Proceedings of a Workshop—in Brief

Medications and Obesity: Exploring the Landscape and Advancing Comprehensive Care

Proceedings of a Workshop—in Brief

On March 19–20, 2024, the Roundtable on Obesity Solutions of the National Academies of Sciences, Engineering, and Medicine (the National Academies) held a workshop that explored the relationship between medications and obesity, including the state of the science around the safety and efficacy of medications in people with overweight or obesity, medications that may cause changes in body composition and weight status, and medications used to treat obesity and related comorbidities. Presenters focused on lived experiences and attention to weight bias and stigma and addressed the implications of pharmacotherapy for obesity on policy and legislation, economics, access, public perception and discourse, and population health.

This Proceedings of a Workshop—in Brief highlights the workshop presentations and discussions and is not intended to provide a comprehensive summary of the information shared.¹ The information summarized here reflects the knowledge and opinions of individual participants and should not be seen as a consensus of the participants, the Roundtable on Obesity Solutions, or the National Academies.

CURRENT STATE OF PHARMACOKINETICS AND PHARMACOLOGY FOR OBESITY

Donna Ryan, Pennington Biomedical Research Center, began by summarizing the current understanding of the biology of body-weight regulation and body composition, citing genetic contribution and events across the lifespan and obesogenic environmental factors (e.g., stress, sleep deprivation, sedentariness) that can trigger obesity in the presence of genes associated with obesity risk. These include somatic changes during puberty and menopause, which affect the distribution and accumulation of body fat in girls and women differently, and age-related weight changes. She explained that body weight is regulated by complex peripheral signals integrated into the central nervous system. Historically, the understanding of body weight regulation and resistance to weight loss has largely focused on leptin, a protein produced by body fat, which plays an important role in metabolic and biologic adaptations to weight loss and the defense of the body’s highest fat mass. However, she noted the other signals that regulate lean mass, and that there is growing interest in the role of myokines, signals from muscle that regulate body weight and muscle mass. Knowledge of the biology of food intake has advanced dramatically in the last 25 years, she explained, and understanding the signals of the gut-brain axis has resulted in successfully targeting glucagon-like peptide-1 (GLP-1), gastric

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inhibitory polypeptide (GIP), glucagon, and amylin for pharmacologic approaches to weight management.

Ryan described anti-obesity medications (AOMs) approved for chronic weight management within the context of drug development attempts over the last 100 years. After many failures were removed from the market due to adverse effects, the past decade of AOM discovery has yielded five with significant effects on weight loss: phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide. She highlighted that the latter two have garnered substantial attention from health care providers and patients due to their effectiveness for weight loss—averaging 15–22 percent of body weight at 1 year—and associated health improvements.

Medications approved for indications other than weight management can also influence weight and body composition, noted Ryan. She listed the broad range of medications associated with weight gain, from antidepressants to antihistamines. However, most of them have alternatives that are weight-neutral or associated with weight loss, which can benefit patients with obesity. She suggested that future approaches to obesity treatment with AOMs should aim to optimize body composition and function—not simply to achieve weight loss. She described how such functional goals should include (1) losing excess abnormal fat mass, (2) preserving lean mass, and (3) optimizing organ function. Intensive weight-loss lifestyle interventions in older adults have been associated with adverse effects, such as loss of lean muscle mass and consequent increased risk of frailty fractures (Johnson et al., 2017). Ryan highlighted emerging approaches to improve body composition along with weight loss, such as activin and myostatin inhibitors that are associated with increased lean mass and reduced fat mass.

David J. Greenblatt, Tufts University School of Medicine, discussed the altered pharmacokinetics and clinical effects of drugs in patients with obesity. He highlighted foundational research that demonstrated how a drug’s effects and distribution relate to its lipid solubility. In subjects with obesity, drugs with greater lipid solubility (e.g., midazolam) had prolonged half-life and increased volume of distribution compared to control subjects, although the drug clearance was similar. In contrast, for water-soluble drugs (e.g., cimetidine), the volume of distribution, half-life, and clearance were similar for both groups. He stated that this indicates the disproportionate distribution of drugs with higher lipid solubility into body weight in excess of ideal weight in individuals with obesity. Greenblatt explained that in an individual with obesity, the pharmacokinetic peripheral compartment of a water-soluble drug increases only slightly because it is not soluble in the additional tissue, but because of the selective solubility of lipophilic drugs in the excess adipose tissue, the compartment increases disproportionately to body size.

Drug clearance, which is independent of the volume of distribution, is a major determinant of half-life and of steady-state concentration during multiple doses, explained Greenblatt. In subjects with obesity, drug clearance has no evident relation to volume of distribution or lipid solubility and no consistent relation to degree of obesity. The lipid solubility of a drug and obesity in an individual combine to determine the volume of distribution, which might modify a loading dose following a single dose. When a loading infusion or step-up regimen is used to rapidly attain a steady state, it may be influenced by the volume of distribution for long half-life drugs. Half-life is important because it determines the duration of action after single doses and rates of accumulation and washout after termination, he added.

