Clinical Insights: Weight management A holistic journey

Olivia Pane, PharmD,

Patrick Gleason, PharmD, FCCP, FAMCP, BCPS

Assistant Vice President, Health

Karim Prasla, PharmD

Vice President, Clinical Outcomes

and Reporting

Katie Lockhart

Senior Manager, Forecasting and Pharmacoeconomics

Jennifer Bostick

Senior Graphic Designer

Lynn Blake

Senior Copy Editor

Chera L. York

Introduction

Obesity is a global epidemic and major public health issue that has grown in prevalence over recent decades in adults, adolescents and children.1

The World Health Organization (WHO) describes obesity as a “chronic, complex disease defined by excessive adiposity that can impair health.”2 In the United States (U.S.) alone, nearly 73.1% of adults have either *overweight or obesity, costing the U.S. health care system almost $173 billion per year.3,4

While there has been much debate over the classification of obesity as a disease state versus a lifestyle disorder, the American Medical Association (AMA) designated obesity as a chronic disease in 2013, which prompted several professional organizations to develop guidelines to address best practices for treatment.5 Recent developments have shown that obesity is a complex condition and is not solely attributed to poor eating and lack of physical activity; rather, it is a multifactorial disease affected by biological, genetic, social, environmental and behavioral factors.6 A systemic disease, obesity can cause a cascade of negative effects, including higher risk for health conditions, such as heart disease, stroke, type 2 diabetes mellitus (T 2DM), certain types of cancer and premature death.7

Current state

U.S. TRENDS

In the U.S., a dramatic rise in the prevalence of obesity in both genders across all age and ethnic groups began in the 1980s, with prevalence increasing from 15% in 1976 to 1980, to 23.3% in 1988 to 1994 and then to 30.9 % in 1999 to 2000.8 The prevalence of people who have overweight or obesity has continued to grow in recent years.

The 2017 to March 2020 National Health and Nutrition Examination Survey (NHANES) Pre-Pandemic Demographics Data show that 41 9 % of adults in the U.S. have obesity, including 9 2% with severe obesity.9 Obesity rates in adults vary according to race and ethnicity; the NHANES data show that 49 9 % of non-Hispanic Blacks, 45.6% of Hispanics, 41 4% of non-Hispanic Whites, and 16 1% of non-Hispanic Asians are affected by obesity.

73.1%

U.S. adults who have overweight or obesity

CDC map: prevalence of obesity based on self-reported weight and height among U.S. adults by state and territory, BRFSS, 2022

In children 2 to 19 years of age, obesity prevalence is 19.7%; prevalence broken down by age group is 12 7% among 2- to 5-year-olds, 20.7% among 6 - to 11-year-olds and 22 2% among 12- to 19-year-olds, with variance by race and ethnicity.10

Data from the Centers for Disease Control and Prevention (CDC) from 2022 show that all states and territories in the U.S. have an adult obesity prevalence >20%, and 22 states have adult obesity prevalence ≥35%, compared to 19 states in 2021.11,12 Notably, there were no

states with an obesity prevalence >35% just 10 years ago. According to these data from the CDC, the Midwest (35.8%) and South (35.6%) have the highest obesity prevalence in the U.S., followed by the Northeast (30.5%) and West (29.5%). Louisiana, Oklahoma and West Virginia have the highest reported obesity rates with prevalence ≥40%. It is important to note that obesity rates in each state are higher in some groups depending on age and ethnicity.

Rise in the prevalence of obesity in both genders across all age and ethnic groups in the U.S. 2017 4 MILLION

All states and territories in the U.S. have an adult obesity prevalence >20%.

4M people die each year from overweight or obesity. 2024

5 MILLION Obesity contributes to about 5M deaths per year from cardiovascular diseases, diabetes, cancer, neurological disorders, chronic respiratory diseases and digestive disorders.

U.S. tops the list with the highest obesity prevalence for both adult males and females in developed countries. How the U.S. ranks against all countries:

GLOBAL TRENDS

According to the WHO, worldwide obesity has tripled since 1975, and by 2035, over 4 billion people are expected to have obesity.13,14 That is more than half of the world’s population. This trend is also reported in the world’s pediatric population, with obesity prevalence rising more than fourfold from 4% to 18% globally in children and adolescents 5 to 19 years of age from 1975 to 2016.15

Data from 2017 show that over 4 million people die each year from having overweight or obesity. Furthermore, data from 2019 suggest that obesity contributes to about 5 million deaths per year from cardiovascular (CV) diseases, diabetes, cancer, neurological disorders, chronic respiratory diseases and digestive disorders.16,17 Among the countries ranked for obesity prevalence, the U.S. sits in 14th place for adult males, with 36 47% obesity, and in 30 th place for adult females, with 38.16% obesity.18 When narrowed down to only developed countries, the U.S. tops the list with the highest obesity prevalence for both adult males and females, followed closely by New Zealand, Australia and Canada.

Obesity rates in adults vary according to race and ethnicity; NHANES data show the following are affected by obesity:

WORLDWIDE OBESITY HAS TRIPLED SINCE 1975. 4% TO 18% RISE IN CHILDREN

Pediatric obesity prevalence rose fourfold from 4% to 18% globally in children and adolescents 5 to 19 years of age from 1975 to 2016

Causes

The emergence of the obesity epidemic in the U.S. during the 1980s is often attributed to major changes in the American diet, including increased consumption of dietary fat, sugar and sugar-sweetened beverages.19,20

A large body of data also supports a link between the rise in U.S. obesity rates and increased intake of ultra-processed foods (UPFs), which are foods that are typically high in calories, salt, sugar and fat and low in dietary fiber and micronutrients (e.g., white bread, sweetened cereals, cookies, cakes, candy, savory snacks, pizza). UPFs became readily available at a low cost to Americans starting in the early 1970s due to the implementation of farm bills by the U.S. Department of Agriculture (USDA), which gave increased subsidies to farmers. This led to rapid food production in the U.S., and subsequently resulted in larger food portions, widespread marketing of energy-dense foods and increased availability and affordability of processed foods.

Lifestyle choices certainly play a key role in an individual’s risk for developing obesity.21,22,23

A person’s food choices, amount of daily movement and physical activity, sleep patterns and stress levels can all influence weight. Often, lifestyle is closely related to social determinants of health, including the conditions in which people live and work, access to healthy and affordable food options, peer and social supports, and policies that

determine community design. Socioeconomic status, including education level and income status, has also been directly correlated with obesity rates.

Additionally, a person’s medical history can influence their propensity to have overweight or obesity.24 Health conditions such as polycystic ovarian syndrome (PCOS), Cushing’s syndrome, hypothyroidism, depression and binge eating disorder can lead to weight gain, as can a variety of medications, including certain antidepressants, antiepileptics, corticosteroids, antihistamines and diabetes medications (e.g., insulin, sulfonylureas).

Family history and genetics have also been found to play roles in a person’s risk for obesity and body fat distribution.25 Moreover, certain genetic disorders like Prader-Willi syndrome and melanocortin 4 receptor (MC4R ) syndromes, though rare, are strongly associated with obesity.

Several hormones play key roles in weight management, and imbalances can lead people to develop overweight or obesity.26 Insulin, the primary hormone responsible for blood sugar homeostasis, has a direct effect on inducing satiety and suppressing hunger. Leptin, which is produced by adipose tissue, serves to decrease hunger, while ghrelin, which is produced in the stomach and duodenum, acts to increase hunger. Glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone produced in the intestine that acts in the gastrointestinal (GI) tract to slow gastric emptying, as well as in the hypothalamus to downregulate hunger.

