Novel strategies for medical management of obesity: mechanisms, clinical implications, and societal impacts—a report from the 25th Annual Harvard Nutrition Obesity Symposium

Abstract

Obesity is a chronic, relapsing disease with a multifactorial etiology. Over the past 5 y, obesity medicine has entered a new era with the advent of novel, game-changing pharmacotherapies that achieve weight loss exceeding 15%–20%. Beyond weight loss, these powerful therapies offer additional benefits, such as cardiovascular improvements. These novel agents, such as glucagon-like peptide-1 receptor agonists, work by reducing appetite, slowing gastric emptying, and increasing feelings of fullness. Recent work also points out the potential role of these medications for other medical conditions, including addictive and neurodegenerative disorders. In June 2024, the National Institutes of Health-funded Nutrition Obesity Research Center at Harvard and the Harvard Medical School Division of Nutrition hosted their 25th annual Harvard Nutrition Obesity Symposium, titled “Novel Strategies for Medical Management of Obesity: Mechanisms, Clinical Implications, and Societal Impacts.” This paper synthesizes the symposium’s discussions, emphasizing the importance of innovative pharmacotherapeutic strategies in addressing the burden of obesity and the associated economic and social inequities, including disparities in access to care in adults and children.

Introduction

Obesity is a major problem globally, resulting in significant comorbidities. The development of highly effective new treatment strategies has provided mechanistic insights and greatly improved the clinical landscape for obesity management, with significant societal implications. The Nutrition Obesity Research Center at Harvard (NORCH) and the Division of Nutrition at Harvard Medical School sponsored a symposium titled, “Novel Strategies for Medical Management of Obesity: Mechanisms, Clinical Implications, and Societal Impacts,” to explore these key questions. For more details on this event, visit https://dev.norch.org/center-events/2024-novel-mechanisms-for-medical-management-of-obesity-mechanisms-clinical-implications-and-societal-impacts/.

Methodology

Following the rapid rise in effective treatments in obesity medicine, the Nutrition Obesity Research Center at Harvard (NORCH) symposium organizing committee chose to explore the topic of “Novel Strategies for Medical Management of Obesity.” Pursuant to this theme, investigators from research institutions in the United States and internationally were selected to participate as speakers based on their recent innovative work in the medical management of obesity. Speaker presentations were organized into 4 sessions: 1) clinical implications and mechanisms of current strategies, 2) altering brain pathways to treat obesity and reduce hunger, 3) equity, costs, and access, and 4) integrating pharmacological therapy into a successful long-term comprehensive care strategy for people with obesity. Speakers were encouraged to integrate their own scientific data as well as literature reviews into their presentations, and organizers critically reviewed presentation content for validity. Presenters were encouraged to use data from clinical trials, physiology studies, and outcome studies, and to cite the most up-to-date literature in their presentations. Unpublished data were recognized and validated by the presenter. Presenters were given the opportunity to collaboratively review their work with other speakers and symposium participants via a discussion after each session. This report summarizes the proceedings of the symposium. The first author (GS) summarized and integrated salient points from each section of the symposium. Speakers were invited to participate as authors, and those agreeing to manuscript preparation provided additional edits to individual sections.

The George L. Blackburn keynote address: current pharmacological strategies for obesity management

In 2023 and 2024, significant scientific breakthroughs emerged with novel glucagon-like peptide-1 receptor agonist (GLP-1RA) class agents and nutrient-stimulated hormonal therapies (NuSH) [1]. This led to rapid growth in the field of obesity medicine, with new antiobesity pharmacotherapies modulating hormone secretion and metabolism. Food and Drug Administration (FDA)-approved drugs for obesity management include tirzepatide, semaglutide, phentermine/topiramate, liraglutide, naltrexone HCl/bupropion HCl, phentermine, and orlistat [2]. The efficacy of these medications ranges up to 22.5% weight loss, with effects of novel medications like tirzepatide and semaglutide approaching outcomes comparable to surgical weight-loss procedures [3,4]. Many more drugs are in development and will be forthcoming in the upcoming years.

The groundbreaking class of GLP-1RA agents has resulted in the first major successes in obesity management in over a quarter of a century of research (Figure 1) [5]. GLP-1 was first discovered in 1985; its increase noted after bariatric surgery [6]. The subsequent discovery of leptin, in 1994, shed light on how adipose tissue defends against starvation [7,8]. By 1995, Leibel [9] demonstrated that obesity, adipose tissue, and inflammation are linked, showing body weight is regulated and defended[7]. In 1997, sibutramine gained approval for chronic weight management [10]. In 2003, crown-like structures, composed of macrophages surrounding dead or dying adipocytes in adipose tissue, were correlated with proinflammation and insulin resistance [11]. Sumithran et al. [12] provided clinical evidence of metabolic adaptation to body weight regain; one year after weight loss with a calorie-restricted diet, participants demonstrated sustained elevations in appetite-stimulating hormones and reductions in appetite-suppressing hormones. In 2012, Thaler et al. [13] linked obesity to neuroinflammation. It was not until 2013 that the American Medical Association declared obesity a disease. During this period, FDA approvals included bupropion/naltrexone SR, phentermine/topiramate ER, and lorcaserin for obesity treatment. A decade later, new obesity medications, like semaglutide, tirzepatide, and setmelanotide, demonstrated increased efficacy and addressed genetic obesity. Other agents under study, like bimagrumab, a human monoclonal antibody to treat muscle loss and weakness, showed promise as well. In the current era of obesity medicine, beyond 2024, precision nutrition and nonsurgical therapies are being further pursued.

FIGURE 1.

Obesity medicine history since 1985. AMA, American Medical Association; CLS, crown-like structures; FDA, Food and Drug Administration; GLP-1, glucagon-like peptide-1.

The discovery of leptin and the neural circuit that controls feeding led to an alternative explanation for obesity rather than a lack of willpower [8]. The interactions among hormonal and neural pathways that regulate food intake and body-fat mass play a crucial role in maintaining overall body weight.

Hormonal pathways

Leptin, produced by adipose tissue, acts as a satiety hormone. When fat stores increase, leptin levels rise, signaling to the brain that energy reserves are sufficient. In response, appetite decreases through a negative feedback loop. Ghrelin, secreted by the stomach, stimulates hunger. Its levels increase before meals and decrease after eating, regulating hunger-related signals through positive feedback. Ghrelin interacts with hypothalamic circuits to influence feeding behavior. Insulin affects food intake by regulating glucose metabolism. It also communicates with the brain to modulate appetite.

Neural pathways

The neurons involved in appetite regulation reside in several brain regions, including the prefrontal cortex, nucleus accumbens, and hypothalamus. These regions play a crucial role in modulating feeding behavior and energy balance. The prefrontal cortex influences decision-making and self-control of eating behavior [14]. The nucleus accumbens is involved in reward processing and motivation related to food [15]. The hypothalamus is a central hub for appetite regulation [16]. Specifically, the hypothalamus contains key nuclei such as the arcuate nucleus (ARC) and the paraventricular nucleus (PVN), which integrate hormonal signals related to hunger and satiety. The ARC houses neurons coexpressing neuropeptide Y (NPY) and agouti-related peptide (AgRP), which are orexigenic (appetite-stimulating), as well as proopiomelanocortin-expressing (POMC) neurons, which are anorexigenic (appetite-suppressing) [8]. POMC neurons release α-melanocyte-stimulating hormone, which acts on appetite-suppressing neurons in the PVN via the melanocortin 4 receptor (MC4R) [8]. AgRP neurons promote hunger by inhibiting POMC neurons directly and by releasing AgRP as a competitive antagonist of MC4R, stimulating food intake [8,17]. ARC neurons also project to other brain regions, influencing food intake and energy expenditure.

Adipose tissue and inflammation

Adipose tissue produces cytokines and adipokines that influence appetite and metabolism. Chronic inflammation in adipose tissue can disrupt hormonal signaling.

Advances in understanding individual variations in metabolism allow for personalized dietary recommendations. Beyond pharmaceuticals, noninvasive approaches like behavioral interventions, cognitive-behavioral therapy, and lifestyle modifications are essential for long-term weight management.

GLP-1RAs mimic the actions of GLP-1, stimulating insulin secretion and slowing stomach emptying [18]. These agents replicate the hormonal effects observed after metabolic surgery, including lowering the body weight set point and promoting diabetes regression following Roux-en-Y bariatric surgery (RYGB). Bariatric procedures, such as sleeve gastrectomy and RYGB, lead to substantial weight loss and metabolic improvements by altering the gastrointestinal (GI) tract [19]. Key hormonal changes include increased satiety hormones (for example, GLP-1) and decreased hunger hormones (for example, ghrelin). Current medical therapies, such as semaglutide and tirzepatide, also mimic GLP-1 effects [3,4]. By binding to GLP-1 receptors in the brain, semaglutide helps control appetite and reduce caloric intake [20]. Additionally, combining GLP-1RAs with other co-agonists, such as glucagon and glucose-dependent insulinotropic polypeptide (GIP), has shown physiological efficacy. GLP-1 enhances glucose-dependent insulin release, reduces glucagon levels, optimizes nutrient absorption by slowing gastric emptying, and limits food intake. GIP, another incretin hormone secreted from gut cells, primarily enhances insulin secretion in response to oral glucose intake. Unlike GLP-1, GIP does not significantly inhibit glucagon secretion; GIP receptor (GIPR) activation contributes to the incretin effect. Glucagon, produced by pancreatic alpha cells, raises blood glucose levels by promoting glycogen breakdown (glycogenolysis) and glucose production from non-carbohydrate sources (gluconeogenesis). GLP-1 inhibits glucagon secretion during hyperglycemia, contributing to glucose control. Overall, GLP-1RAs and related hormones play crucial roles in glucose regulation, appetite control, and metabolic balance. Researchers continue to explore novel approaches to optimize these pathways for treating metabolic diseases.