Greenblatt and colleagues have studied the consequences of obesity in the context of drug safety, finding that lipophilic drugs have delayed washout after chronic therapy and delayed steady state in patients with obesity. Thus, he explained, patients with obesity may attain steady state more slowly than is desirable, potentially requiring treatment modification (e.g., loading infusion, modified loading regimen), which has implications for extended dosing and washout. Given that obesity can influence pharmacokinetics, Greenblatt recommended studying these patients as a special population in drug development and educating care providers about these altered drug dispositions and clinical effects.

Jaya Vaidyanathan, U.S. Food and Drug Administration (FDA), discussed including subjects with obesity in drug development, which is important given the condition’s increasing prevalence. She suggested that as the U.S.

population becomes increasingly diverse, pivotal clinical trials should include the intended patient population. Vaidyanathan noted that a diverse trial population allows for a better assessment of the risk–benefit profile in specific groups of patients and aids in providing recommendations for use. She described that premarket clinical trials aim to limit heterogeneity of treatment effects, typically by studying a population that is homogeneous in disease background to limit variability and maximize the chances of demonstrating treatment effects. This often leads to underrepresenting or excluding certain subpopulations and causes gaps in the prescribing recommendations.

Clinical pharmacology addresses the intrinsic and extrinsic drivers of response to therapy and its variability, Vaidyanathan explained. Their impact on treatment effects in certain patient populations is often evaluated and addressed during drug development in dedicated pharmacokinetic studies; population pharmacokinetics and exposure-response can be appropriate to explore the effects of intrinsic factors, such as obesity. Changes in drug pharmacokinetics in populations with obesity are highly variable and depend on multiple factors, including drug characteristics, degree of obesity, and specific organ function (Jain et al., 2011).

Vaidyanathan highlighted the paucity of data for drugs in subjects with obesity—who are often excluded from clinical trials due to comorbidities—and the lack of dosing information regarding obesity in drug labeling, studies simultaneously evaluating drug products in individuals who have obesity versus without, and best practices or regulatory guidelines. She called for collective efforts to reduce the gap in prescribing information for obesity.

Despite no specific regulatory requirement to include subjects with obesity in clinical trials, patients with high body mass index (BMI) have been included in certain drug development programs for diseases frequently associated with obesity, said Vaidyanathan. She explained that regulatory agencies, including FDA, have moved to promote greater diversity in clinical trials, and multiple regulatory guidances recommend including participants who have obesity. The guidances have also provided more specific recommendations related to obesity, including contraindications, dosing strategies and modifications, monitoring, and administration. She described how model-informed drug development (applying quantitative models to facilitate drug development and decision-making) can be used as a regulatory tool to promote early interaction with FDA and enhance therapeutic individualization. It has already been used to support regulatory decision-making regarding dose capping for patients with obesity.

Ania Jastreboff, Yale School of Medicine, spoke about AOMs in clinical trials or recently approved by FDA. She stated that effectively treating obesity could unlock the ability to mitigate, treat, or even prevent hundreds of related diseases, describing the recent introduction of the new generation of AOMs—such as semaglutide and tirzepatide—as a major leap forward in pharmacotherapy, bringing the field to a watershed moment in treatment capabilities.

Although research on AOMs is exploring numerous mechanisms (e.g., activin pathway receptor inhibitors, melanocortin-4 receptor agonists for monogenic obesity), Jastreboff focused on nutrient-stimulated hormone-based (NuSH)² therapies that have already been approved (semaglutide and tirzepatide) and several therapies in phase 3 trials. Semaglutide is a long-acting injectable GLP-1 receptor agonist that was originally approved for type 2 diabetes and is now approved for chronic weight management in adults and adolescents ≥12 years; it is being evaluated in children aged ≥6 years. In addition to average weight reduction of 16.9 percent at 68 weeks in adults and average BMI reduction of 16.1 percent in adolescents, semaglutide has been associated with improvements in cardiometabolic measures and a composite end point of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death, and results suggest that it reduced risk of kidney disease progression (Wilding et al., 2021). Participants on tirzepatide in a clinical trial demonstrated average weight reduction of 22.5 percent in 72 weeks, with nearly 40 percent losing at least one-quarter of their body weight. In a longer trial, participants demonstrated an average weight reduction of 26 percent at 88 weeks—with >50 percent losing at least one-quarter of their body weight

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(Jastreboff et al., 2022). Tirzepatide has also been associated with improved cardiometabolic measures and diabetes control, with additional trials underway to evaluate its effects on obesity-related conditions and pediatric patients. She stated that given the many different types of obesity, variability is observed in both weight regain and weight reduction with all treatments, including these novel AOMs, and is being further explored.

