioners should use active listening and reflective responses. Assessments and histories may include information regarding patients' stories, experiences, dreams, and rituals and their relevance. Interruptions and excessive questioning should be avoided if possible. Extended periods of silence may occur, and time should be allowed for patients to adjust and process information. Practitioners should avoid asking about family or personal matters unrelated to presenting issues without first asking permission to inquire about these areas. Native American patients often respond best when they are given suggestions and options rather than directions.

WHITE AMERICAN PATIENTS

In 2021, 76.3% of the U.S. population identified as White alone [60]. The U.S. Census Bureau defines White race as a person having origins in any of the original peoples of Europe, the Middle East, or North Africa [46]. While the proportion of the population identifying as White only decreased between 2010 and 2020, the numbers of persons identifying as White and another race/ethnicity increased significantly. The White population in the United States is diverse in its religious, cultural, and social composition. The greatest proportion of this group reports a German ancestry (17%), followed by Irish (13%), English (10%), and Italian (7%) [61].

Providers can assume that most well-accepted treatment approaches and interventions have been tested and evaluated with White American individuals, particularly men. However, approaches may need modification to suit class, ethnicity, religion, and other factors.

Providers should establish not only the patient's ethnic background but also how strongly the person identifies with that background. It is also important to be sensitive to a person's multiracial/multiethnic heritage, if present, and how this might affect their family relationships and social experiences. Assumption of White race should be avoided, as White-passing persons of color have their own unique needs.

BARRIERS TO INCLUSION

Culturally diverse patients experience a variety of barriers when seeking health and mental health care, including:

- Immigration status

- Lower socioeconomic status

- Language barriers

- Cultural differences

- Lack of or poor health insurance coverage

- Fear of or experiences with provider discrimination

- Mistrust of healthcare systems

Such obstacles can interfere with or prevent access to treatment and services, compromise appropriate referrals, affect compliance with recommendations, and result in poor outcomes. Culturally competent providers build and maintain rich referral resources to meet patients' assorted needs.

Encountering discrimination when seeking health or mental health services is a barrier to optimal care and contributor to poorer outcomes in under-represented groups. Some providers will not treat patients because of moral objections, which can affect all groups, but particularly those who are gender and/or sexual minorities, religious minorities, and/or immigrants. In fact, in 2016, Mississippi and Tennessee passed laws allowing health providers to refuse to provide services if doing so would violate their religious beliefs [62]. However, it is important to remember that providers are obligated to act within their profession's code of ethics and to ensure all patients receive the best possible care.

CULTURALLY RESPONSIVE COMMUNICATION

Styles of communication can be classified from high- to low-context [63]. High-context cultures are those cultures that disseminate information relying on shared experience, implicit messages, nonverbal cues, and the relationship between the two parties [64,65]. Members of these cultural groups tend to listen with their eyes and focus on how something was said or conveyed [63,66]. On the other hand, low-context cultures rely on verbal communication or what is explicitly stated in the conversation [64]. Consequently, low-context communicators listen with their ears and focus on what is being said [63,65,66]. Western culture, including the United States, can be classified as a low-context culture. On the other hand, groups from collectivistic cultures, such as Asian/Pacific Islanders, Hispanics, Native Americans, and Black Americans, are from high-context cultures [63].

Communicators from high-context cultures generally display the following characteristics [64,65,66,67]:

- Use of indirect modes of communication

- Use of vague descriptions

- Less talk and less eye contact

- Interpersonal sensitivity

- Use of feelings to facilitate behavior

- Assumed recollection of shared experiences

- Reliance on nonverbal cues such as gestures, tone of voice, posture, voice level, rhythm of speaking, emotions, and pace and timing of speech

- Assimilation of the "whole" picture, including visual and auditory cues

- Emotional speech

- Use of silence

- Use of more formal language, emphasizing hierarchy between parties

On the other hand, low-context communicators can typically be described as [64,65,66]:

- Employing direct patterns of communication

- Using explicit descriptions and terms

- Assuming meanings are described explicitly

- Utilizing and relying minimally on nonverbal cues

- Speaking more and often raising their voices (more animated, dramatic)

- Often being impatient to get to the point of the discussion

- Using more informal language; less emphasis on hierarchy, more equality between parties (more friendly)

- Being more comfortable with fluidness and change

- Uncomfortable using long pauses and storytelling as a means of communicating

Understanding the distinctions between individuals who come from high- and low-context cultures can promote cultural sensitivity. However, it is vital that practitioners take heed of several words of caution. First, it is important not to assume that two individuals sharing the same culture (e.g., low-context culture) will automatically have a shared script for communicating. Second, it is important to not immediately classify an individual into a low- or high-context culture because of their ethnicity. Third, a major criticism of the discussion of low-/high-context cultures is that they reinforce dualism and ultimately oversimplify the complexities and nuances of communication [68].