In addition, GLP-1RAs have multifaceted effects on various physiological systems [18,20,21]. Pancreatic effects: GLP-1RAs stimulate GLP-1 receptors in the pancreas, leading to increased insulin release. This insulin boost helps alleviate hyperglycemia by promoting glucose uptake and utilization. Appetite regulation and weight loss: stimulation of GLP-1 receptors in the hypothalamus reduces appetite and enhances satiety. As a result, GLP-1RAs aid in weight loss by promoting feelings of fullness after meals. Cardiovascular effects: beyond glucose control and weight loss, GLP-1 and GLP-1RAs increase glucose uptake by the myocardium, inhibit cardiac remodeling, reduce oxidative stress, and exert direct effects on atherogenesis and vascular endothelium. Other tissues and effects: GLP-1R is widely distributed in various tissues. GLP1Ras may reduce neuroinflammation, promote nerve growth, improve heart function, delay gastric emptying, regulate blood lipid metabolism, and reduce fat deposition. GLP-1RAs offer a comprehensive approach, affecting multiple systems to improve insulin sensitivity, manage blood sugar, and support overall health.

Previous obesity pharmacotherapies include the following [16]: Naltrexone/bupropion: this combination consists of an opioid antagonist (naltrexone) paired with a dopamine and noradrenergic reuptake inhibitor (bupropion). Phentermine/topiramate: this combination involves a sympathomimetic amine (phentermine) combined with an anti-epileptic agent (topiramate). Orlistat: orlistat is a lipase inhibitor. These FDA-approved medications have been used to address obesity, each with its unique mechanism of action. However, these medications typically achieve only 3%–7% weight loss. Notably, behavioral interventions can lead to 2%–4% body weight loss. Newer therapies now surpass the 10% weight-loss threshold (Figure 2) and offer additional clinical benefits, such as cardiovascular disease (CVD) risk reduction. Many of these therapies, like GLP-1RAs, target hormonal pathways.

FIGURE 2.

Efficacy of antiobesity drugs compared with bariatric surgery. Bariatric surgery remains the best weight loss option; FDA, Food and Drug Administration.

The hormonal pathways targeted by GLP-1RAs involve several key mechanisms of appetite regulation and metabolic control. GLP-1RAs mimic the actions of endogenous GLP-1, which is secreted by the gut in response to food intake, by activating GLP-1Rs. GLP-1R activation leads to insulin release, inhibits glucagon release, and slows gastric emptying, thereby enhancing satiety and reducing food intake [18]. Hypothalamic pathways are also influenced by GLP-RAs through GLP-1R activation in the ARC and PVN, which modulates the activity of NPY/AgRP and POMC neurons [8]. Other hormone pathways affected include those involving ghrelin, leptin, and peptide YY (PYY), which collectively contribute to regulating appetite and energy balance [16].

Additional benefits beyond weight loss

Cardiovascular and heart failure benefits

In the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial [22], a significant breakthrough in the field of obesity medicine, researchers investigated the effects of semaglutide. This trial included individuals with overweight or obesity and established CVD (without diabetes). The results were compelling: semaglutide reduced the risk of major adverse cardiovascular events by 20% over a timeframe of roughly 2–3 y compared with placebo. Previously, semaglutide was known to benefit people with diabetes, but the SELECT trial extended its benefits to a broader population. This breakthrough holds the promise to help the large population of people with overweight/obesity and CVD. The SELECT trial underscores the importance of addressing obesity-related health risks and highlights semaglutide’s potential to improve cardiovascular outcomes.

Furthermore, in a study published in the New England Journal of Medicine, researchers examined the effects of semaglutide in patients with heart failure with preserved ejection fraction and obesity [23]. Treatment with semaglutide led to significantly greater reductions in symptoms, physical limitations, and body weight compared with placebo, with a mean weight loss of –13.3% compared with –2.6% in the placebo group. Patients on semaglutide also showed increased exercise capacity with a 21.5-m increase in the 6-min walk distance compared with 1.2 m with placebo. Additionally, semaglutide reduced C-reactive protein levels by –43.5%, compared with –7.3% with placebo. Overall, semaglutide improved heart failure-related symptoms, physical function, and weight loss in patients with HPpEF and obesity.

In addition, in a clinical trial named SURMOUNT-1 [24], researchers investigated the effects of tirzepatide on 24-h ambulatory blood pressure in adults with obesity. The placebo-adjusted systolic blood pressure changes were as follows: 5 mg tirzepatide: −7.4 mm Hg, 10 mg tirzepatide: −10.6 mmHg, and 15 mg tirzepatide: −8.0 mm Hg. Overall, the findings support positive effects on blood pressure.

Recent kidney outcomes with GLP1-RA (semaglutide)

The Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial [25], which studied the effects of semaglutide on patients with chronic kidney disease and type 2 diabetes (T2D), was discontinued early due to its significant positive results. The trial exhibited a 24% reduction in the composite endpoint of kidney disease progression and mortality. Thus semaglutide effectively slowed down kidney disease progression and reduced mortality from kidney-related causes in the study participants.

Type 2 diabetes

In a systematic review and network meta-analysis published in the British Medical Journal, researchers evaluated the comparative efficacy and safety of GLP-1RAs in adults with T2D [26]. All 15 GLP-1RAs effectively lowered hemoglobin A1c (HbA1c) and fasting plasma glucose concentrations. Tirzepatide resulted in the largest reduction in HbA1c (mean difference with placebo −2.10%) and fasting plasma glucose (−3.12 mmol/L), making it the most effective GLP-1RA for glycemic control. GLP-1RAs showed strong benefits for weight management in patients with T2D. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference −14.03 kg), followed by tirzepatide (−8.47 kg). Semaglutide effectively lowered the concentration of LDL (−0.16 mmol/L) and total cholesterol (−0.48 mmol/L). The study raised awareness of GI adverse events induced by GLP-1RAs. Overall, GLP-RAs offer benefits for glycemic control, weight loss, and lipids in T2D patients.

Metabolic dysfunction-associated steatohepatitis/metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, is a prevalent condition characterized by hepatic steatosis in ≥5% of hepatocytes, in combination with 1 or more cardiometabolic risk factors such as obesity, hypertension, hyperglycemia, or dyslipidemia. MASLD affects approximately one-third to one-fourth of adults and can progress to metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]) and cirrhosis [27]. Insulin resistance is a central factor in the pathophysiology of MASLD/MASH, with higher prevalence in individuals with obesity and diabetes. GLP-1 RAs, although not FDA-approved specifically for MASLD, are used to treat obesity and T2D and have now been investigated in this regard. Indeed, these medications have shown promise in reversing steatohepatitis [28]. The effects of GLP-1 RAs to enhance insulin secretion, inhibit glucagon release, and slow gastric emptying, reduce blood glucose levels and promote weight loss. These effects contribute to the reduction of hepatic steatosis and inflammation, key components of MASLD/MASH.

Several studies have demonstrated the efficacy of GLP-1 RAs in improving liver histology and reducing liver fat content. Randomized controlled trials (RCTs) have shown significant improvements in liver enzymes, fibrosis scores, and overall metabolic health in patients treated with GLP-1 RAs [[28], [29], [30]]. The Study of Tirzepatide in Participants with Nonalcoholic Steatohepatitis (SYNERGY-NASH) Phase 2 study [29], evaluated the efficacy of tirzepatide, a dual GLP-1 and GIPR agonist, in treating MASH. This study included 190 adults with biopsy-proven MASH and stage 2 or 3 fibrosis with or without T2D. The SYNERGY-NASH Phase 2 study demonstrated that tirzepatide significantly improves liver health in patients with MASH, showing promise as a potential treatment option.

Suvodutide, formerly known as BI 456906, is a dual agonist of the glucagon and GLP-1 receptors. It is being investigated for its potential to treat obesity and MASH. In clinical trials, suvodutide has shown promising results in reducing body weight and improving liver health [30,31]. The phase 2 study of suvodutide showed that 83% of adults achieved significant improvement in MASH compared with 18.2% with placebo. Additionally, 64.5% of patients with moderate to advanced liver fibrosis (F2 and F3 stages) saw improvement without worsening of MASH. These results highlight suvodutide’s potential as a potentially effective treatment for MASH and liver fibrosis.

GLP-1 RAs are generally well-tolerated. GI side effects are most common, including nausea and vomiting. Although long-term safety data are limited, current evidence supports the use of GLP1RA’s in patients with MASLD/MASH, especially those with concurrent obesity and T2D. Comprehensive safety data over a 4-y period were recently published through a semaglutide trial conducted by Ryan et al. [32]. The trial monitored adverse events, including GI symptoms, cardiovascular outcomes, and potential thyroid-related issues. Overall, the longer-term safety profile of the trial was consistent with previous shorter-duration trials, indicating that semaglutide is generally well-tolerated. However, mean weight-loss was 10% compared with 15% seen in shorter trials potentially hinting at possible counter-regulatory orexigenic mechanisms to regain lost body weight. Extensive research to establish the long-term benefits and safety of GLP-1 RAs in treating MASLD/MASH and other comorbisites of obesity is needed.