Jastreboff described that NuSH-based therapies in phase 3 trials include the weekly injectables cagrisema (cagrilintide, an amylin analogue, paired with semaglutide), survodutide (dual GLP-1 and glucagon receptor agonist), and retatrutide (triple hormone receptor agonist targeting GIP, GLP-1, and glucagon receptors), the monthly injectable mari-tide (GIP and GLP-1 receptor agonists), and several oral GLP-1 receptor agonists, such as semaglutide (a peptide) and orforglipron (a small molecule). She highlighted that 100 percent of the phase 2 trial participants on the two highest doses of retatrutide exceeded the ≥5 percent body-weight reduction threshold for efficacy set by FDA for AOMs, which is rare in a scientific study (Jastreboff et al., 2023).

Now that medications have made total body-weight reductions of up to 25 percent attainable, the research and clinical focus is extending beyond treating obesity to improving health outcomes, Jastreboff said. This involves considering the quality of weight reduction, including body composition and muscle function. Activin pathway receptor inhibitors (e.g., bimagrumab, taldefgrobep, SRK-439) in development may improve body composition and some degree of weight reduction (Tisdale, 2010). Therefore, combination therapy that pairs new NuSH-based therapies with activin receptor pathway inhibitors may maximize fat loss while minimizing loss of muscle mass. She concluded that obesity treatment should focus beyond weight reduction and optimize health.

ADVANCING OPTIMAL OBESITY TREATMENT: INTERSECTIONS BETWEEN TREATMENT OPTIONS

Karen Glanz, University of Pennsylvania, reflected on her lived experience of obesity and weight control; she is a researcher in obesity, nutrition, and activity and patient who uses AOMs. She recounted her lifelong struggle with her weight, despite her active lifestyle and healthy eating habits. As an avid athlete who completed the Ironman World Championship, she continued to experience weight struggles and embarrassment about her weight. Although her professional research focuses on the intersection of biology, behavior, and healthy nutrition environments, she never imagined that she would take a medication to help with weight loss. However, after her physician recommended a statin for elevated LDL cholesterol, her attitude changed, and she received a prescription for semaglutide. She had a 4-month delay before the medication was available but has since lost 32 pounds over 5 months while maintaining the same level of activity. “To me, it has been like a miracle drug,” she said.

Michele Tedder, Black Women’s Health Imperative, also described her lived experience of obesity. Despite a lifetime of dieting and weight-loss programs, she has experienced obesity since childhood. Her physician helped her to understand that it is a disease and not her fault and encouraged her to consider weight-loss surgery. At the time of her sleeve gastrectomy, she had a BMI of 61 and multiple associated comorbidities (e.g., type 2 diabetes, sleep apnea, high cholesterol, high blood pressure, osteoarthritis). Today, her BMI is down to 45, her diabetes is in remission, and she has experienced major health improvements related to her comorbidities. “Comprehensive individualized obesity care has changed my life,” she reflected. She emphasized that obesity care requires a multipronged approach—tailored to an individual’s unique circumstances—that may include surgery, medication, lifestyle changes, behavioral approaches, and access to healthy foods.

Holly F. Lofton, NYU Langone Health, spoke from the perspective of a provider managing obesity and other weight conditions. Her approach in caring for patients who present with obesity is to focus on how they feel and the status of any weight-related medical conditions rather than their weight or BMI. She highlighted the starkly inadequate number of board-certified obesity medicine specialists in the United States relative to the need, which she stated underscores the importance of engaging nonspecialists. She said that among the many reasons providers cite for not treating obesity are lack of time, knowledge, and reimbursement, biased perceptions of patients with obesity, and even their own overweight/obesity. She also highlighted the requirement for prior

authorization of AOMs as a major barrier to care that undermines physicians’ autonomy to provide the best care. Moreover, given the state of CMS treatment coverage, she stated that BMI often determines access to obesity treatment options (e.g., behavioral therapy, bariatric surgery), and medical therapies are excluded. Lofton noted that more than 80 percent of AOM prescriptions are not filled due to lack of coverage and high drug costs. To bridge the gap in obesity care, she suggested (1) providing weight bias and sensitivity training, (2) expanding access to care (e.g., community-based programs, coverage for AOMs and bariatric surgery), (3) developing EMR tools to assist nonspecialists in providing AOMs, and (4) educating providers about AOMs.