Research has shown that GLP-1 levels are reduced in obesity, which may be correlated with abnormal leptin signaling.27

There has also been a rising interest in the gut microbiome and its potential impact on weight. The gut microbiota may function to increase energy production from food and has also been found to impact carbohydrate, amino acid and lipid metabolism.28,29 In humans, dysbiosis (imbalance) of the gut microbiota has been linked to development of obesity through a variety of mechanisms, including an increase in energy absorption, heightened appetite and enhancement of fat storage. Conversely, the presence of a diverse gut microbiome has been linked to a preventive effect on long-term weight gain. Further research is needed in this realm to better understand how gut bacteria may affect weight gain.

In recent years, several chemicals that may disrupt metabolism, termed “obesogens,” have been identified and postulated to increase risk for weight gain, particularly when exposure occurs during fetal development or in the early years of life.30,31 These obesogens include synthetic chemicals found in plastics, pesticides, household products, flame retardants and cosmetics, and they are thought to interfere with the hormones that regulate metabolism, fat storage capacity, size of fat cells and regulation of hunger and fullness. As such, these chemicals are often referred to as endocrine disrupting chemicals (EDCs). Air pollution may also contain these endocrine disruptors and obesogens.

FACTORS THAT INFLUENCE OBESITY

Diet

Physical activity

Sleep patterns

Stress levels

Living and working conditions

Socioeconomic status

Medical history

Hormonal imbalances

Metabolism

Genetics

Despite the variety of mechanisms by which obesity can occur, an important consensus is that overweight and obesity are largely preventable.32 In addition to individual actions for prevention, the WHO recognizes that addressing the obesity epidemic must also be viewed as a societal responsibility, and contributions from the government, communities, food manufacturers and the health care sector are essential.

The assessment debate

For many years, a widely accepted assessment tool for people ≥20 years of age has been the body mass index (BMI), which provides an estimate of healthy weight and obesity classifications using body weight in kilograms (kg) divided by the square of height in meters (m2).33,34,35

The BMI was first introduced in 1972 and has generally been useful in assessing populationbased mortality and disease-specific mortality, with additional advantages including ease of use, standard cutoff points, strong correlation with body fat levels and low cost.36,37 However, it has become controversial in recent years due to its limitations when used alone to diagnose obesity.38,39 BMI is unable to differentiate between weight associated with muscle versus fat, which may lead to inaccurate assessments in select patients, including those who are muscular and those who are of advanced age. BMI is also incapable of identifying body fat distribution, fails to consider gender or ethnicity, and its cutoffs are mostly based on data from non-Hispanic White populations, which may compromise its accuracy for other races.

WHO CLASSIFICATION OF WEIGHT STATUS

Given these limitations, the American Association of Clinical Endocrinology (AACE) and American College of Endocrinology (ACE) recommend that providers consider a patient’s age, gender, ethnicity, fluid status, and muscularity when assessing BMI.

40 The AMA now recommends that BMI be used in conjunction with other valid measures of risk, including visceral fat, body adiposity index, body composition, relative fat mass, waist circumference and/or genetic and metabolic factors. 41 The Obesity Society (TOS) adds that BMI can be used to screen for obesity, but it is not a measure of body fat and should not supersede clinical judgment. 42

Given the strong association between increased visceral fat and heightened risk for metabolic syndrome, T2DM and CV mortality, weight distribution around the midsection is an important factor of the patient assessment process. 43,44 As such, waist circumference has fallen into favor as an additional assessment measure for obesity, with increased risk for weight-related issues correlating to a waist measurement of ≥35 inches (≥88 centimeters [cm]) for women and ≥40 inches (≥102 cm) for men. 45,46,47 Waist-to-hip ratio (WHR) has also been linked to a stronger association with all-cause mortality than BMI, with ratios >1:1 in men and > 0:8 in women considered significant. 48,49 Although waist circumference has proven to be a beneficial measure in adults, its utility in pediatrics has not been established due to lack of standardization and a paucity of data to show its link to comorbidities.50 As such, BMI remains the most useful obesity assessment measure in children ≥2 years of age.

Other assessments of body fat that are accurate but not practical in all settings include skinfold thickness measurements, dual energy radiographic absorptiometry (DEXA) scans, bioelectric impedance analyses and water displacement studies.51,52

Ideally, accurate assessments consider BMI, in addition to a number of other factors:

• Age

• Gender

• Ethnicity

• Fluid status

• Muscularity Additionally, the AMA now recommends that BMI be assessed in conjunction with:

• Visceral fat

• Body adiposity index

• Body composition

• Relative fat mass

• Waist circumference

• Genetic and metabolic factors

Health impacts

PHYSICAL HEALTH IMPACTS

Obesity poses many risks to an individual’s health and overall well-being, including a significantly higher risk for development of T 2DM.53 Data from NHANES have linked obesity to 30% to 53% of new T 2DM cases each year in the U.S.54 T 2DM subsequently leads to increased risk for heart disease, stroke, chronic kidney disease (CKD), neuropathy, retinopathy and other health issues.55 Obesity is also a risk factor for several CV complications, including hypertension, dyslipidemia, heart disease and stroke. Furthermore, people with obesity are more likely to be affected by metabolic dysfunctionassociated steatohepatitis (MASH, formerly NASH) and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and to have breathing issues including sleep apnea and asthma, as well as osteoarthritis, gout, gallstones, cholecystitis and pancreatitis.56,57 In females, issues with fertility and pregnancy occur more frequently in those who have overweight and obesity.

Obesity has also been linked to a higher risk for several types of cancers through a number of postulated mechanisms.58 Excess adipose tissue may result in higher estrogen levels, which in turn has been associated with breast, endometrial and ovarian cancers. People with obesity may also have increased insulin

and insulin-like growth factor-1 (IGF-1) levels, which can lead to higher risk for colon, kidney, prostate and endometrial cancers. Elevated leptin levels may also play a role, given leptin’s ability to promote cell proliferation. While data showing the association between obesity and cancer are observational, making it difficult to establish causality, evidence from large cohort studies consistently demonstrates the link between obesity and cancer. Furthermore, data from the U.S. Cancer Statistics (USCS) database in a nationwide cross-sectional study

estimated that about 37,670 new cancer cases in men (4.7%) and 74,690 new cancer cases in women (9.6%) were a result of overweight or obese weight status in people ≥30 years of age between 2011 to 2015

With the emergence of the coronavirus disease of 2019 (COVID-19) pandemic, a trend has been observed connecting obesity to increased risk of severe illness from COVID-19 and triple the risk of hospitalization due to COVID-19.59 Of the estimated 900,000

National Cancer Institute

Meningioma cancer in the tissue covering brain and spinal cord

COVID-19 hospitalizations that occurred in the U.S. between the beginning of the pandemic and November 2020 approximately 271,800 (30 2%) were attributed to obesity. A separate study of COVID-19 cases found that higher BMI was associated with increased risk for not only hospitalization, but also intensive care unit admission, invasive mechanical ventilation and death. This association between obesity and COVID-19 has also been reported in the pediatric population, with some studies showing a three-fold higher risk for hospitalization in patients ≤18 years of age with obesity.

From a global perspective, the relationship between COVID-19 severity and obesity holds true; there were 2.5 million COVID-19 deaths reported worldwide by the end of February 2021 and 2.2 million of those deaths occurred in countries where >50% of the population is overweight.60 Interestingly, there may also be a relationship between the COVID-19 pandemic and a rise in obesity rates in the U.S.61 According to data from the 2011 to 2020 Behavioral Risk Factor Surveillance System (BRFSS), adult obesity prevalence was three times higher during the first year of the pandemic (March 13, 2020 to March 18, 2021) compared with a pre-pandemic baseline period from January 1, 2019 to March 12, 2020 This data suggests that behavior changes made during the pandemic may have further exacerbated the existing obesity epidemic.