Obstructive sleep apnea benefits

The study by Blackman et al. [31] investigated the effects of liraglutide on individuals with obesity and moderate to severe obstructive sleep apnea (OSA). Results showed that liraglutide significantly reduced the apnea-hypopnea index (AHI) and body weight compared with placebo over 32 wk. Additionally, liraglutide improved other health markers such as HbA1c and systolic blood pressure. The SURMOUNT-OSA trial [33] evaluated tirzepatide for treating OSA in adults with obesity. Results showed that tirzepatide significantly reduced the AHI by 58.7%, or ∼30 fewer events per hour, compared with placebo. Additionally, 50.2% of participants achieved disease resolution, defined as an AHI of fewer than 5 events per hour or an AHI of 5–14 events per hour with an Epworth Sleepiness Scale score of ≤10.

Patient adherence and compliance to weight management recommendations

Gasoyan et al. [34] investigated the percentage of patients who were adherent with antiobesity medications (AOMs) at the early stage, medium term, and long-term, by AOM agent. The study found that adherence to semaglutide, a newer weight-loss drug, exceeded that of older drugs like naltrexone-bupropion and phentermine-topiramate. Specifically, adults with obesity who took semaglutide had higher odds of continuing with the medication 1 y later. These findings highlight the potential patient adherence benefits of semaglutide in weight management.

Session I: clinical implications and mechanisms of current strategies

Nutrition-stimulated hormone-based therapies for the treatment of obesity: sparks from the pipeline

The prevalence of obesity is rapidly increasing, with nearly half of Americans projected to have obesity by 2030 [35]. This alarming trend highlights the urgent need for effective treatments. Current options, including lifestyle modifications, medications, and bariatric surgery, fall short in achieving sustained weight loss for many individuals. GLP-1 RAs are emerging as promising therapies and are now being explored with combination strategies. The emerging therapies, currently at different stages of development, encompass a range of entero-endocrine and endo-pancreatic agents. These include oral GLP-1 RAs used as standalone treatments, as well as dual and triple receptor agonists.

Oral formulations

Oral semaglutide is the first and, at the time of this writing, only daily oral GLP-1 RA approved by the FDA for managing T2D. Higher doses are being studied for their effects on weight in individuals with obesity and without T2D, in the trials of oral semaglutide in adults with overweight or obesity (OASIS trials) [36]. Danuglipron, an orally bioavailable, selective, small-molecule GLP-1 RA, is under development for treating T2D and obesity [37]. In a phase I study, danuglipron showed dose-dependent reductions in glycemic indices and a weight change of -4.4 kg at day 28 with a 70 mg twice daily dose [38]. Similar to the GLP-1RAs, the most common treatment-related adverse effects were nausea, dyspepsia, and vomiting. Initiating treatment at low doses and gradually increasing the dosage may help manage these side effects. These oral GLP-1 RAs provide a more convenient alternative to injectable forms, though further research is necessary to fully assess their long-term safety and efficacy. Orforglipron [39] is another GLP-1RA oral experimental medication used for weight loss and T2D. Orforglipron is administered orally as a once-daily pill. Clinical trials have shown favorable results, including weight loss and improvements in cardiometabolic measures.

Amylin and amylin/GLP-1RA dual receptor agonists in development

Amylin functions as a peptide-based hormone involved in glucose regulation and appetite control [40]. It can activate the amylin receptor, which may play a role in Alzheimer’s disease. Amylin/GLP1 dual receptor agonists are under development for obesity and T2D [41]. These drugs act as agonists at both the amylin and calcitonin receptors, potentially leading to weight loss. Cagrilintide, an extended-release weekly injectable analog of amylin, has been investigated both as a standalone treatment and in combination with the long-acting GLP-1RA semaglutide [42]. In the phase 1B clinical trial [43], 96 participants with obesity (average BMI 32.1 kg/m²) were administered weekly doses of semaglutide and cagrilintide. After 20 wk (including a 16-wk dose titration), the group receiving the combination treatment experienced a 17.1% weight loss, compared with a 9.8% weight loss in the semaglutide monotherapy group. In the phase 2 clinical trial [44], 706 individuals with obesity (average BMI 37.8 kg/m²) were given escalating doses of weekly cagrilintide, daily liraglutide, or placebo for 26 wk. The highest cagrilintide dose (4.5 mg weekly) resulted in a 10.6% weight loss, compared with 8.4% with liraglutide and 2.8% with placebo. The combination of cagrilintide with semaglutide (cagri-sema) is currently undergoing phase III clinical trials. These early studies underscore the promise of long-acting amylin analogs or amylin/GLP-1 RA combinations as effective strategies for combating obesity.

GIP/GLP-1 dual receptor agonists

GIP/GLP-1 dual receptor agonists selectively bind and activate both GLP-1 and GIP receptors. Notably, tirzepatide, a dual GIPR/GLP-1R agonist, has demonstrated significant anti-hyperglycemic efficacy and positive effects on CVD risk factors, making it an approved treatment for diabetes and obesity in several countries [[45], [46], [47]]. Additionally, ongoing research has investigated other dual agonists targeting both GIP and GLP-1 receptors, including dapiglutide [48] and AMG133 [49]. Dapiglutide, a dual-action GLP-1 and GLP-2 receptor agonist, is the first-in-class peptide for the treatment of obesity and GI diseases. AMG133 (Maridebart Cagrilutide) is an engineered bispecific molecule that targets both GLP-1 and GIP pathways. In a phase 1 clinical trial involving participants with obesity, a high dose of AMG133, given monthly, led to 15% reduction in body weight [49]. These innovative therapies hold promise as effective tools in managing obesity.

GIP/glucagon/GLP-1 triple receptor agonists

GLP-1, GIP, and glucagon affect food intake and satiety differently, collectively contributing to the body’s defended fat mass set point. A tri-agonist formulation could be more effective due to additive effects. Retatrutide [50] is a novel triple agonist that targets GIP, GLP-1, and glucagon receptors. In a 48-wk phase 2 obesity study [50], retatrutide achieved impressive weight reductions: 22.8% with an 8 mg dose and 24.2% with a 12 mg dose. Although not yet FDA-approved, retatrutide shows exciting potential for sustained weight loss and metabolic benefits.

Pharmacological therapies for genetic and hypothalamic obesity

Genetic obesity often requires pharmacological interventions to target specific genetic mutations affecting appetite regulation and energy balance. Setmelanotide, an MC4R agonist, has resulted in significant weight loss and improvements in hyperphagia (increased appetite) for patients with Bardet-Biedl syndrome as well as POMC, proprotein convertase subtilisin/kexin type 1, and leptin receptor mutations [[51], [52], [53]]. Genetically mediated leptin deficiency, another form of congenital obesity, may be effectively treated using leptin replacement to reduce weight and metabolic complications [54]. Hypothalamic damage can lead to hypothalamic obesity (HO) [55]. Recent treatments such as GLP-1RAs (semaglutide and exenatide) and setmelanotide have been shown to effectively treat HO [56,57]. Methionine aminipeptidase inhibitors and Tesomet (tesofensine and metoprolol) may also be effective in treating HO and Prader–Willi syndrome [55,58,59], although the success rate varies. In comparison to more common forms of obesity, these disorders require more specialized approaches due to unique underlying genetic and neuroendocrine mechanisms. Ongoing research is crucial to optimize and personalize these interventions for affected individuals.

Potential “off-target” negative and positive effects of current GLP-1 strategies

The use of GLP-1RAs has expanded beyond glycemic control in T2D to include benefits in weight management, cardio-renal-metabolic health, and potential cognitive and mental health improvements. However, these medications also present a range of “off-target” effects, both positive and negative, that warrant careful consideration. This section explores the multifaceted impacts of GLP-1RAs, including their influence on body composition, bone density, GI health, and cognitive functions, as well as specific concerns for older adults.

Loss of lean mass and effect on bone health

Semaglutide may positively impact body composition in adults with overweight and obesity. In the study by Wilding et al. [60], researchers evaluated the impact of subcutaneous semaglutide on body composition in adults with overweight or obesity. They used dual-energy X-ray absorptiometry to measure total fat mass, total lean body mass, and regional visceral fat mass. The study included 140 participants (mean weight 98.4 kg, BMI 34.8 kg/m²; 76% female). The results of the study demonstrated significant weight loss compared with placebo. Data show a –15% change in body weight in the semaglutide group compared with a -3.6% change in the placebo group across the 68-wk trial. Within the semaglutide group, body composition analysis showed similarly promising results with a –19.3% and –27.4% change in total fat mass and regional visceral fat mass, respectively. Although total lean body mass decreased by –9.7%, the percent of lean body mass relative to total body mass increased by 3%. Overall, participants taking semaglutide showed an improvement in lean body mass to fat mass ratio as their weight decreased. Several mechanisms contribute to bone density loss during weight reduction, including decreased mechanical loading, reduced nutrient intake, changes in gut hormones, and diminished adipose tissue. The decrease in mechanical loading, in particular, can lead to a decline in bone density [61]. Weight-bearing physical activity and resistance training are recommended to mitigate losses in bone mineral density. Calorie restriction may impact nutrient intake and may cause inadequate consumption of calcium and vitamin D. This may contribute to bone mineral loss, alterations in bone microstructure, and reduce the quality of bone matrix. Furthermore, fat loss in bone marrow adipose tissue tends to increase during calorie restriction, which may contribute to bone changes associated with weight loss [62]. Additionally, changes in gut hormones (such as GLP-1) and adipokines (like adiponectin and leptin) may influence bone turnover during weight loss [63]. In summary, strategies to prevent bone density loss should be prioritized during weight loss efforts.