Robyn Pashby, Health Psychology Partners, provided the perspective of an obesity-trained psychologist on the relationship between obesity and AOMs, which is underpinned by a complex interplay of contributing factors. She described how, among patients receiving AOMs, common mental health diagnoses include depression, anxiety, post-traumatic stress disorder, obsessive-compulsive disorder, and suicidality; however, they also experience a host of nonspecific mental health concerns that impact their quality of life (QOL), mental health, and use and management of AOMs. She stated these concerns range from the logistics of the medications to their cost to their potential effects or lack thereof. She called for formal research in this area, because AOM continuation and discontinuation likely hinge on these other nonspecific factors (Arillotta et al., 2023). She encouraged providers to have broader psychological discussions with patients by integrating mental health into primary and specialty care settings.

All AOMs should be prescribed in conjunction with psychological, dietary, and behavioral support to navigate the relationship between eating disorders (EDs) and obesity care, said Pashby. She stated AOMs may be misused—intentionally and unintentionally—by individuals with restrictive EDs and that people at “normal” and higher weights are less likely to seek or be referred for ED treatment, yet up to 45 percent of patients admitted for inpatient ED medical stabilization have a history of high weight. Binge-eating disorder has high comorbidity with obesity, and emerging research suggests that certain AOMs (e.g., semaglutide) are associated with significant binge-eating reductions. Patients on AOMs in her clinical practice report reduced binge eating, food cravings, loss-of-control overeating, and concerns about body image and shape; however, they also report increases in confusion about fullness/hunger signals and restrictive eating. Pashby recommended screening for disordered eating and body image, monitoring weight loss and restrictive eating, and differentiating between pathological and nonpathological restrictive eating among patients on AOMs.

Pashby defined “food noise” as constant and persistent thoughts about food and eating that are difficult to suppress, and they often lead to food-related intrusive thoughts and maladaptive eating behaviors. Silencing food noise is a reason people take AOMs beyond weight loss and physical health, she noted. In her practice, many patients taking AOMs report reduced food noise coupled with increased awareness of its previous effects. More research is needed on food noise and how it relates to addiction, she added.

Pashby emphasized that all prescribers, not just psychiatrists, have a role in monitoring mood and suicidal ideation (SI) in patients on AOMs. She explained that weight stigma is associated with higher suicidality, and EDs are associated with higher rates of depression, anxiety, and suicidality. Reducing weight bias and stigma would help manage health, mood, and SI, she advised. She said that FDA has noted no “…clear relationship with the use of GLP-1 RAs” and SI, and a review of patients with obesity on semaglutide found a 49–73 percent lower risk of first-time SI compared to other AOMs (Wang et al., 2024). Although some patients in her practice have reported worsening mood, anxiety, insomnia, and fatigue, she said they more frequently report mood improvement, lower anxiety, more energy, less fatigue, and increased hope for managing weight.

Denise Wilfley, Washington University in St. Louis, discussed mental and behavioral health considerations for children and adolescents receiving AOMs. She highlighted that the range of mental health issues associated with obesity in youth relates to QOL, conduct, and peer and emotional problems, and this group is more likely to report psychosocial stress events, develop psychiatric

disorders, and experience anxiety and depression. In adolescence, obesity is associated with increased suicide behaviors (Iwatate et al., 2023)—which Wilfley said underscores the need to assess adolescents with higher body weight for suicidality—and higher rates of EDs (Mitchison et al., 2020). Factors that underlie the high level of comorbidity between obesity and mental health disorders include the bidirectional influence of overeating and/or underactivity on mental health symptoms, shared risk factors, stigma, and medication to treat mental health conditions. Across the randomized controlled trials (RCT) conducted on AOMs in youth, she described stringent exclusion criteria that were used for mental health conditions, meaning that AOMs are routinely prescribed to youth not represented in the RCTs—broader samples should thus be included in these RCTs. She noted that the limited data collected from these trials suggest that the AOMs evaluated were not associated with adverse psychosocial outcomes.

Wilfley explained that children and adolescents with weight loss may have unique medical complications of starvation, despite presenting at normal or above-normal weights. Moreover, she stated that inadequate weight gain or energy intake or can cause the same serious medical complications (e.g., refeeding risk) as overt weight loss. Thus, she explained that during AOM treatment or other treatments with the potential for rapid weight loss, patients should be monitored during nutritional rehabilitation. Evidence-based intensive health behavior and lifestyle treatment (IHBLT) focuses on increasing sustainable, healthy behaviors to achieve ongoing improvements in health outcomes and self-worth, said Wilfley. Family-based treatment is a robust IHBLT for prevention and early treatment of ED that helps families to develop positive behaviors and routines, supports positive parenting, promotes positive body image, and increases support through family and peer networks, she explained. The use of IHBLTs to complement AOMs should be further evaluated, she added.