MENTAL HEALTH IMPACTS

The link between obesity and mental health is complex, given that obesity itself can cause mental health issues, while the presence of certain mental health conditions has been tied to increased obesity risk.62,63,64 Higher rates of obesity have been observed in patients with depression, schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder (ADHD), trauma and eating disorders, including bulimia and binge eating disorder. One study found that adults with excess weight had a 55% higher chance of developing depression during their lifetime versus those who did not have overweight or obesity. There are several proposed mechanisms for how obesity may lead

PHYSICAL

People

to higher rates of mental health disorders, including impaired quality of life, poor body image, low self-esteem, physiological issues and weight discrimination. Conversely, the presence of mental health disorders can increase an individual’s risk for weight gain and obesity.65 People may use food as a coping mechanism, and their ability to make healthy dietary choices may be compromised by a mental health disorder, while serotonin deficiencies can result in cravings for carbohydrates and energy-dense foods. Those suffering from depression may also lack the energy or motivation to participate in physical activity. Medications used to treat mental health disorders often can also contribute to weight gain. In youth, evidence has shown that adolescents who experience bullying or teasing related to their weight are at an even higher risk for additional weight gain due to higher likelihood of binge eating or reducing their physical activity levels.66

Equity and barriers to care

Obesity prevalence rates in the U.S. from 2019 to 2021 point to the existence of racial and ethnic disparities.67 Non-Hispanic Black adults had the highest rates of self-reported obesity during that period at 41.7%, followed by nonHispanic American Indian or Alaska Native adults at 38.4% and Hispanic adults at 36.1%. Historically, these groups have dealt with lack of opportunity for economic, physical and emotional health, which may have translated to higher obesity rates.

Access to adequate care might not just be an issue of race and ethnicity, but also a matter of discrimination.68,69 Obesity is a frequently stigmatized condition, and not only the public, but also health care providers, may respond negatively to those who have overweight. Reports of weight discrimination have increased in the U.S., up to 66% between 1995 and 2006, and lack of acknowledgement of obesity as a disease has hindered treatment access for some patients. The ongoing debate between classifying obesity as a health issue versus a cosmetic issue has also affected how the FDA reviews and approves weight loss medications, leading to stringent requirements for approval and low coverage of these medications by insurers, including Medicare.70,71

The AACE has released a consensus statement that addresses stigma and bias in the diagnosis and management of patients with obesity.72 The statement proposes that obesity be referred to as adiposity-based chronic disease (ABCD), with clinical severity stages based on presence and severity of ABCD complications. The statement acknowledges that weight stigma and internalized bias may contribute to weight-related complications and advises to assess for these in all patients and to incorporate them into staging. The AACE also suggests that ethnicity-specific BMI ranges and waist circumference targets be used to classify obesity. The American Diabetes Association (ADA) also recognizes the importance of language used to discuss obesity in its standards of care and recommends using person-centered, nonjudgmental verbiage; for example, “person with obesity” rather than “obese person.”73

Looking beyond access to health care services and obesity medications, other barriers can come into play with regard to implementing changes for weight management. For example, patients may encounter assorted reasons for inability to perform physical activity. A crosssectional study that examined self-perceived barriers to physical activity found that 65.3% of participants noted lack of time as a barrier to exercise.74 This was closely followed by feeling tired (64.7%), pollution (56.1%), weather (49.6%), work (48.1%), young children or family needs (26.4%), limited accessibility of a gym or equipment (25.9 %), safety concerns (23.2%) and cost (22%).

Key players and initiatives

Several key influencers and organizations have been working in tandem to develop policies and strategies for promoting healthy eating, active lifestyles and responsible use of obesity medicines. Please see the key initiatives starting on page 34 of the Appendix for examples of their work.

Clinical practice guidelines

Several professional organizations have published clinical practice guidelines to assist providers in managing overweight and obese weight status in adults. Major guidelines that have shaped today’s practice include the 2013 American Heart Association (AHA)/American College of Cardiology (ACC)/TOS guideline for managing overweight or obese weight status in adults, the 2015 Endocrine Society guideline for the pharmacological management of obesity, the 2016 AACE/ACE comprehensive clinical practice guidelines for medical care of patients with obesity, and the 2022 American Gastroenterological Association (AGA) guideline on pharmacological interventions for adults with obesity.75,76,77,78

The ADA 2024 standards of care in diabetes and the 2022 AACE guideline for development of a diabetes comprehensive care plan also address obesity in their recommendations.79,80

These guidelines generally all agree:

• On an initial weight loss goal of 5% to 10% from baseline within 6 months for most patients with overweight or obesity.81

• To recognize and prioritize diet, exercise and behavioral modification as the key components of a weight management strategy.82,83,84

• For patients with a BMI ≥27 kg/m2 with at least one weight-related comorbid condition (e.g., T 2DM, hypertension, dyslipidemia) and for patients with a BMI ≥30 kg/m2, pharmacotherapy may be utilized in conjunction with lifestyle modifications.

• Maintenance of weight loss is a key aspect of weight management; patients who have lost weight should continue to participate in long-term weight management programs, including regular contact with a trained interventionist and continuation of physical activity and a reduced-calorie diet.85

Notably, the Endocrine Society guideline is in enpanelment, and the AACE is currently in process of updating their obesity algorithm.86,87

The American Academy of Pediatrics (AAP) has also published a clinical practice guideline for the management of obesity and recommends that children ≥6 years of age who have overweight (BMI ≥85th percentile to <95th percentile) or obesity (BMI ≥95th percentile) be provided or referred to health behavior and lifestyle treatment.88 Children between the ages of 2 and 5 years may also be provided or referred for treatment, and adolescents ≥12 years of age with obesity should be offered pharmacotherapy as an adjunct to lifestyle and health behavior treatment.

It is important to note that while treatment options like devices (e.g., intragastric balloons, cellulose/citric acid capsules [Plenity ®]) and bariatric surgery are available for weight management in select patients, this review will focus on lifestyle and behavioral modifications, along with pharmacotherapy options.89,90,91

Lifestyle modifications

Most guidelines include recommendations for dietary patterns that patients should follow to lose weight and promote overall health. The AHA/ACC/TOS recommends an energy deficit of 500 to 750 kilocalories (kcal) per day, which is often achieved by prescribing a calorie goal of 1,200 to 1,500 kcal per day for women and 1,500 to 1,800 kcal per day for men.92 Several dietary approaches, including higher protein diets, lower carbohydrate diets and lower fat diets, are discussed in the guideline, with the main theme centering around a caloric deficit to achieve weight loss. The AGA guideline also discusses calorie goals for women and men and encourages utilization of a tool to support and adhere to low-calorie food intake, such as a structured behavioral program, specific diet plan, exercise program, medication(s), bariatric endoscopic intervention and/or surgery.93

In its 2020 -2025 Dietary Guidelines for Americans, the USDA provides broad nutrition recommendations for healthy eating, including incorporation of vegetables, fruits, whole grains, low-fat dairy or soy products, protein (e.g., lean meats, poultry, eggs, seafood, beans, legumes, nuts, seeds, soy products) and oils (e.g., olive oils, oils found in seafood, nuts, avocados).94 Strategies aimed specifically for weight loss in the Dietary

Guidelines include reducing overall calories from foods and beverages; decreasing consumption of added sugar, saturated fat and sodium; and increasing intake of dietary fiber, calcium and vitamin D.

Recommendations for physical activity also are consistent between the guidelines and agree with the U.S. Department of Health and Human Services (HHS) physical activity guidelines for Americans.95 In general, these recommendations include at least 150 to 300 minutes of moderate-intensity or at least 75 to 150 minutes of vigorous-intensity aerobic activity per week for all adults, preferably spread throughout the week. Additionally, muscle-strengthening activities involving all major muscle groups should be performed at least 2 days per week. These guidelines do state that people who want to lose >5% body weight or who are trying to maintain weight loss may need to perform even more than 300 minutes of moderate-intensity exercise per week to achieve their goals. The AGA also includes a goal of at least 10,000 steps per day in its recommendations, and the AACE/ACE encourages an overall reduction in sedentary behavior through more active leisure activities.96,97

Behavioral interventions are also a key component of a weight management program, and the AHA/ACC/TOS states that an inperson, high-intensity (e.g., ≥14 sessions in 6 months), comprehensive program led by a trained interventionist in either individual or

group sessions is generally most effective.98 Given that this type of intervention is not always feasible, alternative modes of delivery (e.g., internet, phone calls) can be used, though they may result in less weight loss compared to in-person interventions. Many of the guideline recommendations for behavioral interventions are based on data from the Diabetes Prevention Program (DPP), a trial in which participants received 16 individual, inperson counseling sessions with a registered dietitian that were about 30 minutes each.99

In the DPP, participants lost a mean of 7.1 kg (about 7% body weight from baseline) after 6 months and maintained their weight loss at 1 year compared to other study enrollees who were in the placebo group, where no weight loss was observed.