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options, and medication/treatment measures are being provided, the use of an interpreter should be considered. Whenever possible, professional interpreters are preferred. Family interpreters should be avoided if at all possible.

Preferred language and immigration/migration status should be considered. Stressing confidentiality and privacy is particularly important for undocumented workers or recent immigrants, who may be fearful of deportation.

RACIAL AND REPRODUCTIVE JUSTICE

Racial biases in healthcare access, treatment, and outcomes and institutional racism embedded in healthcare institutions contribute to poorer health outcomes in minority populations. Many healthcare organizations are committing to the improvement of racial inequalities by dedicating resources and infrastructure to negating this problem. Healthcare organizations and practitioners have a vital role in acknowledging and dismantling structural racism [69].

Race Forward defines racial justice as "a vision and transformation of society to eliminate racial hierarchies and advance collective liberation, where Black, Indigenous, Latinx, Asian Americans, Native Hawaiians, and Pacific Islanders, in particular, have the dignity, resources, power, and self-determination to fully thrive" [70]. In the context of health care, this concept is related to eliminating race-related health disparities, ensuring access and quality of care for minority groups, and improving quality of life for all persons, regardless of race, color, or ethnicity. This requires that practitioners take a perspective of cultural humility and proactively move to dismantle harmful stereotypes and practices.

It is vital to actively listen and critically evaluate patient relationships. All practitioners should seek to educate themselves regarding the experiences of patients who are members of a community that differs from their own. Resources and opportunities to collaborate may be available from community organizations and leaders.

The term "reproductive justice" was coined by a group of Black women in 1994 [90]. This concept, linked to racial justice, is based on the core belief that sexual and reproductive justice exists when all people have the power and resources to make healthy decisions about their bodies, sexuality, and reproduction. Reproductive justice sheds light on the multiple combined forms of oppression that contribute to the reproductive oppression of women of color. This perspective asserts that intersecting systems of oppression (e.g., race, class, gender) result in the control and exploitation of women, girls, gender-expansive individuals, and others through their bodies, sexuality, labor, and/or reproduction [90]. Persons who experience multiple oppressions experience more severe maternal morbidity. Only addressing all of the systemic issues contributing to poorer maternal health outcomes in persons of color will resolve racial health disparities in the United States.

5. INTERVENTIONS TO REDUCE IMPLICIT BIAS AND RELATED MATERNAL HEALTH DISPARITIES

According to the CDC, interventions to address bias on multiple levels can reduce pregnancy-related deaths [2]. Healthcare systems should foster a respectful maternity culture by hiring and retaining a diverse labor force and training all healthcare staff to identify implicit bias and stigma. The CDC also recommends healthcare systems promote quality improvement measures, focusing on increasing the respectful maternity culture for all women, so all patients feel they are equal regardless of race, ethnicity, or socioeconomic status. It is also ideal for healthcare professionals to strive for all maternal patients to feel respected, understood, supported, and valued throughout their care [2].

The American College of Obstetricians and Gynecologists makes the following recommendations for obstetrician/gynecologists and other healthcare providers to improve patient-centered care and decrease inequities in reproductive health care by [71]:

- Inquiring about and documenting social and structural determinants of health that may influence a patient's health and use of health care

- Maximizing referrals to social services to help improve patients' abilities to fulfill these needs

- Providing access to interpreter services for all patient interactions when patient language is not the clinicians' language

- Recognizing that stereotyping patients using presumed cultural beliefs can negatively affect patient interactions, especially when patients' behaviors are attributed solely to individual choices without recognizing the role of social and structural factors

The CDC has also launched the Hear Her campaign to provide resources for practitioners and pregnant and postpartum women, with an emphasis on preventing pregnancy-related deaths by sharing potentially life-saving messages about urgent warning signs. The Hear Her campaign can be accessed online at https://www.cdc.gov/hearher.

Adherence to guideline-endorsed practice may also help to reduce health disparities. In a Ghanaian study, provider adherence to antenatal care guidelines beginning in the first visit improved delivery and neonatal outcomes [89]. In addition, racial and ethnic disparities in severe maternal morbidity and mortality may be at least partially explained by variation in hospital quality. The majority of Black women who deliver in the United States (75%) do so in only 25% of hospitals; only 18% of White women deliver in those same hospitals [1]. The hospitals more likely to serve Black communities have higher risk-adjusted severe maternal morbidity rates, regardless of the patient's race/ethnicity, than the national average. Improving access to high-quality maternal health care and adherence to antenatal and postpartum guidelines may thus effectively reduce racial disparities in maternal morbidity and mortality.

