GLP-1 RA Effects are Largely Homogeneous but Stronger in Women than Men, With Caleb Alexander, MD, MS

The efficacy of GLP-1 receptor agonists (GLP-1 RAs) in weight loss favors women over men, despite being largely consistent across other key patient subgroups.1

Despite a long history of proven efficacy, past GLP-1 RA trials have included a substantial minority of individuals who failed to achieve weight loss. Because of this, clinicians have suggested a potential variance in efficacy based on patient characteristics, including age, sex, race, ethnicity, baseline body mass index, and baseline hemoglobin A1c.2

“All too often during the course of clinical trials, one really doesn’t learn whether or not a product, such as a GLP-1, is similarly efficacious across different populations of patients,” Caleb Alexander, MD, MS, a professor of epidemiology and medicine at Johns Hopkins University School of Medicine and co-founder and principal of Stage Analytics, told HCPLive in an exclusive interview. “In other words, trials deliver information, on average, about a product, but don’t allow one to really understand whether or not the product may work similarly well across important subpopulations. Our results should reassure clinicians that some of these populations, which may have been excluded from clinical trials, still stand to gain from GLP-1s.”

Alexander and colleagues searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from their respective inceptions through July 26, 2024. Trials including semaglutide, lixisenatide, exenatide, liraglutide, and dulaglutide, as well as GLP-1 or insulin combination products, were eligible. Tirzepatide trials were excluded due to its status as a dual GIP or GLP-1 receptor agonist.1

Phase 3 randomized controlled trials (RCTs) of adult patients ≥18 years with weight as a primary outcome were included – additionally, investigators required trials to compare GLP-1 RAs with placebo or non-GLP-1 RAs. Trials that did not report subgroup analyses or had an analysis without estimates for the non-GLP-1 RA group were excluded.1

A total of 41 articles were ultimately included, representing 64 RCTs. The mean population of participants was 1181 between the 48 RCTs reporting study-level data (standard deviation [SD] 2513). The most frequently evaluated GLP-1 was semaglutide (21 [43.8%]), followed by dulaglutide (9 [18.8%]).1

The vast majority of subgroups saw homogeneous effects from GLP-1 treatment: Alexander and colleagues provided an example of the 7 RCTs reporting stratified analyses by age. Among these 4314 patients, the mean weight loss among those <65 years was 1.98 (95% CI, 0.8-3.15) kg and 1.97 (95% CI, 1.15-2.79) kg among patients ≥65 years (between-group heterogeneity, P = .94).1

However, 4 of the 6 RCTs reporting percentage change in weight by sex saw statistically significantly greater weight loss among women than men. Of the 6 RCTs, including 19,906 patients, the mean reduction was 10.9% (95% CI, 7-14.8%) among women and 6.8% (95% CI, 4.6-9%) among men (between-group heterogeneity, P = .08).1

The team provides several possible explanations for this disparity between men and women. The synergy between GLP-1 RAs and estrogens could potentially increase their effectiveness, as could lower average body weight among women. Both may alter the pharmacokinetics of the treatment, allowing for greater response and increased efficacy by comparison.1

Alexander and colleagues highlighted the implications of these data for both patients and clinicians. Although several patient populations have been underrepresented in or excluded from GLP-1 RA trials, these data indicate the overall homogeneity of treatment effects among most subcategories. Additionally, the team believes that the findings of this trial underscore the importance of examining heterogeneity of similar drugs across underrepresented patient groups. The team also calls for further research into whether these heterogeneity findings extend to other GLP-1 RA indications, including diabetes management, chronic kidney disease, and cardiovascular risk.1

“GLP-1s are a transformational product; they are really a once-in-a-lifetime medical innovation,” Alexander said. “But the value of medicines isn’t an inherent function of the product itself – it depends on how it’s used in the real world. We still need to figure out how to optimize their value and ensure that the patients who get them are those who stand to gain the most from them.”

Editors’ Note: Alexander reports being past chair of the Peripheral and Central Nervous System Advisory Committee (US Food and Drug Administration) and a cofounding principle and equity holder in Stage Analytics outside the referenced work.

References

1. Alexander GC, Xiao X, Dilek S, et al. Heterogeneity of treatment effects of glucagon-like peptide-1 receptor agonists for weight loss in adults. JAMA Internal Medicine. Published online March 2, 2026. doi:10.1001/jamainternmed.2025.8222

2. Wong HJ, Sim B, Teo YH, et al. Efficacy of GLP-1 Receptor Agonists on Weight Loss, BMI, and Waist Circumference for Patients With Obesity or Overweight: A Systematic Review, Meta-analysis, and Meta-regression of 47 Randomized Controlled Trials. Diabetes Care. 2025;48(2):292-300. doi:10.2337/dc24-1678