Colleen Dawkins, Big Sky Medical Wellness, discussed how nutrition interventions can support patients receiving AOMs, which are not intended to be stand-alone treatments. She said that the level of support that patients need will vary over time, and those who receive more support are more likely to achieve good outcomes. Ideally, she said, treatment for obesity draws upon a range of tools to create layers of ongoing support that may include nutrition approaches and AOMs; it should also include anticipating and planning for challenges (e.g., weight-loss plateaus, weight regain, metabolic adaptation) as the patient moves through phases of treatment. She explained that nutrition interventions facilitate reduction of adipose tissue and preserve lean mass while also preventing new health issues from nutrient deficiencies. She added that working with a dietitian can help improve QOL and provide support for making long-term lifestyle changes to help patients achieve their health goals.

Like any aspect of obesity treatment, nutritional support should be customized for each patient’s unique needs, said Dawkins. She described that as part of a comprehensive treatment plan, medical nutrition therapy (MNT)— a nuanced, patient-centered approach to manage certain medical conditions—can optimize outcomes for patients receiving AOMs. For both pediatric and adult care, she suggested that MNT should involve the entire family in nutrition and lifestyle approaches. MNT is underused, and providing it more broadly would benefit patients, said Dawkins, but its coverage and reimbursement by Medicare, Medicaid, and private insurance are limited and variable.

Dawkins underscored the critical role of nutrition in managing the potential adverse effects associated with AOMs. She recommended monitoring patients for potential nutrient deficiencies and electrolyte disturbances, which should avoid a weight-exclusive focus and encompass body composition, laboratory tests, and food and activity logs. Adverse effects can be addressed with strategies such as ensuring sufficient hydration, eating small portions and more frequent meals, and avoiding meals high in fat and sugar. She noted that the evidence base from clinical trials on integrating AOMs with nutrition interventions is not yet robust, with most studies focusing on calorie reduction as the nutrition intervention. However, Dawkins does not find calorie reduction to be necessary with most of her patients; she prefers to focus on the source of calories and when they are consumed.

John Jakicic, University of Kansas Medical Center, outlined physical activity considerations in the context of AOM treatment. Despite the many potential benefits of AOMs, they are also associated with reductions in lean body mass of 25–40 percent, which is as much as twice that observed with lifestyle programs, he explained. More research is needed to understand how reductions in lean mass relate to reductions in muscle mass, he noted, and limited literature suggests that some components of fitness only improve when exercise is added to AOMs, indicating that weight loss itself does not necessarily improve strength, mobility, or cardiorespiratory fitness.

Because lean body mass includes not only muscle mass but also other parameters, such as organ tissue and connective tissues, Jakicic recommended shifting the paradigm from focusing on the volume of lean mass to its quality. Many patients with obesity have a large amount of muscle mass; however, increasing its volume does not necessarily increase fitness—this requires improving its quality through exercise and physical activity, he noted. Moreover, even given lean body mass loss, he explained that exercise increases muscle strength and function, improves cardiorespiratory fitness, enhances glucose regulation, and reduces insulin resistance. Research by Jakicic and colleagues underscores the importance of complementing AOM treatment with physical activity to reduce the risk of sarcopenia-related chronic conditions (Jakicic et al., 2024).

Jakicic suggested developing a valid and reliable measure of body composition to measure changes with weight loss that include measures of muscle mass versus other lean mass and measures of bone health. He also suggested shifting the focus to holistic obesity treatment, rather than weight loss, because physical activity and exercise enhance the quality of body tissues and yield health benefits that are not realized with weight loss alone. Finally, he called for more research to determine the optimal parameters of intensity, volume, and mode of exercise to complement treatment with AOMs.

Dan Bessesen, University of Colorado Anschutz Medical Campus, focused on implications related to the forthcoming generation of highly effective AOMs (HEAOMs). He predicted that they will eventually be widely prescribed, resulting in weight loss comparable to surgery but with advantages of dose flexibility, choice of mechanisms, combinations, and potential additional health benefits—albeit with lifetime costs that will likely be higher than surgery and thus pose a barrier to widespread access. Their emergence will necessitate a paradigm shift toward conceptualizing obesity in the context of health, not weight, in a way that is actionable for clinicians, FDA, and insurers, he said. He noted that this will require refining clinical assessments and developing integrated treatment strategies for obesity and its comorbidities, considering how FDA will approve HEAOMs using criteria beyond BMI, and restructuring insurance coverage to account for comorbidities.

To prepare for HEAOMs, Bessesen recommended reframing the goal of obesity treatment to extend beyond weight loss to other parameters (e.g., body composition, muscle quality, regional adiposity, lower A1C, functional mobility, QOL) so it is actionable for FDA and insurers. He also suggested determining the circumstances in which the cost–benefit ratio is sustainable and considering how to integrate older, less expensive, and less effective AOMs with HEAOMs into clinical care—for example, whether to use a low-dose HEAOM versus an older AOM if less weight loss is needed. Additional considerations related to HEAOMs include the role of complementary lifestyle approaches, whether to initiate therapy preventively, appropriate weight-loss quantity and tempo, and how to prepare patients for substantial weight loss.