A movement that is gaining ground is Food is Medicine (FIM), a program that connects healthy nutrition and health care and is intended to help prevent, manage and/or treat diet-related diseases.100 Some examples of FIM are medically tailored meals or groceries and produce prescriptions.101 According to the Tufts University FIM Institute, 85% of all health care spending is related to managing chronic diseases that are related to diet.102 Notably, about 33.8 million people in the U.S. live in food-insecure households.103 There is both public and private sector involvement with FIM.

In 2022, the White House hosted a conference to end hunger and reduce the prevalence of chronic disease in the U.S. by 2030.

Through congressional action, the Department of HHS would also use strategies to reduce food insecurity to improve health and racial equity, including diet-related research and increasing access to FIM interventions.104 Earlier this year, the first HHS FIM summit connected stakeholders to shine a light on FIM initiatives and ways to advance innovation.105

RECOMMENDATIONS FOR

weight loss

DIET

EXERCISE

150–300

At least 150 to 300 minutes of moderate-intensity aerobic activity per week OR

75–150

At least 75 to 150 minutes of vigorous-intensity aerobic activity per week

2+ sessions

Muscle-strengthening activities involving all major muscle groups at least 2 days per week

10,000 steps

10,000 steps per day and reducing sedentary behavior through more active leisure activities

Pharmacotherapy

MEDICATION OVERVIEW

It is imperative that choice of pharmacotherapy be individualized to each patient based on medical history, preference and weight loss goals. Prescribers and patients must also be reminded that medications should only be used in addition to, not in place of, lifestyle interventions. Aside from phentermine, weight loss medications should be considered longterm therapy, given that these medications have been linked to weight regain when discontinued.106 For most weight loss medications, therapy should be discontinued, and alternative options should be explored, if at least 5% weight loss from baseline has not been achieved in 6 months.107,108

Given the rapidly evolving landscape of obesity medication approvals and the variance in publication dates for the available obesity guidelines, recommendations for choice of pharmacotherapy vary per guideline. However, all agree that medications used for weight management should be FDAapproved, and patients should be monitored regularly for medication efficacy and tolerability, along with continued adherence to lifestyle modifications.109,110,111,112

• The 2015 Endocrine Society guideline discusses that medications can promote adherence to behavior change and can help improve physical functioning to aid physical activity; as such, it suggests the use of an approved weight loss medication over no pharmacological therapy for eligible candidates.113 While the guideline generally avoids recommending specific drugs, it does suggest the use of GLP1 receptor agonists or sodium-glucose cotransporter 2 (SGLT 2) inhibitors for patients with T 2DM. It also recommends against the use of phentermine for those who have uncontrolled hypertension or a history of heart disease, and it recommends against the use of orlistat in patients with cardiovascular disease (CVD).

• The 2016 AACE/ACE obesity guideline recommends pharmacotherapy with phentermine/topiramate extended-release (ER), liraglutide 3 mg, or orlistat to achieve weight loss of ≥10% in patients with excess body weight who are at risk of developing T 2DM.114 Additionally, the guideline includes a detailed table with preferred medications based on comorbidities, including T2DM, hypertension, CVD and CKD.

• The 2022 AGA guideline advises that choice of pharmacotherapy should be based on a patient’s comorbidities, preferences, costs and access to therapy.115 The AGA suggests prioritizing treatment with semaglutide 2.4 mg over other approved therapies for long-term treatment of obesity given its magnitude of benefit, while liraglutide 3 mg is suggested as an additional option.

Phentermine/topiramate can also be considered, particularly for patients with comorbid migraines given the topiramate component, and naltrexone/bupropion can be considered for those with depression or for patients who are attempting smoking cessation. Phentermine is also suggested with low certainty, though it should be avoided in patients with a history of CVD. The AGA suggests against the use of orlistat because its small weight loss benefit typically fails to outweigh its adverse effects.

Prescribers and patients must be reminded that medications should only be used in addition to, not in place of, lifestyle interventions.

For patients with T 2DM, the 2024 ADA standards of care categorize the GLP-1 receptor agonist semaglutide and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide as very high efficacy for weight loss, while the GLP-1 agonists dulaglutide and liraglutide are categorized as high efficacy for weight loss.116 The 2022 AACE guideline and the 2015 Endocrine Society guideline both recommend treatment with medications for T2DM that also promote weight loss, such as the GLP-1 receptor agonists or SGLT 2 inhibitors, in addition to metformin.117,118

FDA-approved medications are further detailed in the table below. Notably, lorcaserin (Belviq®) was withdrawn from the market in 2020 due to a signal for increased risk of cancer and, therefore, is not included in the table that begins on the following page.119

liraglutide (Saxenda®)

3 mg daily (56 weeks)

semaglutide (Wegovy®)

2.4 mg weekly (68 weeks)

tirzepatide (ZepboundTM)

15 mg weekly (72 weeks)

Patients with overweight or obesity, without T 2DM

FDA-APPROVED

Drug class

GI lipase inhibitor

Medication(s) Mechanism of action

orlistat (OTC

Alli® Rx

Xenical®)120,121,122,123

Reversible inhibitor of GI lipases; binds to active serine residue site of gastric and pancreatic lipases in stomach and small intestine and inactivates the enzymes, thereby decreasing GI absorption of fat

Indication(s) Dosing

Common adverse effects

Percent mean weight loss from baseline (placebo)

Notes & considerations

FDA-APPROVED

Sympathomimetic amine anorectic phentermine (Adipex-P ® Lomaira™)124,125,126,127

Activates sympathetic nervous system to cause appetite suppression and to increase resting energy expenditure

Alli (OTC): weight loss in adults with BMI ≥25 kg/m2 when used along with a reduced-calorie, low-fat diet

Xenical (Prescription only): obesity management; including weight loss, weight maintenance, and to reduce the risk for weight regain after prior weight loss; when used in conjunction with a reduced-calorie diet for adults with initial BMI ≥30 kg/m or ≥27 kg/m in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia)

Short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification, and caloric restriction in the management of exogenous obesity for patients ≥17 years of age with an initial BMI ≥30 kg/m or ≥27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia)

Alli: 60 mg orally three times daily with meals containing fat

Xenical: 120 mg orally three times daily with meals containing fat

Oily spotting, flatus with discharge, fecal urgency, fatty/ oily stool, oily evacuation, increased defecation, fecal incontinence

Xenical 120 mg three times daily: 9 6%; (5.6%; 52 weeks)

• Xenical approved by the FDA in 1999; OTC Alli approved in 2007

• Should be taken with a meal containing around 30% calories from fat

• Must be supplemented with a multivitamin containing fat-soluble vitamins, separated by at least 2 hours, or taken at bedtime

• Can affect absorption of other medications (e.g., cyclosporine, levothyroxine, anticonvulsants)

• Rare cases of severe liver injury reported

• Contraindications: pregnancy, chronic malabsorption syndrome, cholestasis

Adipex-P: typical dose is 37 5 mg orally daily before breakfast or 1 to 2 hours after breakfast

