Post Hoc SELECT Analysis Finds Semaglutide's Cardiovascular Benefit Held Regardless of Frailty

JAMA Cardiology published a post hoc secondary analysis of the SELECT cardiovascular outcomes trial online on September 16, 2026, examining whether frailty changes the balance of benefits and risks of semaglutide. The analysis was led by John W. Ostrominski of Brigham and Women's Hospital and Harvard Medical School, with co-authors from Novo Nordisk A/S, Cleveland Clinic, and UT Southwestern Medical Center, among other institutions. Several authors are Novo Nordisk employees; Novo Nordisk manufactures semaglutide and markets it as Wegovy, Ozempic, and Rybelsus.

SELECT (ClinicalTrials.gov identifier NCT03574597) enrolled 17,604 adults with a body mass index of 27 or higher and established cardiovascular disease but no diabetes, randomizing them to once-weekly semaglutide 2.4 mg or placebo. The trial previously reported that semaglutide reduced the composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke compared with placebo. For this analysis, researchers built a 31-item frailty index using the Rockwood cumulative deficit approach and classified participants as not frail (frailty index of 0.210 or lower, 31% of the trial, 5,432 people), more frail (0.211 to 0.310, 47%, 8,349 people), or most frail (0.311 or higher, 22%, 3,823 people). The trial population was 72.3% male and 27.7% female, with a mean age of 61.6 years.

The incidence of the primary cardiovascular outcome increased as baseline frailty increased. Semaglutide's benefit on that outcome was statistically consistent across frailty categories: the hazard ratio versus placebo was 0.84 (95% confidence interval, 0.65 to 1.07) in the not-frail group, 0.70 (95% CI, 0.59 to 0.82) in the more-frail group, and 0.92 (95% CI, 0.76 to 1.10) in the most-frail group, with a formal test for interaction across the categories at p=.09, indicating no significant heterogeneity. The same held when frailty was analyzed as a continuous measure rather than in categories (p=.30 for interaction). Semaglutide's reductions in the composite heart failure outcome, all-cause hospitalization, and all-cause mortality also did not vary meaningfully by frailty status.

Semaglutide's effect on health-related quality of life, measured with the EQ-5D-5L instrument, was larger among participants with higher baseline frailty (p=.02 for interaction). Between baseline and week 104, participants on semaglutide were more likely than those on placebo to see their frailty category improve (odds ratio 2.46, 95% CI 1.80 to 3.37) and less likely to see it worsen (odds ratio 0.47, 95% CI 0.34 to 0.65). The hazard ratios for adverse events leading to permanent treatment discontinuation were lower for semaglutide relative to placebo among participants with higher baseline frailty, a difference the authors flag as statistically significant (p<.001 for interaction) without concluding semaglutide is better tolerated in frail patients generally.

The authors conclude that semaglutide's cardiovascular and mortality benefits in SELECT did not show detectable heterogeneity by baseline frailty, and that its quality-of-life benefit appeared larger in participants who were more frail at enrollment. As a post hoc, non-prespecified subgroup analysis, the findings are considered hypothesis-generating rather than definitive, and the frailty index used was constructed from trial data rather than a bedside frailty assessment tool used in routine clinical practice.

Semaglutide is already approved by the FDA and the European Medicines Agency and registered with Australia's Therapeutic Goods Administration, marketed as Ozempic and Rybelsus for type 2 diabetes and Wegovy for chronic weight management and cardiovascular risk reduction in adults with established cardiovascular disease and overweight or obesity. This analysis does not change that regulatory status in any market and does not establish that semaglutide is appropriate for every frail or elderly patient. It is not treatment or dosing guidance; decisions about GLP-1 receptor agonist therapy in older adults, including those with frailty, should be made individually with a qualified clinician.