There are a number of guidelines on how to manage obesity, but inconsistencies in healthcare access, varying infrastructure, resource constraints and diverse local practices restrict their global applicability. This underscores the need for universal recommendations that address the unique challenges faced by patients and healthcare providers worldwide. Our Global Guidelines emphasise the incorporation of novel therapies while integrating standards of care with the most up-to-date evidence to enable clinicians to optimise obesity management. Context-specific recommendations tailored to individual patient needs are highlighted, providing a thorough evaluation of the risks, benefits and overall value of each therapy, aiming to establish a standard of care that improves patient outcomes and reduces the burden of hospitalisation in this susceptible population. These Global Guidelines provide evidence-based recommendations that represent a group consensus considering the many other published guidelines that have reviewed many of the issues discussed here, but they also make new recommendations where new evidence has recently emerged, and-most importantly-also provide recommendations on several issues where resource limitations may put constraints on the care provided to patients living with obesity. Such 'economic adjustment' recommendations aim to guide situations when 'Resources are somewhat limited' or when 'Resources are severely limited'. Hence, this document presents a comprehensive update to obesity management guidelines, thereby aiming to provide a unified strategy for the pharmacological, non-pharmacological and invasive management of this significant global health challenge that is applicable to the needs of healthcare around the globe.

The Duke Clinical Research Institute hosted a think tank, “Anti-Obesity Pharmacotherapy: Need for Guidance, Access, and Equity” in October 2024. This brought together multi-industry stakeholders to align and advance the field of obesity medications (OMs). Key themes included the need for an evidence-based, patient-centric definition of obesity incorporating alternative measures of excess or dysfunctional adiposity, obesity symptoms, and obesity-related complications; barriers to OM access (cost and availability) that perpetuate inequalities in care; ambiguity in optimal clinical OM use; challenges of novel clinical trial designs; and ethics of placebo-controlled trials. Action items included a cross-stakeholder obesity research roadmap, standardized obesity measures inclusive of and beyond body mass index, strategies to ensure equitable OM access, and a forum to address regulatory and payer challenges. The complex, rapidly developing field of obesity research and OM development requires a strategy to ensure equitable, streamlined research and access to OMs.

Aleniglipron is an oral, small-molecule glucagon-like peptide-1 receptor agonist (GLP1-RA) in development for obesity treatment. The ACCESS phase 2b placebo-controlled, double-blind study randomized 230 adults (mean BMI 39.5 kg m-2, 54% female) with obesity or overweight to examine the effects of once-daily aleniglipron escalated every 4 weeks to 45, 90 or 120 mg. At week 36, the trial met its primary endpoint with a placebo-adjusted LS mean (95% confidence interval) body-weight change from baseline of -8.2% (-11.1 to -5.3%), -9.8% (-12.5 to -7.2%) and -11.3% (-13.9 to -8.6%) for the aleniglipron 45-, 90- and 120-mg arms, respectively (P < 0.0001, all doses versus placebo), with no apparent weight-loss plateau at the end of the double-blind period. Continued weight loss was observed at the interim analysis (median treatment duration of 20 weeks) of the ongoing open-label extension. Gastrointestinal events were generally mild to moderate and decreased in frequency over time, with little to no recurrence of vomiting after reintroduction following permitted dose interruptions. Treatment-related discontinuations were 10.4% across aleniglipron arms, with no events of drug-induced liver injury. Clinically relevant weight reductions of up to 11.3% with a tolerability profile consistent with the GLP-1RA class support further development of aleniglipron for obesity treatment. ClinicalTrials.gov registration: NCT06693843 .

OBJECTIVE:The objective of this study was to investigate the efficacy and safety of the Epitomee capsule versus placebo as an adjunct to high-intensity lifestyle intervention in participants with overweight or obesity. METHODS:The Randomized Evaluation of Efficacy and Safety of the Epitomee Capsule Trial (RESET) was a prospective, double-blind, placebo-controlled pivotal trial in adults with baseline BMI of 27.0 to 40.0 kg/m2. The co-primary endpoints at week 24 were percentage change from baseline in body weight for the Epitomee and placebo groups and proportion of Epitomee-treated patients achieving ≥5% weight loss compared with a 35% threshold. The primary safety endpoint was the incidence of device-related serious adverse events. RESULTS:A total of 138 participants received Epitomee and 141 received placebo. Mean (SD) change in body weight from baseline was -6.6% (6.5%) with Epitomee and -4.6% ( 4.7%) with placebo; least-squares means were -6.1% (0.6%) and -4.2% (0.6%), respectively (p = 0.0054). Fifty-six percent of Epitomee-treated participants attained ≥5% weight loss from baseline, which was significantly greater than the 35% predefined threshold (p < 0.0001). Twenty-seven percent of Epitomee-treated and eleven percent of placebo-treated participants achieved ≥10% weight loss. Adverse event rates were similar between the groups. No device-related serious adverse events occurred. CONCLUSIONS:The Epitomee capsule is a safe and efficacious nonpharmacological option for weight management with potential broad application in participants with overweight or obesity.