Lomaira: typical dose is 8 mg orally three times daily, 30 minutes before meals

Dry mouth, insomnia, dizziness, irritability, increased blood pressure, elevated heart rate 15 mg daily: 5%; 7.5 mg daily:

%; 12 weeks)

• Only approved for short-term use up to 12 weeks; data are limited for longer use

• Late evening administration should be avoided (insomnia risk)

• Dosage adjustments are needed for patients with severe renal impairment

• Contraindications: pregnancy, nursing, history of CVD (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension), glaucoma, hyperthyroidism, history of drug abuse, agitated states, within 14 days of monoamine oxidase inhibitor (MAOI) use

Drug class Medication(s) Mechanism of action Indication(s) Dosing

Sympathomimetic amine anorectic/ antiepileptic combination phentermine/ topiramate ER (Qsymia® 128,129,130

Phentermine activates sympathetic nervous system to cause appetite suppression; topiramate may contribute to appetite suppression through activation of gammaaminobutyric acid (GABA), inhibition of carbonic anhydrase, and glutamate antagonism

Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in:

• Adults with initial BMI ≥30 kg/m2 or ≥27 kg/m2 in the presence of ≥1 weight-related comorbidity (e.g., hypertension, T 2DM, dyslipidemia)

• Pediatric patients ≥12 years of age with initial BMI in the ≥95th percentile, standardized for age and sex

Starting dose:

3 75 mg/23 mg orally once daily for 14 days

Common adverse effects

Percent mean weight loss from baseline (placebo) Notes & considerations

Typical maintenance dose: 7 5 mg/46 mg orally once daily; can be titrated up to a max dose of 15 mg/92 mg daily Paresthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth, depression, arthralgia, pyrexia, influenza, ligament sprain, increased blood pressure, elevated heart rate

15 mg/92 mg daily: 9 8%;

7.5 mg/46 mg daily: 7.8%; (1.2%; 56 weeks)

• First combination medication for chronic weight management approved by the FDA in 2012

• Schedule IV-controlled substance; only available through Risk Evaluation and Mitigation Strategy (REMS) program

• Late evening administration should be avoided (insomnia risk)

• Do not exceed 7.5 mg/46 mg daily for patients with moderate or severe renal impairment or patients with moderate hepatic impairment

• Abrupt discontinuation of the 15 mg/92 mg dosage should be avoided due to seizure risk

• Contraindications: pregnancy, glaucoma, hyperthyroidism, within 14 days of MAOI use

FDA-APPROVED MEDICATIONS TO TREAT OVERWEIGHT AND OBESITY

Drug class Medication(s) Mechanism of action Indication(s)

Opioid antagonist/ aminoketone antidepressant combination naltrexone/ bupropion ER (Contrave® 131,132,133

Exact mechanism is unknown; combination may act in the hypothalamus to regulate appetite and in the mesolimbic dopamine circuit to regulate the brain’s reward system

Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with initial BMI ≥30 kg/ m2 or ≥27 kg/m2 in the presence of ≥1 weight-related comorbidity (e.g., hypertension, T 2DM, dyslipidemia)

Dose escalation schedule:

Week 1

1 tablet a.m.

Week 2

1 tablet twice daily

Week 3

2 tablets a.m., 1 tablet p.m.

Week 4

2 tablets twice daily

Typical maintenance dose:

16 mg/180 mg orally twice daily

Constipation, nausea, headache, vomiting, dizziness, dry mouth, insomnia, diarrhea, increased blood pressure, elevated heart rate

16 mg/180 mg twice daily: 5% (1.8%; 56 weeks)

• Approved by the FDA in 2014

• Should not be taken with a high-fat meal

• Dosage adjustments are required for patients with moderate or severe renal impairment or moderate hepatic impairment

• Not recommended for patients with endstage renal disease (ESRD) or severe hepatic impairment

• Boxed Warning for risk of suicidal thoughts/ behaviors in patients 24 years old who have depression

• Contraindications: pregnancy, uncontrolled hypertension, seizure disorder or history of seizures, bulimia, anorexia nervosa, chronic opiate use or acute opiate withdrawal, within 14 days of MAOI use

FDA-APPROVED MEDICATIONS TO TREAT OVERWEIGHT AND OBESITY

Drug class Medication(s) Mechanism of action Indication(s) Dosing Common adverse effects

Percent mean weight loss from baseline (placebo)

Notes & considerations

Glucagon-like peptide-1 receptor agonists

liraglutide (Saxenda)134,135 semaglutide (Wegovy)136,137

Slows gastric emptying and decreases intestinal motility; promotes satiety by activating GLP-1 receptors in the brain; stimulates insulin secretion and synthesis

Saxenda: adjunct to a reducedcalorie diet and increased physical activity for chronic weight management in:

• Adults with an initial BMI ≥30 kg/m2 or ≥27 kg/m in the presence of ≥1 weightrelated comorbid condition (e.g., hypertension, T2DM, dyslipidemia)

• Pediatric patients ≥12 years of age with body weight >60 kg and initial BMI corresponding to 30 kg/m2 for adults by international cut-offs

Wegovy: Adjunct to a reducedcalorie diet and increased physical activity for chronic weight management in:

• Adults with initial BMI ≥30 kg/m2 or ≥27 kg/m in the presence of ≥1 weightrelated comorbid condition (e.g., hypertension, T2DM, dyslipidemia)

• Pediatric patients ≥12 years with BMI in the ≥95th percentile, standardized for age and sex

Saxenda:

Initial dose: 0 6 mg SC* daily for one week; dose should be increased weekly to a typical maintenance dose of 3 mg SC daily

Wegovy:

Initial dose: 0 25 mg SC weekly for 4 weeks; dose should then be increased every 4 weeks to a typical maintenance dose of 2 4 mg SC weekly

Nausea, vomiting, diarrhea, constipation, esophageal reflux, injection site reactions, headache, fatigue, dizziness, abdominal pain, pyrexia, hypoglycemia

Saxenda: 3 mg daily: 8 6% (2.7%; 56 weeks)

Wegovy: 2 4 mg weekly: 14.9% (2 4%; 68 weeks)

• Saxenda was approved by the FDA in 2014 Wegovy was approved in 2021

• In March 2024 Wegovy was FDA approved in combination with a reduced-calorie diet and increased physical activity to reduce the risk of major adverse cardiovascular events (MACE) (CV death, non-fatal myocardial infarction or non-fatal stroke) in adults with established CVD and either obesity or overweight

• Liraglutide is available for T2DM as Victoza® (SC); semaglutide is available for T2DM as Ozempic® (SC) and Rybelsus® (oral)

• Saxenda and Wegovy were compared headto-head in adults, with Wegovy producing greater weight loss 15.8%) compared to Saxenda (6.4%)138

• Saxenda is available in multiple-dose pens; Wegovy is available in single-dose pens

• Improved CV outcomes in patients with and without T2DM

• Boxed Warning for risk of thyroid C-cell tumors in rodents; human relevance has not been determined

• Pancreatitis has been reported but causality has not been established

• Contraindications: pregnancy, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

* subcutaneous

Drug class

Medication(s) Mechanism of action Indication(s) Dosing

Glucosedependent insulinotropic polypeptide receptor & glucagon-like peptide-1 receptor agonist

tirzepatide (Zepbound)139,140

Binds to and activates GIP and GLP-1 receptors to regulate appetite and caloric intake

Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI ≥30 kg/m2 or ≥27 kg/m in the presence of ≥1 weight-related comorbid condition (e.g., hypertension, dyslipidemia, T2DM, obstructive sleep apnea, CVD)

Initial dose: 5 mg SC once weekly; dose should then be increased in 2 5 mg increments after at least 4 weeks on current dose to a maintenance dose of 5 mg to 15 mg SC weekly

Common adverse effects

Percent mean weight loss from baseline (placebo)