NAVIGATING CLINICAL PRACTICE, ECONOMIC, AND POLICY CHALLENGES OF NEW OBESITY TREATMENTS

Jamy Ard, Wake Forest University School of Medicine, outlined the history of clinical practice guidelines (CPGs) for treatment of obesity in adults in North America. In 1998, the National Institutes of Health (NIH) published the first U.S. CPG; it considered the populations at risk, why overweight and obesity should be treated, and which treatments are effective. In addition to guidelines for the assessment, evaluation, and treatment of obesity—and the adaptation of weight-loss programs to diverse patients—the report included a 10-step practical guide for primary care providers. Over the following decade, spurred by increasing U.S. obesity prevalence, Ard described how NIH convened a panel to update the CPG for the management of overweight and obesity in adults, in collaboration with the American Heart Association,

American College of Cardiology, and The Obesity Society. Published in 2013, the updated CPG and systematic evidence review encompass (1) expected health benefits of weight loss, (2) health risks associated with obesity, (3) effectiveness of dietary strategies, (4) effectiveness of a comprehensive lifestyle approach, and (5) efficacy and safety of bariatric surgery.

The 2013 CPG was criticized for its lack of focus on pharmacotherapy, noted Ard. When it was developed, the AOMs on the market had recently been (rimonabant) or were about to be (sibutramine) withdrawn. Lorcaserin and phentermine/topiramate extended release had been approved in 2012, so the CPG did not include emerging data on them. The implications of the lack of focus on AOMs were substantial, he described. Payers made decisions about treatment coverage using the CPG, which did not provide recommendations on pharmacotherapy. He also said policy makers interpreted the lack of inclusion of AOMs as an indication of decreased significance, and clinicians based their practice on a CPG that did not include the latest evidence on AOMs. Professional societies stepped in to fill in these gaps by creating their own obesity CPGs and treatment algorithms. Although this was beneficial, the number of competing guidelines led to contention about which should be dominant and used to determine reimbursement, added Ard.

Ard highlighted other CPGs recently developed to shift practice. For example, the American Society for Metabolic and Bariatric Surgery and International Federation for the Surgery of Obesity and Metabolic Disorders put forth a new guideline that changed the indication for metabolic and bariatric surgery in 2022. The Canadian Medical Association and Obesity Canada made an extensive effort to develop comprehensive CPGs for adult obesity—which are living documents updated regularly as new evidence emerges—released in 2020 and adopted by other countries lacking the infrastructure to develop their own guidelines.

Ard emphasized that CPGs are a function of the questions asked and available evidence and resources; even the most comprehensive CPGs are limited by the availability of high-quality evidence. He suggested that clinical decisions be informed by best-practice standards in the absence of a CPG, particularly in obesity medicine, where non-science-based therapies abound and comparative effectiveness evidence is limited. CPGs are also shaped by the perspectives and agendas of the entities that develop them, he added. In the context of multiple CPGs, Ard concluded that it is critical to consider which authoritative body defines the predominant guideline used as the basis for decisions about reimbursement and coverage of care in indications for treatment.

Sarah Barlow, University of Texas Southwestern Medical Center, reviewed the CPGs around AOMs for pediatric populations. She stated FDA recently approved three AOMs for adolescents with obesity: liraglutide, phentermine/topiramate combination, and semaglutide. In 2023, the American Academy of Pediatrics released its Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity, which includes 13 Key Action statements to direct clinical practice. For instance, Key Action Statement 9 states that overweight and obesity in children and adolescents should be treated “…using a family-centered and non-stigmatizing approach that acknowledges obesity’s biological, social, and structural drivers” (Hampl et al., 2023).

Barlow highlighted Key Action Statement 11—which recommends providing IHBLT for patients aged ≥2 years with overweight or obesity— and Key Action Statement 12, which holds that patients aged ≥12 years with obesity should be offered weight-loss pharmacotherapy “… as an adjunct to health behavior and lifestyle treatment.” IHBLT has measurable benefits, including improved BMI and cardiovascular risk factors, and some studies show a reduction in disordered eating, but more research is needed to evaluate its effects on EDs and other mental health conditions (Hampl et al., 2023). She suggested that IHBLT is more practical and effective in community settings than individual office visits, but the former is rarely covered by insurance. Pharmacotherapy benefits for pediatric obesity can include reduced adiposity and improved metabolic health, with additional desired goals of improved nutritional intake, physical activity, QOL, and mental health. However, she cautioned about the potential negative impacts of AOMs on physical (e.g., loss of muscle and bone mass, limited linear growth, and excessive or too rapid weight loss) and emotional (e.g., heightened risk of EDs, reduced or unimproved QOL) health.

