Frailty may not limit semaglutide benefits

Patients with greater frailty showed larger improvements in health-related quality of life, while cardiovascular treatment effects did not differ significantly across frailty categories.

By
Andrea Surnit
October 16, 2026
5 min

MDSpire News

Overview

In a post hoc analysis of 17,604 SELECT participants with established cardiovascular disease, overweight or obesity, and no diabetes, semaglutide was associated with favorable cardiovascular outcomes across baseline frailty categories, with no statistically significant treatment-by-frailty interaction. Greater frailty was associated with higher cardiovascular event rates, while semaglutide recipients had more frequent frailty-category improvement and larger health-related quality-of-life gains in the more frail groups. The subgroup findings are exploratory, and treatment discontinuation was more frequent with semaglutide.

Background

Frailty can affect cardiovascular risk and health-related quality of life among people with established cardiovascular disease and overweight or obesity. SELECT enrolled adults aged 45 years or older with established cardiovascular disease and a body mass index of at least 27, excluding people with diabetes. Participants were randomized to once-weekly semaglutide 2.4 mg or placebo, and frailty was classified using a 31-item index of accumulated health deficits. The FDA added a cardiovascular risk-reduction indication for semaglutide 2.4 mg in eligible adults with established cardiovascular disease and overweight or obesity in March 2024.

Data Highlights

Baseline frailty category	Primary cardiovascular outcome, semaglutide vs placebo	Relative hazard reduction	Permanent treatment discontinuation, semaglutide vs placebo
Not frail (n=5,432; 31%)	4.1% vs 4.9%	16%	15.5% vs 5.5%
Intermediate frailty (n=8,349; 47%)	5.7% vs 8.1%	30%	16.8% vs 8.3%
Greatest frailty (n=3,823; 22%)	11.3% vs 12.2%	8%	17.6% vs 11.7%

The primary outcome was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. There was no statistically significant interaction between baseline frailty and treatment; cardiovascular benefit was not independently established in the least and most frail subgroups.

Key Findings

The analysis included 17,604 SELECT participants; mean age was 61.6 years. Frailty categories were defined using a 31-item accumulated-deficit index.
Primary cardiovascular outcome rates rose with greater frailty in both treatment groups. Among placebo recipients, incidence increased from 1.5 events per 100 person-years in those without frailty to 3.9 among those with the greatest frailty.
Semaglutide was associated with favorable effects on the composite heart failure outcome, all-cause hospitalization, and all-cause mortality, without statistically significant variation across frailty categories.
Health-related quality-of-life improvements were larger among participants with greater frailty, primarily reflecting mobility, self-care, and usual activities.
Frailty category improved over 104 weeks in 34% of semaglutide recipients versus 18% of placebo recipients; it worsened in 10% versus 19%, respectively.
Serious adverse events were less frequent with semaglutide across frailty categories, but permanent treatment discontinuation was more frequent; gastrointestinal events were the most common reason.

Clinical Implications

The authors state that baseline frailty should not necessarily preclude consideration of semaglutide in otherwise eligible patients with cardiovascular disease and overweight or obesity. The analysis was exploratory and hypothesis-generating; frailty was measured by accumulated health deficits rather than physical measures such as muscle weakness, gait speed, or falls, and the study was not designed to test frailty as a treatment-effect modifier.

Conclusion

In SELECT, semaglutide-associated cardiovascular outcomes did not vary significantly by baseline frailty, while quality-of-life and frailty-status changes favored treatment in the reported analyses. These findings require cautious interpretation because the subgroup analysis was not designed to establish treatment effects within individual frailty categories.