Endocrine Society Calls for Obesity Treatment Goals Beyond Weight Loss

The arrival of highly effective obesity medications has outpaced clinicians’ understanding of how to individualize treatment, assess success beyond the scale, and manage long-term safety, according to a new Endocrine Society scientific statement published in Endocrine Reviews.¹

“This Statement highlights major advances in obesity science and outlines areas of research needed to improve our understanding of the disease, optimize treatment, personalize care and improve long-term health outcomes for people living with obesity,” Daniel J. Drucker, MD, of Mount Sinai Hospital in Toronto, Ontario, Canada, lead author of the Scientific Statement writing group, said in a press release.² “The rapid adoption of highly effective obesity medications has changed the treatment landscape, but important questions remain about their long-term use, individualized treatment strategies, side effects and the best ways to measure treatment outcomes.”

The statement identifies 6 priority areas for research: obesity pathophysiology and the regulation of “defended” fat mass; heterogeneity in treatment response; treatment targets beyond percentage of total body weight lost; the physiology of weight reduction, plateau, and maintenance; health outcomes associated with pharmacotherapy; and long-term safety.¹

The authors emphasized that the document is not intended to provide treatment guidance. Instead, it outlines evidence gaps that have become increasingly important as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists, and other emerging therapies produce weight reductions that can exceed 20% to 25% in some individuals.¹

Moving Beyond Percentage Weight Loss

Percentage change in body weight remains the primary efficacy endpoint in phase 3 obesity trials, but the authors argued that it is not an adequate measure of treatment success for every patient. BMI does not directly measure body fat, body composition, or adipose tissue distribution, and patients may require different degrees of weight reduction to improve specific obesity-related complications.¹

Health improvements in blood pressure and glycemia can begin after weight reductions of approximately 3% to 5%, whereas mechanical complications such as obstructive sleep apnea (OSA) and osteoarthritis may require reductions of 10% to 15% or more. Conversely, some patients—particularly those who begin treatment with a BMI below 30 kg/m²—may reach their health goals with less weight loss and could experience an undesirably low BMI if treatment produces reductions exceeding 20%.¹

The statement called for treatment targets that incorporate body composition, waist circumference, cardiometabolic measures, functional status, quality of life, and improvement or remission of obesity-related complications. The authors also highlighted the need for targets tailored to age, race and ethnicity, sex, life stage, and baseline disease burden.

Treatment Response Remains Highly Variable

Despite large differences in average efficacy among lifestyle intervention, pharmacotherapy, and metabolic surgery, individual responses to each approach vary substantially. Across several treatment modalities examined in the statement, the standard deviation in total body weight loss was approximately 10% to 12%.¹

Current genetic and clinical measures cannot reliably identify which patients will respond best to a particular obesity medicine. Although more than 1000 genetic loci have been associated with common obesity, polygenic risk scores have not predicted clinically meaningful differences in weight loss after intensive lifestyle intervention, bariatric surgery, or treatment with GLP-1–based medications.¹

The authors also questioned the routine escalation of obesity medications to a maximum or near-maximum tolerated dose. Dose-escalation schedules generally reflect clinical trial designs and prescribing information, but wide variation in dose response means some patients may experience intolerance, overly rapid weight reduction, or excessive weight loss. Studies comparing the minimum effective dose with the maximum tolerated dose are needed, particularly as more potent agents enter clinical development.

Health Benefits Extend Beyond the Scale

Evidence reviewed in the statement indicates that modern obesity medications can improve outcomes across several organ systems. In the SELECT trial, semaglutide 2.4 mg reduced major adverse cardiovascular events by 20% and all-cause mortality by 19% among adults with overweight or obesity and established cardiovascular disease but without diabetes.¹

In obesity-related heart failure with preserved ejection fraction, semaglutide improved symptoms, physical limitations, and walking distance, while tirzepatide reduced the composite risk of cardiovascular death or worsening heart failure by 38% in the SUMMIT trial. Tirzepatide also reduced the apnea-hypopnea index by approximately 60% in adults with obesity and moderate to severe OSA.¹

Other findings reviewed in the statement showed improvements in glycemia, kidney outcomes, metabolic dysfunction-associated steatohepatitis, osteoarthritis-related pain, and weight-specific quality of life. However, investigators have not fully determined which benefits result from weight reduction and which reflect weight-independent pharmacologic effects.

Questions Remain About Maintenance and Safety

Obesity is a chronic disease, and trials of semaglutide and tirzepatide have documented weight regain and deterioration in cardiometabolic measures after treatment withdrawal. However, the optimal approach to maintenance—including whether doses can be reduced, dosing intervals extended, or patients transitioned to other therapies—remains uncertain.¹

Long-term safety data are also limited, particularly for children and adolescents, older adults, pregnant or breastfeeding patients, and individuals without type 2 diabetes or established cardiovascular disease. Registration trials are generally too short, too small, and too narrowly enrolled to characterize rare adverse events or decades-long exposure.

Rapid and substantial weight reduction can involve losses of lean mass and bone as well as adipose tissue, potentially increasing the risk of sarcopenia, falls, and fractures in susceptible patients. The statement noted that evidence is insufficient to determine whether resistance exercise, higher dietary protein intake, slower weight reduction, or investigational muscle-preserving therapies can meaningfully reduce these risks.

The authors identified real-world data as an essential complement to randomized trials for evaluating long-term effectiveness, treatment persistence, rare adverse events, pregnancy exposure, compounded products, and lower-dose prescribing patterns. Ultimately, they concluded that obesity treatment should be assessed according to its ability to improve health—not weight reduction alone—while balancing individual benefits, risks, treatment goals, and access.

Reference

1. Jastreboff AM, Ard JD, Hall KD, et al. Obesity science, research gaps, and opportunities in the new era of obesity medicines: an Endocrine Society scientific statement. Endocr Rev. Published online September 9, 2026. doi:10.1210/endrev/bnag025
2. The Endocrine Society. Endocrine Society Scientific Statement provides research roadmap for what's next in obesity science. News release. Published September 9, 2026. Accessed September 10, 2026. https://www.endocrine.org/news-and-advocacy/news-room/2026/obesity-scientific-statement