In addition to these strategies, practitioners should act to address their own implicit biases. 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 [72]. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

PERSPECTIVE TAKING

Perspective taking is a strategy of taking on a first-person perspective of a person in order to control one's automatic response toward individuals with certain social characteristics that might trigger implicit biases [73]. The goal is to increase psychological closeness, empathy, and connection with members of the group [39]. Engaging with media that presents a perspective (e.g., watching documentaries, reading an autobiography) can help promote better understanding of the specific group's lives, experiences, and viewpoints. In one study, participants who adopted the first-person perspectives of Black Americans had more positive automatic evaluations of the targeted group [74].

EMPATHY INTERVENTIONS

Promoting positive emotions such as empathy and compassion can help reduce implicit biases. This can involve strategies like perspective taking and role playing [75]. In a study examining analgesic prescription disparities, nurses were shown photos of White or African American patients exhibiting pain and were asked to recommend how much pain medication was needed; a control group was not shown photos. Those who were shown images of patients in pain displayed no differences in recommended dosage along racial lines; however, those who did not see the images averaged higher recommended dosages for White patients compared with Black patients [76]. This suggests that professionals' level of empathy (enhanced by seeing the patient in pain) affected prescription recommendations.

In a study of healthcare professionals randomly assigned to an empathy-inducing group or a control group, participants were given the IAT to measure implicit bias prior to and following the intervention. The level of implicit bias among participants in the empathy-inducing group decreased significantly compared with their control group counterparts [77].

INDIVIDUATION

Individuation is an implicit bias reduction intervention that involves obtaining specific information about the individual and relying on personal characteristics instead of stereotypes of the group to which he or she belongs [39,73]. The key is to concentrate on the person's specific experiences, achievements, personality traits, qualifications, and other personal attributes rather than focusing on gender, race, ethnicity, age, ability, and other social attributes, all of which can activate implicit biases. When providers lack relevant information, they are more likely to fill in data with stereotypes, in some cases unconsciously. Time constraints and job stress increase the likelihood of this occurring [78].

MINDFULNESS

Mindfulness requires stopping oneself and deliberately emptying one's mind of distractions or allowing distractions to drift through one's mind unimpeded, focusing only on the moment; judgment and assumptions are set aside. This approach involves regulating one's emotions, responses, and attention to return to the present moment, which can reduce stress and anxiety [79]. There is evidence that mindfulness can help regulate biological and emotional responses and can have a positive effect on attention and habit formation [39]. A mindfulness activity assists individuals to be more aware of their thoughts and sensations. This focus on deliberation moves the practitioner away from a reliance on instincts, which is the foundation of implicit bias-affected practice [39,80].

Mindfulness approaches include yoga, meditation, and guided imagery. One approach to mindfulness using the acronym STOPP has been developed as a practical exercise to engage in mindfulness in any moment. STOPP is an acronym for [81]:

- Stop

- Take a breath

- Observe

- Pull back

- Practice

Mindfulness practice has been explored as a technique to reduce activation or triggering of implicit bias, enhance awareness of and ability to control implicit biases that arise, and increase capacity for compassion and empathy toward patients by reducing stress, exhaustion, and compassion fatigue [82]. One study examined the effectiveness of a loving-kindness meditation practice training in improving implicit bias toward Black and unhoused persons. One hundred one non-Black adults were randomized to one of three groups: a six-week loving-kindness mindfulness practice, a six-week loving-kindness discussion, or the waitlist control. The IAT was used to measure implicit biases, and the results showed that the loving-kindness meditation practice decreased levels of implicit biases toward both groups [83].

COUNTER-STEREOTYPICAL IMAGING

Counter-stereotypical imaging approaches involve presenting an image, idea, or construct that is counter to the oversimplified stereotypes typically held regarding members of a specific group. In one study, participants were asked to imagine either a strong woman (the experimental condition) or a gender-neutral event (the control condition) [84]. Researchers found that participants in the experimental condition exhibited lower levels of implicit gender bias. Similarly, exposure to female leaders was found to reduce implicit gender bias [85]. Whether via increased contact with stigmatized groups to contradict prevailing stereotypes or simply exposure to counter-stereotypical imaging, it is possible to unlearn associations underlying various implicit biases. If the social environment is important in priming positive evaluations, having more positive visual images of members in stigmatized groups can help reduce implicit biases. Some have suggested that even just hanging photos and having computer screensavers reflecting positive images of various social groups could help to reduce negative associations [86].

