This post hoc analysis of the SELECT RCT evaluated whether frailty (measured by a 31-item Rockwood frailty index) modifies the efficacy and safety of semaglutide 2.4 mg weekly vs. placebo in 17,604 adults with established cardiovascular disease and overweight/obesity (BMI ≥27) without diabetes, over ~104 weeks.
Semaglutide's benefit on the primary MACE outcome (CV death, nonfatal MI, nonfatal stroke) was consistent across frailty categories (not frail HR 0.84, more frail HR 0.70, most frail HR 0.92; P=.09 for interaction). Frailty itself was more likely to improve (OR 2.46; 95% CI 1.80–3.37) and less likely to worsen (OR 0.47; 95% CI 0.34–0.65) with semaglutide vs. placebo at 104 weeks. Quality-of-life gains were larger in frailer participants (P=.02 for interaction), and adverse event–related discontinuation rates were paradoxically lower with higher frailty (P<.001 for interaction).
- Post hoc, non-prespecified subgroup analysis limits causal inference. - The frailty index was constructed from available trial data and may not fully capture clinical frailty. - The trial excluded patients with diabetes, limiting generalizability to the broader GLP-1 RA–eligible population.
Frailty should not be used as a reason to withhold semaglutide in patients with CV disease and obesity — benefits on MACE, heart failure, hospitalization, and quality of life appear consistent or even enhanced across frailty levels. Frail patients may also experience meaningful improvement in frailty itself with treatment.