Concerns for older adults

Semaglutide and other GLP-1RA medications can pose significant risks for people over the age of 65 y [64]. GI adverse effects such as nausea and vomiting may lead to dehydration, malnutrition, and adverse body composition outcomes. Promoting adequate fluid intake is crucial to avoid possible orthostatic symptoms, unsteadiness, falls, and fractures. GLP-1 drugs can lead to rapid weight loss, which may result in muscle loss and/or sarcopenia. Muscle loss is problematic for older adults, as it can increase the risk of frailty, falls, and loss of functional independence. Obesity pharmacotherapy clinical trials have not included functional outcomes in significant numbers of older adults >65 y of age, so data on long-term effects is limited. Older adults often take several medications and have multiple medical conditions, increasing their risk of drug side effects. Thus, supervision by a specialist is crucial when prescribing these highly effective obesity medications.

Cognitive benefits on dementia, depression, binge-eating

GLP-1 drugs may be beneficial for diseases and disorders beyond excess and dysfunctional adiposity. Investigators recently examined the protective effects of trizepatide on learning and memory disorders [65,66]. Fontanella et al. [66] found that tirzepatide activates the phosphorylated protein kinase B (pAkt)/cyclic AMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway, providing neuroprotection and counteracting hyperglycemia and insulin resistance-related effects at the neuronal level. This highlights tirzepatide’s potential role in addressing diabetes-related effects on the central nervous system. A study by NØrgaard et al. [67], reported an association between GLP-1RA treatment and a reduced risk of dementia in individuals with T2D, suggesting a promising avenue for mitigating dementia risk in this population.

Studies have also provided valuable insights into the effects of semaglutide and GLP-1 on mental health. Wang et al. [68] investigated the association between semaglutide use and suicidal ideation in a real-world cohort. Semaglutide was linked to a reduced risk of both incident and recurrent suicidal ideation in patients with overweight or obesity, with or without T2D, and showed no increased risk compared with non-GLP-1RA medications. Kim et al. [69] explored the role of GLP-1 modulation in depression, suggesting that GLP-1RA therapies may help to overcome impaired neurogenesis, neuroinflammation, neurotransmitter imbalances, and synaptic dysfunction in the brains of people with depression.

GLP-1RAs hold promise in reducing disordered eating patterns in individuals with binge eating disorder (BED) and bulimia nervosa [70]. BED and bulimia nervosa are characterized by episodes of consuming unusually large amounts of food in a short time, often accompanied by a sense of loss of control. Treatments typically include psychological and pharmacological interventions, but existing medications like topiramate and lisdexamfetamine carry notable side effects, underscoring the need for innovative therapies [16]. GLP-1RA medications may reduce binge eating episodes in BED and bulimia nervosa and offer a more favorable side effect profile compared with older standard pharmacotherapies [71]. Animal studies show that GLP-1RAs influence hedonic-driven food consumption via the anorexic effect of these NuSH [72]. Furthermore, GLP-1RAs may mitigate emotion-driven eating by influencing neural circuits involved in emotional regulation [73]. By enhancing satiety and reducing cravings, GLP-1RAs can mitigate maladaptive eating patterns in individuals with disordered eating. GLP-1RAs may indirectly enhance psychological well-being by improving cardiometabolic health and alleviating weight-related concerns, with better physical health positively influencing mental health and eating behaviors. By driving beneficial changes in eating patterns, body weight, mental health, and cardiometabolic outcomes, GLP-1RAs may offer a more comprehensive approach to treating disordered eating.

Risk of GI adverse side effects and preoperative recommendations for GLP1-RAs before surgery and endoscopy

Semaglutide and GLP-1RAs are known to delay gastric emptying, and this has raised concerns for perioperative pulmonary aspiration [74]. In a recent study, researchers examined the association between GLP1-RAs and GI adverse effects [75]. The study found that compared with the obesity medication bupropion-naltrexone, GLP-1RAs were associated with an increased risk of pancreatitis, gastroparesis, and bowel obstruction. The American Society of Anesthesiologists recommends holding daily GLP-1RA on the day of procedure and holding weekly GLP-1RA 1 wk before procedure, irrespective of indication and dosing [76]. If the GLP-1RA is for T2D indication, the Society recommends consulting an endocrinologist for bridging the diabetes care to avoid perioperative hyperglycemia [77].

Session 2: altering the brain pathways to treat obesity and reduce hunger

Obesity and addictive disorders

Over the past 2 decades, scientific advancements have shed light on the neurobiological mechanisms underlying the development and maintenance of substance use disorders (SUDs), including the more severe forms, often referred to as addiction. Addiction is a chronic, relapsing treatable disease characterized by changes in brain function, affecting reward circuits, stress responses, and executive functions such as decision-making and self-regulation [[78], [79], [80]]. Recognizing SUDs as a brain disease can significantly influence health and social policy strategies, underscoring the need to integrate biological, behavioral, and social-context components in treatment approaches. Thus, multidisciplinary research may yield insights to increase understanding of and address, SUDs through novel treatments. There are 3 stages of addiction: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation [81,82]. Each stage involves specific changes in brain circuits and neurotransmitters. Binge/intoxication stage: this stage involves the rewarding effects of drugs, driven by changes in dopamine and opioid peptides in the basal ganglia. Withdrawal/negative affect stage: during this stage, there is a decrease in the function of the dopamine system and an increase in stress neurotransmitters like corticotropin-releasing factor and dynorphin in the extended amygdala. Preoccupation/anticipation stage: this stage is characterized by cravings and deficits in executive function, involving dysregulation of projections from the prefrontal cortex and insula to the basal ganglia and extended amygdala. Of note, these mechanisms are important not only in drug addiction but also in the neurobiological mechanisms related to pathological overeating [81,82]. Consistent with that, imaging human studies have shown that dopamine plays a crucial role in both SUDs and obesity [83], suggesting common pathways between these conditions.

Role of GLP-1RAs in neuronal circuitry

GLP-1RAs have shown significant effects on neuronal circuitry and reward pathways [84,85]. GLP-1Rs are widely expressed in brain regions associated with reward, such as the hypothalamus and orbitofrontal cortex. Activation of these receptors modulates dopamine and glutamatergic neurotransmission, which are some of the key components of brain reward processing. This modulation can reduce the intake of palatable foods and decrease the use of addictive substances in animal studies.

GLP-1 RAs, such as liraglutide and semaglutide, are known to have neuroprotective effects [86]. These medications support neuronal growth and increase cell viability by elevating levels and altering the phosphorylation of key signaling molecules (cAMP, protein kinase A, CREB, glycogen synthase kinase-3 beta, protein kinase B, extracellular signal-regulated kinase, and mechanistic target of rapamycin). These changes are crucial for cell survival and overall brain health. In humans, GLP-1 RAs have been shown to reduce food cravings and hedonic drive by affecting brain activity in areas related to food anticipation and consumption [[87], [88], [89]]. GLP-1 RAs hold promise not only for their metabolic benefits but also for their potential in treating reward-related disorders and enhancing brain health.

Alcohol use disorder

Alcohol use disorder (AUD) is a major global health issue, contributing to ∼88,000 deaths annually in the United States alone [90]. The economic burden of AUD in the United States is substantial, costing ≥$249 billion annually [90]. Existing pharmaceutical and behavioral treatments can help reduce alcohol use or promote abstinence. However, only 3 medications are approved by the FDA to treat AUD (naltrexone, acamprosate, and disulfiram), and more research is needed to expand the armamentarium of options in treating people with AUD.

Role of GLP1-RAs in treating AUD

Recent research suggests that GLP-1RAs show promise in treating AUD [[91], [92], [93], [94], [95], [96], [97]]. Animal studies have consistently shown that GLP-1RAs reduce the rewarding properties of alcohol and other addictive substances, leading to decreased motivation and intake. Although these findings are promising, more research is needed to confirm the efficacy and safety of GLP-1RAs in treating AUD. For example, a randomized, placebo-controlled clinical trial investigated the use of the GLP-1RA exenatide subcutaneously compared with placebo once weekly for 26 wk, alongside cognitive-behavioral therapy, for AUD [95]. Exenatide did not significantly reduce heavy drinking days (a priori primary endpoint) compared with placebo. On the other hand, exenatide significantly reduced alcohol cue reactivity in key brain regions for reward and addiction. Furthermore, lower dopamine transporter availability was observed in the exenatide group compared with placebo. Exploratory analyses indicated that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of patients with BMI >30 kg/m², whereas placebo was superior in those with a BMI <25 kg/m². This study provides new insights into the potential of GLP-1RAs as a novel treatment target for addiction, further highlighting the need for research aimed at understanding who may benefit from these medications among people with AUD.

Recent human work further supports the role of GLP-1RAs in AUD. For example, analysis of social media language and pharmacoepidemiological studies analyzing electronic medical records show that semaglutide and/or tirzepatide are associated with a reduction in alcohol consumption or AUD diagnosis in individuals taking these medications for diabetes and/or obesity [[98], [99], [100], [101], [102], [103]]. These studies, among others, support GLP-1RAs as promising pharmacotherapy in treating AUD; however, the GLP-1RA class agents are currently only approved by the FDA for metabolic disorders and randomly assigned clinical studies are needed to further test the hypothesis that these medications may be effective in people with AUD and/or other SUD [104]. For a recent comprehensive review focused on the emerging literature on the role of GLP-1RAs in AUD and SUD, see Bruns et al. [105].