Notes & considerations

BENEFITS OF PHARMACOTHERAPY BEYOND WEIGHT LOSS

Recent clinical trial data have demonstrated that the GLP-1 receptor agonists may have additional benefits beyond weight loss for patients with overweight or obesity. In the SELECT trial, which included adults with overweight or obesity who had established CVD (secondary prevention) without T 2DM, semaglutide 2.4 mg SC weekly was associated with an absolute risk reduction of 1 5% for MACE (e.g., CV death, nonfatal MI, nonfatal stroke) compared to placebo.141 Based on the SELECT trial, Wegovy recently became the first weight management medication to be approved for secondary CV prevention in adults who have obesity or overweight.142 Furthermore, in the STEP HFpEF trial, compared to placebo, treatment with semaglutide 2.4 mg SC weekly resulted in larger reductions in heart failure-related symptoms and physical limitations, greater improvements in exercise function and greater weight loss in adults with heart failure with preserved ejection fraction and obesity.143 FDA-APPROVED

Nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, gastroesophageal reflux disease (GERD)

15 mg weekly: 20.9%; 3 1%; 72 weeks)

• Approved by the FDA in 2023

• Boxed Warning for risk of thyroid C-cell tumors in rodents; human relevance has not been determined

• Contraindications: pregnancy, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Additionally, the SURMOUNT-MMO trial is underway to evaluate CV outcomes for tirzepatide in adults with obesity and will include patients with and without established CVD.144 This trial will investigate both primary and secondary prevention, and data are anticipated in late 2027.

Other agents that are in the pipeline for obesity, including survodutide and cagrilintide/semaglutide, are also being evaluated in CV outcomes trials.145,146

Social media, influencers and the GLP-1 craze

According to recent statistics, social media use has increased worldwide to 4.9 billion people and is expected to rise even higher to 5.85 billion users by the year 2027.147 This uptick in social media use has created an unchartered new territory for health and wellness information to spread and for people to be exposed to content that impacts their own body image and self-esteem.

The online documentation of transformative weight loss coupled with endorsements from celebrities and social media influencers has created an unprecedented demand for new obesity medications, particularly GLP-1 receptor agonists.148,149 A cross-sectional analysis of Google search volumes in the U.S. found that online searches for GLP-1 receptor agonists increased by 295.2% between 2016 and 2021.150 The popular social media platform TikTok even has pages dedicated to the use of GLP-1 receptor agonists for weight loss.151

While the prescription weight loss drug market grew 72% more than originally predicted in 2023, there has also been a dramatic increase in the off-label use of GLP-1 receptor agonists that are only approved for use in T2DM.152 For example, prescriptions for Ozempic rose by 152% in 2023 compared to 2022. This off-label use has generated concern for patients with T 2DM who need access to these high-demand medications, and it has also led to issues with distribution of counterfeit medications.153,154

To add to the buzz surrounding GLP-1 receptor agonists, new medications that are dual agonists of both GLP-1 and GIP receptors have recently entered the market. Tirzepatide, which was first approved for management of T 2DM as Mounjaro, has now been approved for weight management as of November 2023 as Zepbound.155,156 Although data directly comparing Zepbound to other GLP-1 receptor agonists for weight loss are not yet available, it produced up to 20.9 % weight loss, or 22 kg,

in clinical trials when compared to placebo, while Wegovy has produced up to 16% weight loss, or 17 kg, in separate trials compared to placebo.157,158 The possibility of even more potent weight-lowering effects could create a heightened demand for dual GLP-1/GIP agonists.

While GLP-1 receptor agonists have displayed efficacy in producing weight loss, with one agent also showing potential CV benefits, it is important to reiterate that not all patients are candidates for these drugs, and individual patient characteristics and preferences must be factored into pharmacotherapy selection. The potential adverse effects of these drugs also cannot be understated. For instance, the FDA is evaluating three potential safety signals (alopecia, aspiration, suicidal ideation) with all GLP-1 receptor agonists per the FDA Adverse Event Reporting System (FAERS), and the European Medicines Agency (EMA) is evaluating reports of possible suicide or self-harm risk with use of semaglutide and liraglutide for weight loss.159,160 Furthermore, a recent cohort study found that use of GLP-1 receptor agonists was associated with increased risk of pancreatitis, gastroparesis and bowel obstruction when compared with use of naltrexone/bupropion.161

social media IMPACT

Increased usage of social media worldwide Anticipated usage of social media worldwide

4.9 BILLION PEOPLE 5.85 BILLION PEOPLE

BY 2027

Online searches for GLP-1 receptor agonists

295.2% INCREASE

2016–2021

72% HIGHER In 2023, the prescription weight loss drug market grew THAN 2023 PREDICTIONS

Real-world data — medication adherence, persistence and total cost of care

An analysis of real-world integrated pharmacy and medical claims data by pharmacy benefit manager (PBM) Prime Therapeutics and Magellan Rx (Prime and Magellan Rx) showed that 68% of individuals who newly started GLP-1 receptor agonist drugs for weight loss were no longer taking the drug after one year.162 The data also showed a substantial increase in health care costs in the first year among those who started the drugs. Among those individuals who initiated GLP-1 receptor agonists for weight loss at the one-year follow-up, this real-world analysis found a significantly higher total cost of care, at $7,727 per person. Adherence to these drugs was also poor, with just 27% of individuals taking their GLP-1 receptor agonist after one year. Among adherent individuals, the increase in costs was even higher, double that of the matched controls, at $13,218 higher total cost of care per person.

Prime and Magellan Rx analyzed integrated pharmacy and medical claims data from 16 million commercially insured members; this analysis was limited to members who newly initiated a GLP-1 receptor agonist between January 1, 2021, and December 31, 2021.163

Members were required to have an obesity diagnosis prior to this time, a prediabetes diagnosis, or a BMI ≥30 kg/m2. Individuals were excluded from the analysis if they had a prior diabetes diagnosis or diabetes drug therapy. Please refer to the study’s scientific abstract for additional details and study design.

GLP-1 receptor agonist weight loss treatment rates vary by region and coverage decisions.

Assessing historical utilization and spend patterns, Prime and Magellan Rx found that a 1% increase in GLP-1 receptor agonist weight loss utilization by an insured population would bring an additional $10+ per member per month (PMPM) expense for most self-insured employers, an increase of >5% of their entire drug spend budget.

Presented April 16, 2024 at the national Academy of Managed Care Pharmacy (AMCP) annual conference, a Prime analysis of 16 5 million commercial members identified that 1 1% or 1 in 100 members meet the newly published New England Journal of Medicine

SELECT study criteria of age ≥45 years and BMI ≥27 or obesity diagnosis, with preexisting CVD and without diabetes mellitus.164 Currently, only 1 in 43 of these members are receiving GLP-1 treatment. If all untreated SELECT study qualifying members receive

treatment, at a $10,000 annual GLP-1 cost per individual treated, there would be $8 96 in new PMPM expenditures. Health plans and self-insured employers should plan for substantial new PMPM costs due to the SELECT study findings and potential expanded role in secondary CVD prevention.

What’s more, at $11 500 to $14 000 annual wholesale acquisition price for GLP-1 receptor agonist weight loss treatment, a cost-effectiveness analysis conducted by the Institute for Clinical Economic Review (ICER) identified that these therapies are overpriced two-fold to their expected value in weight loss-associated reduction in CV events and diabetes development avoidance over a lifetime.165 The ICER findings, coupled with Prime and Magellan Rx’s analysis, indicate that GLP-1 receptor agonist weight loss products should have pharmaceutical manufacturer, patient-centered value-based arrangements with health plans or PBMs to ensure fair pricing.166

Coverage

Insurance coverage for anti-obesity medications is low. Medicare does not offer coverage for obesity medications when used for the indication of weight loss; in fact, Medicare is prohibited by law from covering weight loss drugs.167 The Congressional Budget Office (CBO) expects that Medicare Part D will cover weight loss medications, including GLP-1 receptor agonists, if the Treat and Reduce Obesity Act (TROA) is approved by Congress.168 For the first time, in March 2024, the Centers for Medicare & Medicaid Services announced that Medicare Part D plans can cover anti-obesity drugs if approved for an additional medically accepted indication.169 Notably, Medicare Part B does cover obesity screenings and behavioral counseling if performed in a primary care setting where a personalized prevention plan can be coordinated with other care.170

In September 2023, Manatt Health, the Obesity Action Coalition (OAC) and TOS published a white paper that discusses obesity as a chronic disease and advocates for coverage of antiobesity medications under Medicare Part D.173 GLP-1 receptor agonists are highlighted in the paper given their efficacy for producing weight loss and their potential to treat a number of obesity-related comorbidities.

