Semaglutide’s cardiovascular benefits hold up with frailty

Clinical takeaway: Do not exclude otherwise eligible adults with cardiovascular disease and overweight or obesity from semaglutide treatment based on frailty alone. Assess nutritional status, muscle health, functional limitations, and tolerability individually because this post hoc analysis did not directly evaluate sarcopenia.

Concerns about weight loss, tolerability, and reduced treatment benefit may make clinicians hesitant to prescribe GLP-1 drugs to patients with frailty. A post hoc analysis of the SELECT trial suggests that frailty alone should not rule out semaglutide in eligible adults.

The analysis included 17,604 adults with established cardiovascular disease and a BMI of 27 or higher who did not have diabetes. Participants received once-weekly semaglutide 2.4 mg or placebo. A 31-item index based on accumulated health deficits classified 31% as not frail, 47% as more frail, and 22% as most frail.

Over a mean follow-up of 39 months, cardiovascular risk increased with greater frailty. However, semaglutide’s effect on cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke did not differ significantly by frailty category. Benefits for heart failure outcomes, all-cause hospitalization, mortality, and kidney outcomes also appeared consistent across frailty levels.

At 104 weeks, frailty category improved in 33.7% of semaglutide recipients versus 18.0% of placebo recipients and worsened in 10.0% versus 19.3%, respectively. Quality-of-life improvements were greater among participants with higher baseline frailty, particularly for mobility, self-care, and usual activities.

Serious adverse events were less frequent with semaglutide across all frailty groups. Adverse events leading to discontinuation, primarily gastrointestinal effects, remained more common with semaglutide than placebo, but the relative difference narrowed as frailty increased. Serious bone and joint events were uncommon and were not increased with semaglutide.

The findings are exploratory and reflect a deficit-based frailty measure rather than physical features such as weakness or slow gait. Participants with diabetes, end-stage kidney disease, or a BMI below 27 were not represented.

“Overall, these findings suggest the benefit-risk balance with semaglutide can be favorable even in people with frailty and may inform shared decisions around semaglutide initiation in routine care,” the study authors wrote.

Source: Ostrominski JW, et al. (2026 Sep 16) JAMA Cardiol. Efficacy and safety of semaglutide according to frailty status: A post hoc analysis of the SELECT randomized clinical trial