Long-term effects and potential for weight regain: resetting the hunger threshold

To fully grasp pivotal concepts in medicine, it is essential to delve into human evolutionary history, particularly the evolution of energy regulation. Early hunter-gatherers subsisted primarily on a diet of fruits and seeds and likely experienced harsh environmental conditions. Despite debate over famine or food scarcity, these conditions likely led to adaptations in human metabolism for energy conservation in response to stress. This trait, evolved over millennia, defends our body’s weight set point, resisting weight loss even in extreme conditions. Energy balance is thus an evolved physiologic characteristic.

A notable example of this metabolic adaptation was highlighted in a 2011 study published in the New England Journal of Medicine [12]. During the study, 50 individuals with obesity underwent an 8-wk low-calorie diet, consuming only 500–550 kcal per day. By the end of this period, participants had lost an average of 30 pounds. Despite transitioning to a weight maintenance program postdiet, follow-up measurements taken 1 y later revealed that the subjects had regained an average of 11 pounds. Moreover, they reported increased hunger and a greater preoccupation with food compared with their preweight loss state. Even 1 y after ceasing the calorie-restricted diet, it appears that the body retains a “memory” of the stress it endured. This is evidenced by elevated levels of appetite-stimulating hormones and reduced levels of hormones that suppress appetite. The study demonstrated that long-term changes in peripheral signals regulating appetite were associated with heightened subjective feelings of hunger 1 y following significant weight loss.

Recent clinical trials have demonstrated that metabolic adaptation continues even after medication cessation. Specifically, in STEP 4, the cessation of semaglutide resulted in sustained weight gain among patients who were switched to a placebo [106]. Similarly, in SURMOUNT 4, the discontinuation of tirzepatide led to continued weight gain in patients transitioned to a placebo [107]. Consequently, the absence of treatment allows the weight set point to return to its original pathological state.

Concerns about weight regain have been more pronounced with first-generation AOMs, which achieved <10% weight loss. In contrast, a drug is considered highly effective if it results in >10% weight loss (Figure 3).

FIGURE 3.

Pink zone represents an inadequate response; the yellow zone indicates a moderate response; and the green zone signifies the desired outcome for weight loss. TBWL, total body weight loss.

According to this diagram (Figure 3), the pink zone represents an inadequate response; the yellow zone indicates a moderate response; and the green zone signifies the desired outcome for weight loss. However, with today’s advancements in obesity medicine, new therapies are achieving clinical benefits that surpass 10% weight loss and are helping bridge the gap to bariatric surgery.

The introduction of novel AOMs has caused a rightward shift in the Gaussian distribution curve of weight loss outcomes toward more effective therapies and results. This shift implies that an increasing number of patients will potentially achieve a BMI <30 or even <25—categories considered healthy weights today. It is important to note that “healthy” rather than “normal” is used here because there is no universally accepted definition of normal BMI due to variations across races, ethnicities, and other population variables.

As a result of ongoing work, 3 main phenotypes have been identified regarding weight maintenance after successful weight loss response, defined as a BMI <30 kg/m² after treatment with AOM and adjunctive lifestyle therapy. The first is phenotype A, controlled obesity maintained on generic AOMs (Figure 4). This is also the most common phenotype encountered in clinical practice. These patients have had a successful response initially, often achieving a BMI <30 kg/m², and in some cases, a BMI <25 kg/m². They require generic oral AOMs, sometimes at low dosages, to maintain their weight long-term.

FIGURE 4.

Patient A: controlled obesity, maintained on generics. In patient phenotype A, the obesity is controlled long-term and maintained on generic antiobesity medications. This is also the most common type of obesity. Depicted here is a 50-y-old patient with a history of asthma, vitamin D deficiency who was initially a nonresponder to previous weight management therapies. Her laboratory assessment was normal. At her initial visit with the medical obesity provider, she had a documented weight of 228 pounds, BMI 36.9 kg/m². She was subsequently treated with oral semaglutide, injectable semaglutide (2.4 mg), and then switched over to tirzepatide (15mg). Overall, she lost –90 lbs, –39.5% of her total body weight, with a nadir BMI of 22.3 kg/m². She continues now to maintain her weight on daily metformin (MTF; 750 mg) once-daily and topiramate (25 mg), low dosage, daily as needed. TWL, total weight loss; Wt, weight.

The second phenotype is phenotype B, obesity in remission, not requiring any AOMs (Figure 5). This is very rare. These individuals are successful responders not only to the initial treatment phase but also to the weight maintenance phase. The phenotype B patients do not require further AOMs to maintain their weight, and therefore, the obesity is considered “in remission.”

FIGURE 5.

Patient B: obesity in remission, off antiobesity medications. In patient phenotype B, the obesity is in remission, and antiobesity medication (AOM) is not required for weight maintenance. In this case, the patient presented with an initial weight of 381 pounds with a BMI of 63.4 kg/m². She had underlying interstitial lung disease and was a pretransplant candidate. Ultimately, the patient underwent a vertical sleeve gastrectomy (VSG) in 2016. At that time, her weight was 238 pounds with a BMI of 39.6 kg/m² and a total body weight loss (TBWL) –37.5%. Subsequently, she began to experience reflux and had concerns with malabsorption. She underwent revisional surgery with a conversion to a Roux-en-Y Gastric Bypass (RYGB) in 2021. When she presented for an initial medical obesity evaluation, her BMI was 35.9 kg/m² with a weight of 216 pounds. She was prescribed combination therapy with phentermine, topiramate, and semaglutide (2.4 mg/wk). Ultimately, she responded successfully to the point that AOM was discontinued, and she continued to maintain her weight at a BMI of 20, weight 126 lbs, with a TBWL of –41.6% via the medial intervention and –66.9% TBWL with a combined surgical and medical obesity intervention. At follow-up, she continues to maintain her BMI at 21 kg/m². Wt, weight.

The third phenotype, patient phenotype C, is perhaps the most difficult to treat (Figure 6). The obesity is uncontrolled with weight regain, and these patients require long-term novel AOMs such as the GLP1-RA class agents. Due to current shortages, access concerns, and cost considerations on novel AOMs, these patients are challenging to treat and manage.

FIGURE 6.

Patient phenotype C: uncontrolled obesity with regain, requiring novel AOMs. In patient phenotype C, there is uncontrolled obesity with weight regain. These patients require novel antiobesity medication (AOM) to treat the weight regain. This is often challenging as the AOMs requirement is long-term. In this case, a 74-y-old patient with hypertension (HTN), hyperlipidemia (HLP), sleep apnea (OSA), hypothyroidism, and prediabetes presents with an initial BMI of 49.4 kg/m² and 288 pounds. The patient responds favorably with weight loss on off-label semaglutide (2.0 mg), approaching a nadir of 182 pounds, BMI 31.2 kg/m², and –36.8% total body weight loss (TBWL). However, due to insurance changes, loss of coverage, viral infections with COVID-19, the patient is unable to continue the semaglutide (2.0 mg). A trial of several generic AOMs considered, including bupropion, naltrexone, metformin, topiramate, zonisamide, and hydrogel capsules. Unfortunately, the patient remains a nonresponder to these alternative options. Hence, the patient continues to regain the weight, BMI 46.2 kg/m², +83% weight regain from nadir, 270 pounds. Patient did not wish to pursue bariatric surgery, although that option was discussed. wt, weight.

Role of muscle in weight maintenance and novel activin/myostatin inhibitors

Sarcopenic obesity is a condition characterized by the combination of obesity and sarcopenia, the age-related loss of muscle mass and strength [108,109]. This condition is particularly concerning because it involves both an increase in body fat and a decrease in muscle mass, leading to a range of health issues. Sarcopenia is exacerbated in individuals with obesity, where muscle fibers decrease in both number and size, resulting in thinner and weaker muscles. Hormonal changes, such as reduced levels of testosterone and insulin-like growth factor, contribute to muscle loss, as these hormones are crucial for muscle growth and maintenance. A sedentary lifestyle is a significant risk factor, as lack of physical activity accelerates muscle atrophy and increases fat accumulation. Sarcopenic obesity is associated with metabolic issues like insulin resistance and inflammation, which further impair muscle function and promote fat storage. The loss of muscle mass and strength can severely affect an individual’s ability to perform daily activities, leading to increased frailty, a higher risk of falls, and a reduced quality of life.

Additionally, growth factors activin A and myostatin are important targets in muscle atrophy. Myostatin and activin A are mediators of skeletal muscle atrophy. Activin A and myostatin inhibit muscle growth by signaling through the activin receptor, leading to muscle degradation. Blocking these pathways has shown promise in increasing muscle mass and improving muscle function. Animal knock-out models of myostatin have demonstrated muscle hypertrophy [110]. Fully human monoclonal antibodies, such as trevogrumab, garetosmab, and bimagrumab [111], inhibit myostatin and activin A, respectively, or in combination (taldefgrobep), and are presently being studied in obesity and in clinical development. Combining these inhibitors with GLP-1RAs may improve the quality and quantity of weight loss (>30%–40% total body weight loss) by preserving lean mass while reducing fat mass [112].

Managing sarcopenic obesity and maintaining weight

Addressing sarcopenic obesity requires a comprehensive approach that includes lifestyle changes and medical management to improve muscle mass and overall health. Lean mass is also lost during actual weight loss and can account for 20%–50% of the total weight loss. Nutrition rich in protein sources and incorporation of resistance training to preserve muscle mass can enhance overall weight regain and well-being during the weight maintenance phase [113].