CHIEF EQUITY OFFICERS

Equity teams are encouraged to help with implicit bias in healthcare institutions. A chief equity officer has strong relationships in the delivery system and works to ensure health equity is prioritized. Those in this role are leaders with practical oversight of healthcare delivery and implementation. Equity officers are distinct from chief diversity officers, who focus more on internal recruiting, retention, and inclusion opportunities. An equity officer drives an agenda that addresses internal performance in quality and access for all patients, particularly vulnerable patients [87].

Chief equity officers often concentrate on staff preparation, responsibility, and biases, and work to assess and improve how staff regard and treat all patients, regardless of race, ethnicity, gender/sex, or socioeconomic status. Chief equity officers implement approaches to engage providers and the wider community to support and address medical and nonmedical (social determinants) risks to health outcomes [87].

6. RESOURCES

Maternal Mortality Review Committees

http://reviewtoaction.org/tools/networking-map

CDC Working Together to Reduce Black Maternal Mortality

https://www.cdc.gov/healthequity/features/maternal-mortality/index.html

American Bar Association Diversity and Inclusion Center

Toolkits and Projects

https://www.americanbar.org/groups/diversity/resources/toolkits

National Implicit Bias Network

https://implicitbias.net/resources/resources-by-category

New Jersey Maternal Care Quality Collaborative (NJMCQC)

https://www.nj.gov/health/maternal/mcqc

Ohio State University

The Women's Place: Implicit Bias Resources

https://womensplace.osu.edu/resources/implicit-bias-resources

Ohio State University

Kirwan Institute for the Study of Race and Ethnicity

http://kirwaninstitute.osu.edu

Partnership for Maternal and Child Health of Northern New Jersey

https://www.partnershipmch.org

University of California, Los Angeles

Equity, Diversity, and Inclusion: Implicit Bias

https://equity.ucla.edu/know/implicit-bias

University of California, San Francisco, Office of Diversity and Outreach

Unconscious Bias Resources

https://diversity.ucsf.edu/resources/unconscious-bias-resources

Unconscious Bias Project

https://unconsciousbiasproject.org

7. CONCLUSION

There is no question that maternal health disparities are a significant problem in the United States. Inequalities have been associated with many factors, including education level, literacy, age, and socioeconomic status. However, the greatest disparities have been noted among racial/ethnic minority women and have been linked to explicit and implicit biases in healthcare providers and systems. It is of the utmost importance that those caring for patients in the peripartum and postpartum period are committed to lowering the morbidity and mortality rates of all mothers of color. Promoting equity and cultural competence, effectively addressing modifiable risk factors, improving communication and monitoring, and engaging in regular training are needed to improve the health and outcomes of this population.

8. GLOSSARY

Pregnancy-associated death: A death during or within one year of pregnancy, regardless of the cause [88].

Pregnancy-related death: A death during or within one year of pregnancy, from a pregnancy complication, a chain of events initiated by pregnancy, or the aggravation of an unrelated condition by the physiologic effects of pregnancy [88].

Preventability: A death is considered preventable if there was at least some chance of the death being prevented by one or more reasonable changes to patient, family, provider, facility, system, and/or community factors. This definition is used by maternal mortality review committees to determine if a death they review is preventable [88].

Maternal death: The death of a woman while pregnant or within 42 days of termination of pregnancy, regardless of the duration and the site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management, but not from accidental causes. This definition is used by the National Center for Health Statistics and the World Health Organization [88].

Maternal mortality ratio: The number of maternal deaths (as defined) per 100,000 live births. Also referred to as the maternal mortality rate [88].

Maternal mortality: Number of deaths during pregnancy, childbirth, and the postpartum period up to 365 days from the end of pregnancy [88].

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Evidence-Based Practice Recommendations Citations

1. American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, Kilpatrick SK, Ecker JL. Severe maternal morbidity: screening and review. Am J Obstet Gynecol. 2016;215(3):B17-B22. Available at https://www.acog.org/clinical/clinical-guidance/obstetric-care-consensus/articles/2016/09/severe-maternal-morbidity-screening-and-review. Last accessed October 16, 2023.

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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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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

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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

1. U.S. Preventive Services Task Force. Behavioral weight loss interventions to prevent obesity-related morbidity and mortality in adults: U.S. Preventive Services Task Force recommendation statement.JAMA. 2018;320(11):1163-1171. Available at https://jamanetwork.com/journals/jama/fullarticle/2702878. Last accessed November 28, 2023.

2. Department of Veterans Affairs Management of Overweight and Obesity Working Group.VA/DoD Clinical Practice Guideline: Management of Adult Overweight and Obesity (OBE). Washington, DC: Department of Veterans Affairs, Department of Defense; 2020. Available at https://www.healthquality.va.gov/guidelines/CD/obesity/VADoDObesityCPGFinal5087242020.pdf. Last accessed November 28, 2023.

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