A substantial gap persists between children who would benefit from treatment and those who receive it, said Barlow. Barriers include insurance coverage exclusions, shortages of AOMs, obesity-related stigma, providers’ unfamiliarity with treatments, and structural racism and bias. To address these barriers, Barlow recommended (1) applying the Reach-Effectiveness-Adoption-Implementation-Maintenance framework to evaluating obesity treatment implementation in children; (2) improving AOM affordability and coverage; (3) delivering IHBLT outside current health care structures; (4) training providers to prescribe AOMs and provide IHBLT; and (5) further studying the physical and mental health sequelae of AOMs.

Alison Sexton Ward, University of Southern California Schaeffer Center for Health Policy & Economics, explored the potential benefits of expanding Medicare coverage for AOMs, given that the average U.S. adult may soon be considered to have obesity. She said that according to 2023 U.S. population data, obesity is most prevalent among the Black population (60 percent), followed by the Hispanic (51 percent) and White (41 percent) populations. In the Medicare population, Black and Hispanic populations also have greater prevalence of obesity-related comorbid conditions that are associated with higher medical spending, decreases in health-related QOL, and shorter longevity, she explained. However, the uptake of AOMs remains exceptionally low, as they are excluded by Medicare Part D and most private insurers. She highlighted current bipartisan legislation in Congress—the Treat and Reduce Obesity Act (TROA)—that would allow Medicare coverage for FDA-approved AOMs and expand it for intensive behavior therapy, potentially increasing access to weight-loss treatment in that population. This could spur a domino effect throughout the insurance industry, leading to broader private coverage, she added.

To model the potential social benefits and medical cost offsets from passing TROA, Ward and colleagues used the Future Adult Model, an economic-demographic micro-simulation model, to simulate four insurance coverage scenarios: (1) status quo, (2) Medicare coverage only, (3) Medicare and private coverage, and (4) universal coverage, including both the uninsured and Medicaid populations. The simulation shows that treating obesity through widespread access to AOMs would generate enormous social benefits that increase over time, she reported. Compared to the status quo, Medicare coverage alone would offset the total Part A, B, and D costs by $176 billion in 10 years, $479 billion in 20 years, and $704 billion in 30 years; the greatest cost savings would come from Part A, due to improved health. When private insurance is included, she explained, the cost offsets to Medicare are much higher, especially over time, because providing access to weight-loss treatment at an earlier age reduces the risk of chronic conditions in later life. She stated that Medicare would see dramatic reductions in chronic disease prevalence from universal uptake within a decade and, after 20 years, diabetes prevalence would decrease by an estimated 17 percent. She added the value for the U.S. population is even greater for the universal coverage scenario: the cumulative social benefit would be roughly $4 trillion at 10 years, $10 trillion at 20 years, and $17.6 trillion at 30 years. The model does not account for AOM drug costs, but she predicted that greater access to and uptake of AOMs—coupled with new approvals—will likely increase competition and reduce prices. In addition to contributing to longer lives and reduced disability, broader access to AOMs could help alleviate health disparities in minority populations who are less likely to respond to behavioral weight-loss interventions, Ward stated.

Noelia Duchovny, Congressional Budget Office (CBO), considered how expanding Medicare’s coverage of AOMs would affect the federal budget. Medicare Part D plans are prohibited from including AOMs in the standard prescription drug benefit, but they do cover GLP-1 agonists for type 2 diabetes, she explained. CBO has analyzed a policy to allow Medicare Part D to cover AOMs based on two main components: their direct costs and the potential offsetting budgetary savings associated with improved health outcomes. Duchovny stated that CBO expects that Medicare coverage would result in considerable demand for and use of AOMs by enrollees and that AOMs would cost the federal government more than it would save from reducing other health care spending, leading to an overall deficit increase over the next 10 years.

Duchovny explained that the determinants of direct costs include both current and future prices. The current price for a 4-week supply of a GLP-1 AOM is $1,100–1,300,

minus any rebates and discounts from manufacturer to insurance plans and other payers. If Medicare covered it as an AOM, she explained, enrollees would pay for some of its cost through higher premiums and cost-sharing. Although the price trajectory of AOMs is uncertain and reflects several factors, CBO expects that semaglutide will be selected for price negotiation by the Department of Health and Human Services within a few years. She explained that would lower its price and could, by spurring competition, lower prices of other AOMs. Additionally, new AOMs might have greater effectiveness, fewer side effects, or other improvements that could translate to higher average prices, even if prices decline for current AOMs, she observed. She added that CBO is not aware of empirical evidence directly linking AOM use to reduced health care spending, but simulations show a reduction in spending on other types of health care due to the drugs’ use.