Work by Lundgren et al. [114], published in the New England Journal of Medicine in 2021, investigates strategies for maintaining weight loss in individuals with obesity. The study compared the effectiveness of exercise, liraglutide, and a combination of both in maintaining weight loss after an initial low-calorie diet. The combination of exercise and liraglutide was the most effective, leading to greater weight loss and improvements in metabolic health compared with either treatment alone^. Participants in the combination group lost an average of 9.5 kg over 1 y, compared with 4.1 kg in the exercise group and 6.8 kg in the liraglutide group. The combination strategy also resulted in a significant reduction in body-fat percentage and improvements in insulin sensitivity and cardiorespiratory fitness.

Session 3: equity, costs, and access

Benefits of Medicare coverage for weight-loss drugs

As of 2022, >2 in 5 United States adults have obesity, with the prevalence increasing from 30.5% in 1999–2000 to 42.4% in 2017–2018 [115,116]. Severe obesity has also risen, from 4.7% to 9.2% in the same period [115].

Obesity disproportionately affects certain racial and ethnic groups. According to Centers for Disesae Control and Prevention data, non-Hispanic Black adults have the highest prevalence, with 38 states reporting obesity rates of 35% or higher among this group. Hispanic adults also have high rates, with 34 states reporting obesity rates of 35% or higher [115]. Obesity is linked to several chronic diseases and comorbidities, including diabetes, heart disease, and certain cancers. These conditions are more prevalent among minority groups, exacerbating health disparities.

Despite gains in health coverage, disparities persist. As of 2022, nonelderly Black and Hispanic people had higher uninsured rates compared with their White counterparts [117]. For example, according to the Kaiser Family Foundation, the uninsured rate for Black people was 10.0%, compared with 6.6% for White people. Medicare plays a crucial role in providing health coverage for older adults and those with disabilities. However, disparities in access to care and health outcomes remain. Black and Hispanic beneficiaries are less likely to have their chronic conditions under control compared with White beneficiaries [118].

Obesity significantly shortens life expectancy [119]. Extreme obesity can reduce life expectancy by ≤14 y. This is due to the increased risk of mortality from various causes, including heart disease, stroke, diabetes, and certain cancers. Obesity has a profound impact on health-related quality of life (HRQoL). Studies have shown that the negative effects of obesity on HRQoL can be worse than aging 20 y. Obesity is associated with a range of physical and mental health issues that severely affect daily living and overall well-being. Addressing these disparities requires targeted public health interventions and policies that promote equitable access to healthcare and healthy living environments for all communities.

Despite decades of concerted public health efforts, the trajectory of obesity continues to rise, posing a significant challenge to health systems worldwide. Initiatives such as the Centers for Disease Control and Prevention's High Obesity Program have aimed to address this issue through policy, systems, and environmental changes. However, the complexity of obesity, influenced by factors like socioeconomic status, cultural norms, and food environments, has made it difficult to achieve sustained reductions. Although some localized successes have been noted, the overall prevalence of obesity remains high, indicating that current strategies may need to be re-evaluated and enhanced to effectively combat this persistent public health crisis.

The Treat and Reduce Obesity Act (TROA) is a bipartisan bill aimed at expanding Medicare coverage to include more comprehensive obesity treatment options. TROA seeks to expand medicare Part D to cover FDA-approved medications for chronic weight management. It also aims to broaden the intensive behavioral therapy benefit, allowing a wider range of qualified healthcare providers to offer these services. The act addresses the high prevalence of obesity among Medicare beneficiaries and the associated health risks, such as heart disease, diabetes, and certain cancers. This legislation is significant because it aims to provide more effective and accessible treatment options for obesity, which is a major public health issue.

The Affordable Care Act mandates that private insurance plans cover recommended preventive services without any patient cost-sharing. This requirement applies to all services that receive an A or B rating from the United States Preventive Services Task Force (USPSTF). Notably, the weight-loss prevention recommendations (behavioral interventions) issued by the USPSTF in 2012 and updated in 2018 did not include coverage for pharmaceutical interventions.

Estimating social benefits

Using the future adult model (FAM), a well-established microsimulation model, investigators at the University of Southern California’s Schaeffer Center for Health Policy and Economics studied the social benefits of broader access to newer weight-loss drugs [120]. The FAM projects the long-term health, economic, and life expectancy outcomes for a representative sample of American adults. This facilitates analysis of very long-term outcomes associated with healthcare and health policy interventions. It is especially useful in contexts, like obesity, where long-term randomized trial data do not exist, because simulation modeling approaches mitigate or avoid the selection bias that contaminates analysis of nonrandom observational data. In this research, the FAM was used to project the long-term health and economic outcomes resulting from broader access to weight-loss drugs for clinically eligible patients. Three different insurance coverage scenarios were modeled by FAM: 1) coverage for all clinically eligible medicare beneficiaries; 2) coverage for all clinically eligible medicare and privately insured beneficiaries; and 3) coverage for all clinically eligible adults. Each of these scenarios assumes that treatment produces an initial 20% BMI reduction and that patients remain on continuous therapy to maintain this initial weight loss. To allow for posttreatment fluctuations, we assume patients follow empirically derived BMI trajectories after treatment but cap their total posttreatment gain (or loss) at a maximum of 5%, until individuals reach 75 y of age, at which point the caps are lifted. The 3 coverage scenarios were compared with the “status quo” of current coverage and weight trajectories. The results of this simulation demonstrate considerable gross social benefits (Figure 7). This includes: 1) reduction in obesity rates: lower obesity rates can lead to decreased incidences of related conditions like heart disease and diabetes, which in turn reduces overall healthcare costs. 2) Economic savings: Medicare and partial coverage is estimated by the FAM model to save between $176 and $245 billion in the first 10 y alone with cumulative health benefits of $770–$927 billion.

FIGURE 7.

Social value of Medicare from covering and treating obesity. $B, billions of US dollars; Prv, Private.

Exploring variations by population subgroups

The social benefits of weight loss treatment can vary significantly across different population subgroups. Younger populations might see more long-term benefits due to a longer period of reduced healthcare costs, whereas older populations might see immediate health improvements. Different racial and socioeconomic groups might experience varying levels of benefit due to differences in baseline health conditions and access to healthcare [120]. For instance, FAM analysis indicates that compared with White adults, Black and Hispanic adults receive greater social benefits from weight loss treatment. Individuals with higher initial BMI might see more significant health improvements and cost savings compared with those with lower BMI. Obesity has been a force for higher inequality in health outcomes for economically disadvantaged groups and under-represented minorities; left unchecked, these trends are likely to continue. This analysis using the FAM suggests that broader access to novel weight-loss drugs could help reverse these trends toward inequality.

This study suggests that concerted public investments in antiobesity treatment might be needed to unlock these considerable benefits. The example of hypertension is instructive. For many years, the primary methods for managing high blood pressure were exercise and reducing salt intake. The introduction of hydrochlorothiazide, a diuretic, in the 1950s revolutionized treatment. This was soon followed by the development of other oral medications, including beta blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. Despite these advancements, there was still significant resistance to the clinical acceptance of antihypertensive therapy even 20 y later, as noted by Rubin and Bladen in 1982 [121]. Ultimately, subsequent research, meta-analyses, and RCTs provided compelling evidence supporting these treatments, which prompted change [[122], [123], [124]]. Additionally, President Nixon’s establishment of the National High Blood Pressure Education Program played a crucial role. This program mobilized 15 federal agencies, 50 state health departments, over 150 national organizations, and ∼2000 community control programs.

Overall, significant work remains if we are to provide affordable and equitable obesity treatment. FAM analysis shows the potential benefits of extending insurance coverage for novel treatments, potentially providing enormous social and health benefits to the overall population. Novel pricing arrangements may also help achieve affordability; these include subscription pricing models, pay-for-performance arrangements, and 3-part pricing arrangements [125]. Mobilizing policy to address obesity treatment is an important consideration to reduce disparities and address the obesity epidemic.

Equity and access to new therapeutics for obesity

The current landscape of obesity drug coverage in the United States is quite varied and complex. Despite the broad coverage provided by the Medicaid Prescription Drug Rebate Program, which allows Medicaid to cover nearly all FDA-approved drugs from participating manufacturers, obesity treatments remain specifically excluded by Congress. This exclusion is based on outdated views of obesity’s pathophysiology and overlooks significant downstream health impacts. Although states have the option to cover obesity treatments, many choose not to. Coverage for FDA-approved obesity drugs varies significantly by state.

Similarly, Medicare Part D plans are prohibited from covering AOMs. With the advent and expanding use of GLP-1 medications, this disparity becomes increasingly evident, raising questions about why these medications are covered for conditions like diabetes, OSA, and congestive heart failure, but not for obesity itself. Coverage for AOMs under private insurance plans also varies widely. Some plans may cover these medications, but often with restrictions such as prior authorization and quantity limits.

Clinical lifestyle intervention (CLI) programs are heterogenous, structured behavioral interventions focused on nutrition, exercise, and motivational weight loss coaching designed to help individuals adopt healthier lifestyles. CLIs are covered by many insurances after receiving a grade B from the USPSTF, although there exists considerable variability across public and commercial payers’ policies. They typically last 1–2 y, with frequent sessions in the first year and a maintenance phase thereafter. These programs are managed by a diverse team of healthcare professionals, including primary care physicians, behavioral therapists, psychologists, registered dietitians, exercise physiologists, and lifestyle coaches. They often provide supplemental equipment and tools to support participants. Medicare Part B and some Medicaid programs cover the Diabetes Prevention Program (DPP), a well-known CLI curriculum. Evidence-based CLIs, like DPP, report an estimated 5% weight loss for participants, such that some payers’ value-based policies require achievement of comparable outcomes for payment. Although CLIs are less effective than AOMs in terms of degree of weight loss, they are minimally invasive and less costly with negligible negative side effects, rendering them a valuable complementary treatment method for obesity and related chronic diseases.