In a 2023 report from the Pharmaceutical Strategies Group (PSG), which details traditional drug benefit trends among employer, union and health plan respondents (n=149), 43% of respondents covered weight loss medications, 28% did not cover weight loss medications but were considering coverage in the next 1 to 2 years, and 22% did not cover weight loss medications and were not considering coverage.174 The respondents who did not cover these medications were asked to provide reasons for exclusion, and top responses included consideration of weight loss pharmacotherapy as lifestyle drugs (38%), high cost (34%), concern for inability to produce long-term weight loss (19%) and indefinite duration of use (5%). $10+ 1%

Medicaid states can opt to cover weight loss drugs as indicated by their state plan amendments.171 Furthermore, Medicaid coverage for adults varies for obesity drugs that can be excluded from coverage according to services chosen by each state.172 For children enrolled in Medicaid, the Early and Periodic Screening, Diagnostic and Treatment (EPSDT) benefit covers all medically necessary services, including obesity-related services.

TRADITIONAL DRUG BENEFIT TRENDS FROM A 2023 SURVEY OF EMPLOYER, UNION AND HEALTH PLANS

43% of respondents covered weight loss medications

28% did not cover weight loss medications but were considering coverage in the next 1 to 2 years

22% did not cover weight loss medications and were not considering coverage Reasons for exclusion/ top responses included 38% Consideration of weight loss pharmacotherapy as lifestyle drugs

34% High cost

19% Concern for inability to produce long-term weight loss

5% Indefinite duration of use

Market trends and forecasts

Weight management medications have seen considerable growth in the past few years. Between 2010 and 2020, prescription medications indicated for the treatment of obesity averaged <$600 million (M) in annual sales in the U.S.175 In 2023, these medications had combined sales of $4 9 billion (B), of which $4.3B was from semaglutide (Wegovy) alone. With the introduction of tirzepatide (Zepbound) in late 2023, another blockbuster medication for the treatment of obesity, it is forecasted that the obesity market will exceed $10B in total sales in 2024, of which GLP-1 receptor agonists will account for approximately 97% of the total. This unprecedented growth is expected to continue over the next 5 years, with the obesity market forecasted to reach an astonishing $30B by end of 2028. Since the introduction of semaglutide (Wegovy) in 2021 and until the end of 2028, the compound annual growth rate (CAGR) for obesity drugs is expected to be 66%. GLP-1 receptor agonists having an obesity indication will be the main driver of this growth as they are expected to have a CAGR of 75%.

It is forecasted that by 2028 diabetes medications will have combined sales of approximately $42B, which would be approximately 1.4 times the sales of total obesity drugs ($30B), considerably less than the 34 times more in 2019. The growth of GLP-1 receptor agonists is expected to continue over the next 5 years in both obesity and diabetes with a CAGR of 23% and 5%, respectively. It is forecasted that, by 2028, the utilization for the two leading GLP-1 receptor agonists used for the treatment of obesity, semaglutide (Wegovy) and tirzepatide (Zepbound), will have higher sales ($24 3B) than their counterparts semaglutide (Ozempic) and tirzepatide (Mounjaro) used to treat diabetes ($21 5B). Please refer to Figures 1-3 for trends and forecasts.

Pipeline

The pipeline for GLP-1 receptor agonist therapies is robust. There are investigational GLP-1 therapies in the pipeline as well as GLP-1s that are FDA approved for diabetes and weight loss that are being studied for other indications. Moreover, multiple new molecular entities are being studied for weight loss and diabetes. This pipeline is detailed in the Prime and Magellan Rx Clinical Perspectives: The evolution of GLP-1s.176 The Prime and Magellan Rx Pipeline+ Weight Management Front Runners also provides a snapshot of weight loss candidates in the U.S.177

This unprecedented growth is expected to continue over the next 5 years, with the obesity market forecasted to reach an astonishing $30B by end of 2028.

FIGURE 1. DIABETES AND

FIGURE 1. DIABETES AND OBESITY SALES (2024-2028 forecasted)

$30,000.00

$20,000.00

$10,000.00

FIGURE 2. GLP-1 SALES (2024-2028 FORECASTED) $-

$35,000.00

$30,000.00

$25,000.00

$20,000.00

OUR PERSPECTIVE

At Prime and Magellan Rx, we aim to provide the same care we would want for our loved ones. We are guided by four primary tenants of practice for chronic weight management, centered on evidence, adherence, cost and holistic care. Our overarching perspectives are summarized in these four pillars.

EVIDENCE

Guided by an evidence-based approach to GLP-1 management with a focus on long-term outcomes data

ADHERENCE

Improve patient adherence and persistence to treatment and minimize waste through tailored medically guided programs

COST

Drive value and advocate for responsible and affordable GLP-1 access for patients, taking into consideration the total cost of care and leveraging real-world insights plus integrated medical and pharmacy claims data

HOLISTIC CARE

A holistic approach to chronic weight management, encompassing various aspects of health, including lifestyle and behavioral modifications, targeting an individualized plan to achieve safe, realistic and sustainable weight goals for patients

Summary

The landscape of weight management has seen rapid and groundbreaking changes within the last few years. There has been recognition of obesity as a disease state. This is coupled with the rise in popularity for GLP-1 anti-obesity medications, fueled in part by social media and celebrity influencers. The growth trend is forecasted to continue to put pressure on patient access, coverage and total cost of care. The clinical community has a unique opportunity to support and guide patients to appropriate options for weight management in the setting of a global obesity epidemic. Lifestyle modifications and behavioral therapy are non-negotiable cornerstones of treatment for all patients with overweight or obesity, and pharmacotherapy may serve as a useful adjunctive strategy for select patients when clinically appropriate. It is critical that providers make evidencebased guideline-supported decisions when approaching weight management while also ensuring that individual patient characteristics and preferences are considered.

Organization Key initiatives

Academy of Nutrition and Dietetics178

American Board of Obesity Medicine (ABOM)179

American College of Physicians (ACP)

180,181

• Organization of credentialed food and nutrition professionals

• Provides educational information on nutrition and health

• National Nutrition Month annual campaign

• Maintains standards for assessment and credentialing of physicians

• Key goal is to improve access to high-quality clinical services for patients with obesity by increasing the number of competent physicians that can treat obesity

• Current initiative is aimed at advancing equitable access to obesity care, which includes:

» Developing new clinical guidelines and recommendations

» Expanding physician education resources to help diffuse and dispel misinformation and bias

• Provides clinicians with Obesity Management Learning Hub, which promotes initiation of patient conversations and counseling on treatment options for obesity

American Society for Metabolic and Bariatric Surgery (ASMBS)182,183

• Aims to advance metabolic and bariatric surgery interventions to improve the lives of people with obesity and related diseases

• Provides education and toolkits for practicing clinicians

• Publishes Surgery for Obesity and Related Disease (SOARD) journal

• Obesity Political Action Committee (PAC) represents the needs of bariatric surgeons and their patients and advocates for nationwide coverage of bariatric surgery

Organization Key initiatives

Center for Science in the

• Science-based consumer advocacy organization

• Aims to improve the food system to support healthy eating by advocating for industry and government to make positive contributions to public health

• National Alliance for Nutrition and Activity (NANA)

» Promotes better understanding of the importance of lifestyle modification and obesity control to the nation’s health and health care costs

» Aims to cultivate champions for nutrition, physical activity and obesity prevention in Congress and federal agencies

» Passed Healthy, Hunger-Free Kids Act

• Published list of 2023 Farm Bill priorities

Centers for Disease Control and Prevention (CDC)

• Division of Nutrition, Physical Activity, and Obesity (DNPAO) provides tools and resources to national, state and local partners to offer:

» Early Childcare and Education (ECE)

» Childhood Obesity Research Demonstration (CORD)

» Clinical and Community Data Initiative (CODI)

» Childhood Obesity Management with MEND Implementation Teams (COMMIT!)