CBO continues to monitor trends in the use of AOMs, along with their prices, effects on health, and coverage by insurance plans, said Duchovny. She suggested that useful avenues of future research would include (1) factors affecting the use of AOMs on the market (e.g., uptake rates, adherence), (2) expectations about prices and effectiveness of AOMs being developed, and (3) near- and long-term clinical impacts of AOMs and their effects on patients’ use of and spending on other medical services.

Shawn Gremminger, National Alliance of Healthcare Purchaser Coalitions, offered the employers’ perspective on ensuring comprehensive care for the workforce. His organization represents about 45 million people in individual employer purchaser coalitions across the country. Coverage of AOMs is of significant interest to member coalitions, he said. According to the organization’s 2023 annual survey of employers, 80 percent offered lifestyle programs, 68 percent provided coverage for bariatric surgery, and 56 percent offered coverage of AOMs for those with certain conditions; around one-third provided coverage for GLP-1s, yet roughly half indicated that they were not planning to cover them, primarily due to cost and lack of research.

In response to that survey, the National Alliance of Healthcare Purchaser Coalitions convened the National Obesity Advisory Council, which released an employer position statement in 2023 recommending that employers develop comprehensive guidelines for obesity care and create reimbursement structures that are consistent with an emerging standard of practice. The council also developed comprehensive guidance for AOM coverage decisions, which spans four different approaches, with advantages and disadvantages outlined for each option. One option is to cover the product fully, although this is relatively uncommon, he noted. An option that is increasingly popular with employers is to cover the product with conditions: for example, including individuals exceeding a BMI threshold of 35, targeting recommended weight loss, requiring complementary behavior change programs, or educating about side effects. Another option is to cover the product through centers of excellence that route prescriptions through a specialized network or vendor. Employers can also refuse coverage altogether. Gremminger predicted that full coverage and full refusal will be the least common approaches, with most employers covering the product with conditions or through centers of excellence.

Gremminger concluded by referencing the STOP Obesity Alliance’s comprehensive guide for employers on the core components of obesity care, which has been adopted by the Office of Personnel Management, which manages benefits for 8 million federal employees. The recommended benefit package includes five elements: screening and prevention, intensive behavioral therapy, pharmacotherapy support, bariatric surgery, and weight maintenance.

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DISCLAIMER This Proceedings of a Workshop—in Brief has been prepared by Anna Nicholson as a factual summary of what occurred at the meeting. The statements made are those of the rapporteur or individual workshop participants and do not necessarily represent the views of all workshop participants; the planning committee; or the National Academies of Sciences, Engineering, and Medicine.

*The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop—in Brief rests with the institution. The planning committee comprises Ihuoma Eneli (Co-chair), University of Colorado Anschutz Medical Campus; Nicolaas P. Pronk (Co-chair), HealthPartners; David Arterburn, Kaiser Permanente Washington Health Research Institute; Jeanne Blankenship, Academy of Nutrition and Dietetics; Christina R. Chow, Emerald Lake Safety, LLC.; Laura Higginbotham, U.S. Food and Drug Administration; Joseph Nadglowski, Jr., Obesity Action Coalition; Anand K. Parekh, Bipartisan Policy Center; and Kristen R. Sullivan, American Cancer Society.

REVIEWERS To ensure that it meets institutional standards for quality and objectivity, this Proceedings of a Workshop—in Brief was reviewed by Christina R. Chow, Emerald Lake Safety, LLC, and Susan J. Woolford, University of Michigan. Leslie J. Sim, National Academies of Sciences, Engineering, and Medicine served as the review coordinator.

SPONSORS This workshop was partially supported by the Academy of Nutrition and Dietetics; Alliance for a Healthier Generation; American Cancer Society; American Council on Exercise; American Society for Nutrition; Bipartisan Policy Center; Eli Lilly and Company; Found; General Mills, Inc.; The JPB Foundation; Mars, Inc.; Nemours Children’s Health System; Novo Nordisk; Obesity Action Coalition; Partnership for a Healthier America; Reinvestment Fund; Rudd Center for Food Policy and Health; Robert Wood Johnson Foundation; SHAPE America; Society of Behavioral Medicine; The Obesity Society; Trust for America’s Health; Wake Forest Baptist Medical Center; and Walmart.

STAFF Heather Del Valle Cook, Amanda Nguyen, Cypress Lynx, and Meredith Parr, Food and Nutrition Board, Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine.

For additional information regarding the workshop, visit https://www.nationalacademies.org/event/42135_03-2024_medications-and-obesity-exploring-the-landscape-and-advancing-comprehensive-care-a-workshop.

SUGGESTED CITATION National Academies of Sciences, Engineering, and Medicine. 2024. Medications and obesity: Exploring the landscape and advancing comprehensive care: Proceedings of a workshop—in brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/27872.

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