MassHealth (Massachusetts Medicaid) recently introduced coverage for GLP-1RAs in January 2024, highlighting an interesting case study in statewide coverage of pharmacological obesity treatment. Coverage for these drugs was built into the pharmacy budget as a “per member per month” payment system to accountable and managed care organizations. This coverage was structured on a scale to provide increased oversight over costlier medications. For instance, GLP-1RAs with indications for diabetes can be covered without prior authorization. AOM approved for weight loss, in contrast, requires prior authorization to facilitate weight loss.

In addition to the TROA act, currently pending in the United States Congress, further standards are necessary in the Medicaid program medical drug rebate program to prevent a state-by-state decision process in AOM coverage. Downstream effects of increased coverage, which in the short-term may increase health insurance costs, should be anticipated. Advocacy efforts can focus on ways to increase negotiations with drug manufacturers to sustain stability in costs and prevent price increases. Increasing medicare drug cost negotiation allowances could be 1 measure to anticipate potential increases while maintaining coverage for patients.

Overall, although there is some coverage for AOMs, considerable gaps and inconsistencies remain, particularly among Medicaid and Medicare programs. The current landscape reflects a patchwork of policies that can limit access to effective obesity treatments for many individuals and likely exacerbate existing health disparities.

Session 4: integrating pharmacological therapy into a successful long-term comprehensive care strategy for people with obesity

Who, when, and how to treat obesity using modern pharmacologic therapies

Assessing patients with obesity is crucial in managing their overall health and well-being. The American Heart Association/American College of Cardiology/The Obesity Society [126] guidelines provide a structured approach to ensure comprehensive evaluation and treatment. By following these guidelines, healthcare providers can identify and address the various health risks associated with obesity, ultimately improving patient outcomes.

The initial step involves a routine patient encounter to discuss their health and concerns. Next, the healthcare provider measures the patient’s height and weight to calculate their BMI. On the basis of the BMI, the patient’s weight category is determined: underweight (BMI < 18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25.0–29.9), obesity class I (BMI 30.0–34.9), obesity class II (BMI 35.0–39.9), or obesity class III (BMI ≥ 40.0) [126,127].

The provider then assesses and treats CVD risk factors and obesity-related comorbidities. This includes evaluating hypertension, dyslipidemia, and diabetes by measuring blood pressure, fasting blood glucose, and lipid profiles. Additionally, conditions such as sleep apnea, fatty liver disease, osteoarthritis, and certain cancers are assessed, which may involve further tests and specialist referrals. A treatment plan is then developed, which may include lifestyle modifications, pharmacotherapy, and possibly bariatric surgery, depending on the severity of the obesity and associated health risks.

Finally, the provider reviews the patient’s weight history, including any previous weight loss attempts, patterns of weight gain, and factors contributing to weight changes. They also evaluate the patient’s lifestyle habits, such as dietary habits, physical activity levels, sleep patterns, and psychological factors like stress and emotional eating. This assessment helps identify areas for intervention and support, ensuring a holistic approach to managing obesity and related health issues.

Pharmacotherapy treatment is recommended with adjunctive lifestyle therapy based on BMI as follows:

• •BMI 27–29.9: consider pharmacotherapy if comorbidities are present.
• •BMI 30–34.9: pharmacotherapy is recommended, especially with comorbidities.
• •BMI ≥35: pharmacotherapy is strongly recommended, particularly with comorbidities.

Updated guidelines also recommend bariatric surgery in patients with a BMI >30 kg/m² with weight-related complications such as T2D and BMI >35 kg/m², irrespective of medical complications.

To effectively manage weight loss and support patient health, tracking weight loss progress by monitoring excess and total body weight at each visit is important. Listening to patients’ cues about hunger, satiety, and any side effects they experience can help guide weight management strategies. Encouraging healthy lifestyle behaviors—such as balanced nutrition, regular physical activity, and consistent sleep patterns—is essential, as weight loss medications should complement, not replace, these foundational efforts. Recent research and guidelines underscore the importance of integrating nutritional and behavioral interventions to optimize the efficacy of GLP-1 receptor agonists and support long-term metabolic health [128]. If a patient achieves a superior response to medication, defined as a 5%–10% loss of total body weight, it may be beneficial to continue the medication indefinitely. Additionally, women of childbearing age should be advised to discontinue weight loss medication before conception to ensure safety. These guidelines help effectively manage weight loss and support patients throughout their journey. Figure 8 provides a case example of applying these guidelines for treating and managing obesity.

FIGURE 8.

A 54-y-old woman has a medical history that includes migraine headaches, untreated hypertension, gastroesophageal reflux disease, and irritable bowel syndrome. She retained 20 pounds with each of her 2 pregnancies. Despite trying many commercial weight loss programs, she experienced unsustainable weight loss, losing 20 pounds with each attempt. Her most significant weight loss occurred in the 1990s when she lost 50 pounds over 6 mo. She is currently interested in weight loss through medications and behavioral treatment. The patient was started on behavioral therapy with a successful response, approaching a nadir BMI of 30–31 kg/m². However, she approached a plateau, after which she was started on phentermine and topiramate combination therapy to achieve a BMI of 28.5 kg/m².

New approaches to obesity treatment for children and adolescents

Clinical practice guideline

In the United States, 14.7 million adolescents and children are grappling with obesity. Despite care recommendations set forth by the American Academy of Pediatrics in 2007 [129], the prevalence of obesity and overweight conditions remains high. The emergence of new research highlighting pediatric obesity-related health concerns underscores the urgency for updated guidelines [130]. Over the past 5 y, advancements in pediatric obesity have been groundbreaking. Notably, there was a 20-y gap between the last medication, which had limited efficacy, and liraglutide (not including phentermine, which was initially approved by the FDA in 1959 for short-term use in adolescents over 16). Meanwhile, research has predominantly concentrated on lifestyle interventions, providing extensive data to support these measures.

Recent updates in the treatment of obesity for children and adolescents emphasize a more comprehensive and proactive approach. In January 2023, the American Academy of Pediatrics released a new Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity (CPG) for the first time in 15 y, highlighting the importance of early and intensive treatment [131]. These guidelines recognize obesity as a complex and chronic condition that requires more than just lifestyle changes. In developing the CPG, an extensive review process was conducted. Ultimately, nearly 400 studies were included in the final 2 technical reports, forming the basis of the CPG. The evidence reviewed included studies for the USPSTF and Comparative Effectiveness articles, covering research up to the year 2022.

Key updates include the introduction of AOMs and surgical options for children and adolescents, marking a significant shift from previous recommendations. The guidelines suggest that for children aged 6 and older, and in some cases as young as 2, intensive behavioral and lifestyle changes should be the first-line of treatment. These interventions are most effective when including ≥26 h of face-to-face counseling over the course of a year.

Comprehensive treatment for pediatric overweight and obesity includes several key interventions. Motivational interviewing is used to engage children and their families in behavior change by exploring and resolving ambivalence. Intensive health behavior and lifestyle treatment programs focus on structured changes in diet, physical activity, and behavior, often involving a multidisciplinary team of dietitians, psychologists, and exercise specialists. For older children and adolescents, weight loss pharmacotherapy may be prescribed when lifestyle interventions alone are insufficient. Additionally, referrals to comprehensive pediatric bariatric surgery programs are considered for adolescents with severe obesity and related health issues, providing thorough evaluation and long-term follow-up care. These interventions are tailored to different age groups to ensure they are developmentally appropriate and effective.

Additionally, the guidelines stress the importance of addressing obesity early, rather than adopting a “watchful waiting” approach. This proactive stance is based on evidence showing that early intervention can lead to better long-term health outcomes. The new recommendations also consider the role of genetic, socioeconomic, and environmental factors in the development of obesity, acknowledging that it is not merely a result of personal choice.

Overall, these updates reflect a more nuanced understanding of obesity and aim to provide more effective and comprehensive care for children and adolescents struggling with this condition.

Clinical trials and controversy

The following novel medications have been FDA-approved for the treatment of obesity in children and adolescents aged 12–17 y.

Liraglutide

In a double-blind clinical trial [132], patients using liraglutide (3.0 mg) daily lost an average of 5.0% of their body weight over 56 wk, which was significantly more than the placebo group. Emerging evidence suggests that liraglutide may positively influence body composition by preserving muscle mass during weight loss. Although liraglutide has shown a favorable efficacy compared with a safety balance, continuous surveillance for adverse effects is recommended.

Phentermine/topiramate

Phentermine-topiramate [133] has been identified as one of the most effective drugs for weight reduction, with patients experiencing significant weight loss compared with lifestyle modifications alone. Adolescent studies [133,134] have shown phentermine-topiramate to be highly effective in lowering body weight, with a mean difference of ∼8%–10% body weight reduction. However, this combination is associated with increased adverse events leading to drug discontinuation, highlighting the need for careful monitoring.

Semaglutide

The STEP trials demonstrated that semaglutide (2.4 mg) weekly, combined with lifestyle intervention, resulted in substantial and sustained weight loss. Participants lost an average of 15%–20% of their body weight over 68 wk. Semaglutide has been shown to be particularly effective in adolescents [135], with a high proportion of participants achieving significant weight loss milestones. Although effective, semaglutide is associated with GI side effects, such as nausea and vomiting, which led to some participants discontinuing the treatment. These findings highlight the potential of these pharmacotherapies in managing obesity, although careful consideration of their safety profiles is essential.

