Semaglutide's Cardiovascular Benefits Hold Regardless of Frailty in SELECT

Frailty does not appear to diminish the cardiovascular benefits of semaglutide in adults with cardiovascular disease and overweight or obesity, according to a secondary analysis of the SELECT randomized clinical trial published in JAMA Cardiology. The analysis was conducted by Ostrominski and colleagues for the SELECT Trial Investigators.

The study addressed whether frailty modifies the benefit-risk balance of glucagon-like peptide-1 receptor agonists, evaluating semaglutide, 2.4 mg once weekly, against placebo in adults with a body mass index of 27 or higher and established cardiovascular disease but no diabetes.

Among 17,604 participants (mean age, 61.6 years; 72.3% male), investigators built a 31-item frailty index (FI) using the Rockwood cumulative deficit approach, classifying 5,432 patients (31%) as not frail (FI ≤0.210), 8,349 (47%) as more frail (FI 0.211-0.310), and 3,823 (22%) as most frail (FI ≥0.311). The primary composite outcome — cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke — occurred more often with higher baseline FI, but semaglutide's benefit appeared consistent across categories (hazard ratio, 0.84 for not frail; 0.70 for more frail; 0.92 for most frail; P = .09 for interaction).

Semaglutide also reduced the composite heart failure outcome, all-cause hospitalization, and all-cause mortality regardless of frailty category. Improvements in health-related quality of life, measured by the EQ-5D-5L, were larger among patients with higher FI (P = .02 for interaction). Semaglutide-treated patients were also more likely to have their frailty category improve (odds ratio, 2.46) and less likely to have it worsen (odds ratio, 0.47) by week 104, and adverse events leading to treatment discontinuation were less frequent with semaglutide among those with higher baseline frailty (P < .001 for interaction).

The study authors concluded that semaglutide showed consistent benefit across a broad range of clinical outcomes in SELECT without detectable heterogeneity by baseline frailty, and noted that these hypothesis-generating findings suggest frailty status should not preclude consideration of semaglutide in eligible patients.

Source: Ostrominski JW, Jeppesen OK, Lincoff AM, et al, for the SELECT Trial Investigators. Efficacy and Safety of Semaglutide According to Frailty Status: A Post Hoc Analysis of the SELECT Randomized Clinical Trial. JAMA Cardiol. Published online 2026. doi: 10.1001/jamacardio.2026.3566