Tirzepatide Yields Greater Weight Loss in Women Than Men

Women tended to reap greater weight loss from tirzepatide (Zepbound), a subgroup analysis of the SURMOUNT trials found.

Across all studies and doses, females lost up to 24.6% of body weight from baseline whereas men lost a maximum of 18.1% of weight from baseline (P<0.05), Luis-Emilio García-Pérez, MD, PhD, of Eli Lilly in Indianapolis, reported at the European Association for the Study of Diabetes (EASD) annual meeting in Madrid.

When compared with placebo, female participants lost 11.5-27.6% greater body weight on the drug, whereas males lost 8.8-18.9% more with it (P<0.001 for all comparisons with placebo).

“We don’t have a clear reason on why this may happen,” García-Pérez said. Some running hypotheses include a difference in body fat distributions and body composition and hormones. “But we don’t have an answer right now.”

“For lifestyle intervention and other interventions, this seems to be the other way around,” he added. Prior data, including data from this post-hoc analysis, found that men lost more weight than women with diet and exercise.

García-Pérez also suggested this could be due to pharmacological differences in how the drug works. “There seems to be similar effects with semaglutide,” he said.

Tirzepatide is a first-in-class injectable: a combination of a glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GLP-1/GIP) agonist. Semaglutide (Ozempic, Wegovy) is one of several approved GLP-1 receptor agonists.

“If we see the same [sex differences] with semaglutide, then it probably has more to do with GLP-1 than GIP because the GIP is not in semaglutide,” commented session moderator Luc Van Gaal, MD, PhD, of the University of Antwerp in Belgium.

While the reason driving these differences requires more research, García-Pérez underscored that both sexes benefited from tirzepatide.

In all four trials, a higher proportion of females achieved a 15% or greater weight reduction than males, though this was only significantly different in the third installment:

• SURMOUNT-1: 83.9% vs 66.3%, respectively, on 15 mg
• SURMOUNT-2: 62.3% vs 40.7% on 15 mg
• SURMOUNT-3: 81.6% vs 61% on maximum tolerated dose
• SURMOUNT-4: 20.5% vs 6.1% on maximum tolerated dose

Females also experienced a numerically higher rate of some gastrointestinal side effects. Across the trials, the proportion of females who experienced nausea ranged from 9.3-47.5%, and 5.5-22.7% experienced vomiting. Only 5.1-26.4% of males experienced nausea and 6.0-10.4% experienced vomiting.

While the higher rates of nausea and vomiting could play into why females lost more weight, García-Pérez said this is unlikely to be a main factor because these adverse events usually occur at the beginning of treatment initiation — during the dose-titration phase — and participants continued to lose weight throughout the trials’ duration.

The two sexes had similar rates of diarrhea, constipation, dyspepsia, and decreased appetite.

The post-hoc analysis included data from phase III SURMOUNT-1, -2, -3, and -4 trials. The first two underpinned the November 2023 approval of tirzepatide for chronic weight management in adults. It was initially approved under the trade name Mounjaro for type 2 diabetes in May 2022.

SURMOUNT-1 tested tirzepatide against placebo for 72 weeks in people with overweight (BMI ≥27) or obesity (BMI ≥30) without diabetes, while SURMOUNT-2 included those with overweight or obesity plus type 2 diabetes.

The third SURMOUNT trial installment tested tirzepatide for 72 weeks after a 12-week intensive lifestyle intervention lead-in period in adults with obesity or overweight with weight-related comorbidities, but no type 2 diabetes. SURMOUNT-4 also excluded people with type 2 diabetes and involved a 36-week, open-label lead-in period in which all participants took tirzepatide, and a subsequent 52-week double-blind treatment period in which participants were randomized to either continue on tirzepatide or switch to placebo.

There was a consistently higher proportion of females across all studies — up to 70% in one trial. Proportion of males ranged from 29.4% to 49.3%.

García-Pérez said his group is currently looking into any weight reduction differences when stratified by age, including across reproductive-age, menopausal, and post-menopausal women.

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