Women treated with GLP-1 for weight loss show significantly higher rates of weight loss compared with men, but notably, no significant differences are observed in a variety of other patient characteristics, findings from a new meta-analysis show.

“Although our synthesis suggests that GLP-1s produce greater weight loss among women than men, their efficacy was consistent across many other important subpopulations of patients who may be eligible for treatment,” report the authors in research published this month in JAMA Internal Medicine.

“These findings are important because of the prevalence and cost of GLP-1s as well as the continued high demand for evidence to inform practitioners regarding their overall risks and benefits in clinical practice,” they note.

Despite highly favorable efficacy of GLP-1 drugs in achieving reductions in body weight, some studies show approximately 15%-20% of patients do no achieve such successful weight loss, with some small studies suggesting factors such as age, race, sex, and other variables could influence treatment success.

Among issues known to curtail weight loss is drug discontinuation, explained the study’s senior author, Hemalkumar B. Mehta, PhD, an associate professor of epidemiology at the Bloomberg School of Public Health, Johns Hopkins University, in Baltimore.

“Despite the potential value of GLP1s, nonadherence rates are through the roof — a remarkable number of people stop taking them within a few months of starting the medicines,” Mehta told Medscape Medical News.

“Further work is needed to understand what groups of individuals truly stand to gain the most from these medicines and how to optimize their adherence to treatment.” 

To take a closer look at the potential factors, Mehta and his colleagues conducted a meta-analysis of 41 articles representing 64 randomized trials comparing GLP-1s to placebo or other medications.

Of the trials, 48 could be individually characterized, the mean study population was 1181 participants; 51 of the trials had a parallel design and 51 were multicenter trials. The most frequently evaluated GLP-1 was semaglutide (21 studies), followed by dulaglutide (nine studies). 

In the studies, heterogeneity of treatment effects was most commonly evaluated based on baseline BMI (75.0%), A1c (50.0%), and age (43.8%), with less common evaluations based on ethnicity (25.0%), race (22.9%), and sex (20.8%).

For six trials, involving 19,906 patients, that analyzed treatment efficacy based on sex, weight loss was shown to be significantly greater among women than men (10.9% vs 6.8%).

Conversely, no significant treatment differences were observed based on age (seven trials involving 4314 patients), race (nine trials; 25,229 patients), ethnicity (seven trials; 8328 patients), baseline BMI (15 trials; 9473 patients across three analyses), or baseline A1c (four trials; 1886 patients).

Mechanisms of Sex Differences? 

Key factors that could explain the higher response among women include the way in which GLP-1s interact with estrogens, Mehta said.

“These findings may be due to several factors, including synergistic interactions with estrogen, differences in how women’s bodies process the drug, and women’s lower median body weight,” he said.

In addition, “it has been speculated that women are better at managing the side effects of GLP-1s compared to men and continue taking these medications.”

Overall, however, the findings notably suggest that, aside from sex, the drugs’ effects span patient subgroups, Mehta said.

“A reason that this is important — and reassuring — is that unfortunately, randomized trials don’t reflect the diversity of patients that receive these products in the real world,” he explained.

“Our findings suggest that results may extend similarly to populations underrepresented in clinical trials, [and] regardless of age, race/ethnicity, starting weight or A1c.”

Commenting on the study, Areesha Moiz, a clinical research associate at the Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, noted that the differences between women and men are “an interesting signal, but it shouldn’t be interpreted as meaning the drugs only work well in women.”

“Men in these trials still experienced clinically meaningful weight loss,” she noted.

Moiz agreed that mechanisms behind the higher weight loss in women than men could be pharmacologic exposure. 

“These drugs are given at fixed doses, so differences in average body size could affect how much drug people are effectively exposed to,” she noted. 

“Another possibility involves biological differences in appetite regulation and hormones, including potential interactions with estrogen. It’s also possible that differences in side effects such as nausea, which can reduce appetite, could play a role.”

Among limitations to consider is that “many obesity trials tend to enroll a majority of women,” noted Moiz, who, with colleagues, recently published a systematic review in the Annals of Internal Medicine of GLP-1s among adults without diabetes.

“In our own systematic review, we found that women represented a large proportion of participants across many of the trials which can influence subgroup comparisons,” she said.

Furthermore, “many meta-analyses rely on published subgroup averages rather than individual-level patient data,” she added. “Without individual participant data, residual confounding and ecological bias are always concerns.”

Overall, however, “the finding that women may experience somewhat greater average weight loss is interesting and worth exploring further, but it shouldn’t change how clinicians think about prescribing these medications,” Moiz said.

“Individual responses vary widely, and both men and women can benefit.”

Mehta and Moiz had no disclosures to report.