» High Obesity Program (HOP)

» Racial and Ethnic Approaches to Community Health (REACH)

» State Physical Activity and Nutrition (SPAN)

• Department of Health and Human Services (HHS) offers school-based obesity prevention strategies for state policymakers

Organization Key initiatives

Congress189

• Treat and Reduce Obesity Act of 2021 (TROA)

» Bill that expands Medicare coverage of intensive behavioral therapy for obesity

• Allows coverage under Medicare’s prescription drug benefits for obesity medications

Healthy People 2030190

• Provides a plan of action for distribution of information and tools to help communities, states and organizations improve overall health and wellbeing

• Conducts ongoing assessment of progress toward national objectives

• Goals include:

» Reducing overweight and obese weight status by helping people eat healthy and get physical activity

» Reducing proportion of children and adolescents with obesity

» Increasing proportion of health care visits by adults with obesity that include counseling on weight loss, nutrition or physical activity

» Reducing proportion of adults with obesity

• Reducing consumption of added sugars by people aged ≥2 years

National Collaborative on Childhood

Obesity Research (NCCOR)191

• Goal is to accelerate progress in reducing childhood obesity by:

» Identifying, designing and evaluating interventions, especially in high-risk populations

» Increasing and improving national, state and local surveillance of childhood obesity

» Improving ability of researchers and program evaluators to conduct research and program evaluation

» Providing national leadership to accelerate implementation of evidence-based practice and policy

• Working with non-traditional health partners to integrate childhood obesity priorities with synergistic initiatives

Organization Key initiatives

National Institute of Environmental Health Sciences (NIEHS)192

National Institutes of Health (NIH)193

• Epidemiological and animal model research investigating link between air pollution/environmental contaminants and increased risk of obesity and metabolic dysfunction

Obesity Action Coalition (OAC)194

• Supports obesity-related research to identify contributing factors and to design and test strategies for prevention and treatment of obesity

• Established the NIH Obesity Research Task Force to accelerate progress in obesity research

• National nonprofit organization that aims to provide a voice for patients affected by obesity and empower them on their journey to better health

• Advocates for access to care and access to obesity treatment

Obesity Care Advocacy Network (OCAN)195

• Comprised of many organizations that are key stakeholders in the obesity space

• Works to increase access to evidence-based obesity treatments through education, policy and legislative efforts

• Congressional Advocacy Priorities and Strategies (CAPS) workgroup advocates for passing legislation that supports coverage of and access to obesity treatment, prevention and care

Obesity Medicine Association (OMA)196

• Promotes a comprehensive, evidence-based approach to treating obesity

• Publishes educational materials for clinicians, including Obesity Algorithm

• Overcoming Obesity conference

Strategies to Overcome and Prevent Obesity (STOP) Obesity Alliance197

• Group of business, consumer, government, advocacy and health organizations

• Aims to reverse the obesity epidemic in the U.S. through research, policy recommendations and development of hands-on tools for providers, advocacy groups, policymakers and consumers

Organization Key initiatives

The Obesity Society (TOS)198,199

• Goal is to advance the science-based understanding of the causes, consequences, prevention and treatment of obesity

• Provides awards and grants for innovations and research in obesity

• Publishes Obesity journal

• Obesity Week international conference for obesity researchers and clinicians

United States Department of Agriculture (USDA)

200,201,202,203

• Publishes Dietary Guidelines for Americans (DGA)

• MyPlate

» Official symbol of the 5 food groups: vegetables, fruits, grains, protein and dairy

» Provides patients and providers with resources for structured eating plans, meal planning, and food shopping

• Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) offers federal grants to states for food, health care referrals and nutrition education for low-income women and children who are at nutritional risk

• Child and Adult Care Food Program (CACFP) provides reimbursements for nutritious meals to eligible children and adults at childcare centers, day care homes and adult day care centers

• Supplemental Nutrition Assistance Program (SNAP) offers nutritional support for low-income seniors, people with disabilities and other people with low incomes

• SNAP Education (SNAP-Ed) partners with state and local organizations to teach SNAP participants how to make healthy meals and lead active lifestyles

• Expanded Food and Nutrition Education Program (EFNEP) provides nutrition education to low-income populations

• Agricultural Science Center of Excellence for Nutrition and Diet (ASCEND) for Better Health promotes food and nutrition security for all Americans through research, data and engagement

Organization Key initiatives

World Health Organization (WHO)204,205,206

• Global Strategy on Diet, Physical Activity, and Health describes actions needed to support healthy diets and regular physical activity

• 2030 Agenda for Sustainable Development focuses on reducing mortality from non-communicable diseases through prevention and treatment

• WHO Acceleration Plan to Stop Obesity offers recommendations to stimulate and support multi-sector country-level action for prevention and management of obesity

• Global Action Plan on Physical Activity 2018-2030 provides actions to increase physical activity globally

• Health Service Delivery Framework for Prevention and Management of Obesity integrates health and social systems responses that can be adapted according to country, context, circumstance and need

World Obesity Federation207

• Global organization to represent stakeholders in high-, medium- and low-income countries

• Provides goals up to 2025 that include better food systems, improved health systems and reducing childhood obesity

• World Obesity Day

• ROOTS Framework to address obesity:

» R: recognize obesity

» O: obesity monitoring

» O: obesity prevention

» T: treatment of obesity

» S: systems-based approach

YMCA 208

• Offers adapted Diabetes Prevention Program at over 200 facilities to individuals who are overweight or obese and who have prediabetes

1 World Health Organization: WHO. Obesity. https://www.who.int/health-topics/obesity#tab=tab_1. Accessed October 16, 2023.

2 World Health Organization, Branca F, Celletti F, et al. Health service delivery framework for prevention and management of obesity. Updated 2023. https://iris.who.int/bitstream/handle/10665/367789/9789290073239-eng.pdf?sequence=1 Accessed October 16, 2023.

3 Definition and facts for adult overweight and obesity. National Institute of Diabetes and Digestive and Kidney Diseases. Reviewed May 2023. https://www.niddk.nih.gov/health-information/weight-management/adult-overweight-obesity/definition-facts. Accessed October 16, 2023.

4 Why it matters. Centers for Disease Control and Prevention. Reviewed July 19, 2022. https://www.cdc.gov/obesity/about-obesity/why-it-matters.html Accessed October 16, 2023.

5 Policy Finder AMA. Recognition of obesity as a disease H-990.892. Last modified 2023. https://policysearch.ama-assn.org/policyfinder/detail/obesity?uri=%2FAMADoc%2FHOD. xml-0-3858.xml Accessed October 16, 2023.

6 Obesity. National Institute of Environmental Health Sciences. Reviewed July 31, 2023. https://www.niehs.nih.gov/health/topics/conditions/obesity/index.cfm Accessed October 16, 2023.

7 Obesity is a Common, Serious, and Costly Disease. Centers for Disease Control and Prevention. Reviewed May 17, 2022. https://www.cdc.gov/obesity/data/adult.html Accessed October 16, 2023.

8 Obesity is a Common, Serious, and Costly Disease. Centers for Disease Control and Prevention. Reviewed May 17, 2022. https://www.cdc.gov/obesity/data/adult.html Accessed October 18, 2023.

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