Controversies

Clinical trials typically last around 1 y, often showing weight regain by the study’s end. In practice, clinicians extend treatment durations beyond FDA recommendations, incorporating gradual weaning and lifestyle modifications. Despite discontinuation of medication, chronic conditions like asthma, diabetes, depression, and fertility issues often persist. The effectiveness of medications varies significantly among individuals, as seen in both intervention and control groups. This highlights several research gaps: identifying predictive and prognostic biomarkers to guide pharmacotherapy initiation, exploring medication combinations to overcome treatment resistance, and understanding the genetics of treatment response.

Studies use various metrics (such as BMI, weight, z-score, BMI, 95% percentile of BMI, and the percentage of participants reaching a threshold of weight reduction), making it difficult to compare efficacy across studies. Populations in these studies typically exclude patients with existing mental health concerns and those whose obesity may be medication-related. Additionally, these studies mostly enroll white participants from mid to high socioeconomic status backgrounds and are majority female, despite obesity being more common among low socioeconomic status and minority populations.

Eating disorders are more common among patients with obesity, including BED, night eating syndrome, and atypical anorexia nervosa. Lifestyle-oriented treatment reduces the risk of eating disorders in patients with obesity [136]. This brings to light further research gaps: how to identify patients at risk for eating disorders, whether and how to use AOMs in patients at risk for or with eating disorders, and how to provide ongoing surveillance for eating disorders while patients are on AOMs. For example, GLP1-RAs are not effective in patients with Prader-Willi syndrome, raising the question of whether these novel agents will be effective in real-world cohort settings [137]. A prevalent bias suggests that if medications are ineffective, it is the individual’s fault, ignoring the complex biological factors at play.

Obesity treatment for children and adolescents is recommended without delay. High-quality evidence and current guidelines advocate for early treatment of obesity in children. Lifestyle treatment is the foundation of all pediatric obesity care, with newer generation medications targeting multiple physiological pathways implicated in obesity. Controversy over obesity medications highlights both genuine research gaps and issues of weight bias and stigma. There are still many evidence gaps that need to be addressed to guide best clinical practice. Additionally, many criticisms of obesity medications are driven by pervasive weight bias and stigma.

Limitations and future directions

Lack of long-term safety data for GLP-1RAs

Despite the promise of GLP-1RAs in weight management and in improving metabolic comorbidities, the novelty of GLP-1RA’s translates into a dearth of long-term safety data. Future longitudinal studies should focus on the potential long-term impacts of GLP-1RAs and similar medications on cardiovascular and GI health, bone density, and other potential iatrogenic pathologies.

Homogeneity in study populations

Current evidence in the field is largely derived from studies with homogeneous patient populations, which limit the generalizability of current findings. Future research should aim to recruit individuals with more diverse age, gender, and ethnic backgrounds, as well as those suffering from comorbid conditions. This will help ensure that results are applicable to a broader patient population, informing the field on the efficacy and indications for GLP-1RAs in these groups.

Variability in study designs

The studies reviewed during this symposium vary significantly in their design, ranging from differences in dosages, duration of treatment, and outcome measures. Standardizing these parameters in future trials, with a focus on long-term trials, would aid in cross-study comparisons and may lead to more robust conclusions about treatment effects, duration, sustainability, and adverse effects.

Limited data on pediatric populations

Despite the rise of pediatric obesity globally, there is a significant gap in evidence regarding the use of GLP-1RAs and other novel therapeutics in pediatric patients (Table 1). Exploration of safety, efficacy, and long-term outcomes of GLP-1RA use in pediatric populations will inform future treatment strategies and may help address the burden of childhood obesity.

TABLE 1.

Research gaps in pharmacotherapeutic intervention for management and treatment of obesity.

Research direction	Description
Longitudinal studies on safety and efficacy	Conduct long-term, large-scale, randomized controlled trials to assess the safety and efficacy of GLP-1RAs and other novel therapies over extended periods in diverse populations to ensure generalizability.
Mechanistic studies	Investigate the underlying mechanisms of action of GLP-1RAs and other emerging therapies to better understand how they influence weight loss, metabolic health, and other physiological processes.
Comparative effectiveness research	Compare the effectiveness of different pharmacological and nonpharmacological interventions for obesity management. This includes head-to-head trials of various GLP-1RAs, combination therapies, and lifestyle interventions to determine the most effective strategies for different patient subgroups.
Pediatric research	Prioritize research on the use of obesity treatments in pediatric populations. This includes studies on the safety, efficacy, and long-term outcomes of GLP-1RAs and other therapies in children and adolescents.
Real-world evidence	Collect and analyze real-world data on the use of GLP-1RAs and other obesity treatments in clinical practice.
Cost-effectiveness analyses	Conduct cost-effectiveness analyses of GLP-1RAs and other novel therapies to determine their economic impact and value in the healthcare system.

Abbreviation: GLP-1RA, glucagon-like-peptide-1 receptor agonist.

In conclusion, the discovery of leptin in 1994 ignited a revolution in obesity treatment, ultimately leading to groundbreaking obesity research. The current landscape of obesity management has expanded remarkably, with combinatory incretin, NuSHs, and activin/myostatin inhibition monoclonal antibody pharmacotherapeutic agents that can now control obesity, induce remission, significantly reduce the risk of weight regain while alleviating the associated medical, societal, and mental health complications of obesity in adults and children and adolescents. However, this new era also brings challenges. To ensure lasting success, it is vital to address the weight maintenance phase after weight loss to prevent rebound weight gain. The role of muscle mass and exercise in maintaining weight should not be underestimated. Future research should delve into biologics, predictive markers, and the phenotypic and genotypic traits of individuals who are either highly responsive or less responsive to these novel therapies after achieving their weight loss goals. Finally, without equitable access of these novel drugs by those who need them most, the success of these newer drugs will be limited.

Author contributions

The authors’ responsibilities were as follows – GS: wrote the paper and spoke at the symposium; TLS, EAL, SKG, SLC, CRH: provided edits for the paper; GS, SLC, CRH: primary responsibility for final content; CMA, JPA, LL, DNL, MD, CS, FCS, SA: presented at the symposium; and all authors: read, reviewed, and approved the final manuscript.

Funding

This conference was funded by Nutrition Obesity Research Center at Harvard sponsored by NIH P30 DK040561.

Conflict of interest

GS reports advisory fees from Novo Nordisk, Eli Lilly, and Rhythm; Speaker’s Bureau for Rhythm and Novo Nordisk and research grant support from Eli Lilly. TLS received grant funding to her institution from Pfizer, Inc. for serving as site-PI of an industry-sponsored study. EAL received financial support and study drug from Tonix Pharmaceuticals for investigator-initiated research studies; and received royalties from UpToDate. In addition, she is an inventor on United States. provisional patent application no. 63/467,980: Oxytocin-Based Therapeutics to Improve Cognitive Control in Individuals with Attention Deficit Hyperactivity Disorder. EAL and/or immediate family member holds stock in Thermo Fisher Scientific, Zoetis, Danaher Corporation, Intuitive Surgical, Merck and West Pharmaceutical Services. CMA reports participating on advisory boards for Altimmune, Inc., BioAge, Bioinq,CinFina Pharma, Inc., Cowen and Company, LLC, EPG Communication Holdings Ltd., Form Health, Inc., Fractyl Health, Inc., Gelesis, Srl., Lilly USA, LLC, L-Nutra, Inc., NeuroBo Pharmaceuticals, Inc., Nutrisystem, OptumRx, Inc., Pain Script Corporation, Palatin Technologies, Inc., Pursuit By You, Redesign Health Inc., ReShape Lifesciences Inc., Riverview School, Roman Health, Vida Ventures Inc., Veru Inc., Wave Life Sciences and Xeno Biosciences. CMA also reports receiving research funding from the NIH, PCORI and GI Dynamics, Inc. JPA reports serving on advisory boards and consulting with Novo Nordisk, Boehringer Ingelheim, and Eli Lilly and Company. LL is a United States federal employee at the NIH and is supported by the NIH Intramural Research Program (IRP; NIDA/NIAAA). Outside LL’s federal employment, he reports honoraria from the UK Medical Council on Alcohol (Editor-in-Chief for Alcohol and Alcoholism) and book royalties from Routledge. DNL reports over the last 3 y speaker fees, travel assistance, or consulting income from the following sources: Amgen, Genentech, Gilead, GRAIL, Mylan, Novartis, Otsuka, Perrigo, Pfizer, and Sorrento Therapeutics. DNL also owns equity in Precision Medicine Group, for which he previously served as a consultant. DNL is also Co-Founder and Chief Scientific Officer of EntityRisk, Inc., which develops software and analytic tools for use by healthcare firms. MD and CS have no disclosures to report. FCS reports financial support provided by the NIH and funding grants provided by Amazon. FCS reports a relationship that includes consulting and advisory for the following: Eli Lilly and Company, Novo Nordisk, Amgen, Boehringer Ingelheim, Rhythm Pharmaceuticals, Gelesis, Doximity, GoodRx, and Currax Pharmaceuticals. SA reports serving as the chair for the American Academy of Pediatrics and leads a section on obesity. SA also reports serving as a consultant for the American Academy of Pediatrics’ Institute for a Healthy Childhood Weight. SKG reports grant support through his institution from NIH, Kowa Pharmaceuticals America, Inc., Gilead Sciences, Inc., and ViiV Healthcare for the conduct of the study; personal fees from Theratechnologies and ViiV; and service on the Scientific Advisory Board of Marathon Asset Management, all outside the submitted work.