Early response (ER) to treatment is predictive of longer-term weight loss. In this post hoc analysis, ER to an oral shape-shifting superabsorbent hydrogel capsule (Epitomee) combined with a lifestyle intervention was compared to placebo combined with a lifestyle intervention. Participants (age = 48.5 ± 12.5 and 48.6 ± 12.4; BMI = 34.1 ± 3.3 and 33.7 ± 3.4, in the Epitomee and placebo groups, respectively) were randomised to Epitomee (N = 138) or placebo (N = 141) with lifestyle intervention. Analyses included body weight measurements taken at baseline, week 8, and week 24. Of the 279 participants enrolled in the study, 250 (90% of the ITT population) provided weight data, including 124 participants in the Epitomee group and 126 in the placebo group. Participants with missing weight data at week 24 were classified as non-responders. Early response (ER) was defined as a weight loss of ≥ 2% at week 8. Weight loss at week 24 was greater in ER to Epitomee compared to placebo (9.3% ± 6.0% vs. 6.9% ± 4.3%; p < 0.0001). The odds ratio for ER to achieve > 5% weight loss at week 24 was 4.10 (95% CI: 1.02, 16.46) for Epitomee and 2.38 (95% CI: 0.62, 9.21) for placebo. A greater proportion of ER to Epitomee, compared to placebo, achieved > 5% (76% vs. 62%; p = 0.0472), ≥ 7% (61% vs. 38%; p < 0.0045) and ≥ 10% (39% vs. 17%; p < 0.0025) weight loss at week 24. ER response to Epitomee was associated with greater weight loss at 24 weeks compared to placebo. Monitoring ER to Epitomee and titrating treatment based on ER may enhance weight loss.

Precision medicine approaches have gained attention for their potential to more effectively manage obesity by tailoring diagnosis and treatment strategies to individual characteristics, including genetic background, phenotypes, metabolic profiles, and environmental exposures. The current review evaluates the evidence for precision medicine in weight management by summarizing the proceedings of a Pennington Biomedical Scientific Symposium titled "Precision Prevention, Diagnostics, and Treatment of Obesity: Pipedream or Reality?" This review discusses the extent to which we can classify and predict obesity risk based on individual-level factors; whether we have the diagnostic capability to prospectively identify people who will benefit most from specific interventions; whether prospective trials demonstrate superior prevention and treatment of obesity when precision approaches are applied; and whether evidence is sufficient to guide policy decisions. Expert opinions were presented on the current evidence of precision medicine for obesity to collectively evaluate key barriers and opportunities for implementation of precision approaches in clinical and public health settings.

This JAMA Insights article explores a variety of current and emerging nutrient-stimulated, hormone-based medications for the treatment of individuals with obesity.

Diagnosis of clinical obesity has been highlighted by the recent publication from a Commission Report in The Lancet, suggesting the addition of a new diagnostic category, “Preclinical Obesity,” to the already existing ones. Diagnostic criteria for obesity began in the first half of the 20th century, when life insurance companies provided information tables of ideal body weight levels and/or desirable body weight levels based on actuarial associations with mortality. This was replaced by the body mass index or BMI in the third quarter of the 20th century. This tool documented the epidemic of obesity in the US in the last three decades of the 20th century. The recognition of the importance of fat distribution, pioneered by the work of Jean Vague in France, provided a new understanding of obesity. The limitations of BMI and the availability of effective new treatments have heightened the need for new diagnostic guidelines. Obesity represents an increase in body fat and an alteration in its distribution and function. But at the same time, obesity is a stigmatized word and a pejorative term. This communication discusses ways to better diagnose the increase in body fat and its abnormal distribution. We ask whether there is an alternative word to replace obesity and suggest that adiposity or healthy weight could be options.

BACKGROUND:Maridebart cafraglutide (known as MariTide) is a long-acting peptide-antibody conjugate that combines glucagon-like peptide-1 receptor agonism and glucose-dependent insulinotropic polypeptide receptor antagonism and that is intended for the treatment of obesity. METHODS:We conducted a phase 2, double-blind, randomized, placebo-controlled, dose-ranging trial that included 11 groups as two cohorts. Participants with obesity (obesity cohort) were randomly assigned in a 3:3:3:2:2:2:3 ratio to receive maridebart cafraglutide subcutaneously at a dose of 140, 280, or 420 mg every 4 weeks without dose escalation; 420 mg every 8 weeks without dose escalation; 420 mg every 4 weeks with 4-week dose escalation; 420 mg every 4 weeks with 12-week dose escalation; or placebo. Participants with obesity with type 2 diabetes (obesity-diabetes cohort) were randomly assigned in a 1:1:1:1 ratio to receive maridebart cafraglutide at a dose of 140, 280, or 420 mg every 4 weeks (all without dose escalation) or placebo. The primary end point was the percent change in body weight from baseline to week 52. RESULTS:We enrolled 592 participants. In the obesity cohort (465 participants; female sex, 63%; mean age, 47.9 years; mean body-mass index [BMI, the weight in kilograms divided by the square of the height in meters], 37.9), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand (intention-to-treat approach) ranged from -12.3% (95% confidence interval [CI], -15.0 to -9.7) to -16.2% (95% CI, -18.9 to -13.5) with maridebart cafraglutide, as compared with -2.5% (95% CI, -4.2 to -0.7) with placebo. In the obesity-diabetes cohort (127 participants; female sex, 42%; mean age, 55.1 years; mean BMI, 36.5), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand ranged from -8.4% (95% CI, -11.0 to -5.7) to -12.3% (95% CI, -15.3 to -9.2) with maridebart cafraglutide, as compared with -1.7% (95% CI, -2.9 to -0.6) with placebo. The mean change in the glycated hemoglobin level on the basis of the treatment policy estimand in this cohort was -1.2 to -1.6 percentage points in the maridebart cafraglutide groups and 0.1 percentage points in the placebo group. Gastrointestinal adverse events were common with maridebart cafraglutide, although less frequent with dose escalation and a lower starting dose. No unexpected safety signals emerged. CONCLUSIONS:In this phase 2 trial, once-monthly maridebart cafraglutide resulted in substantial weight reduction in participants with obesity with or without type 2 diabetes. (Funded by Amgen; ClinicalTrials.gov number, NCT05669599.).