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

Objective:

To assess whether baseline frailty modified semaglutide’s cardiovascular effects and other outcomes in adults with established cardiovascular disease and overweight or obesity, without diabetes.

Approach:

Study design: Exploratory analysis of 17,604 participants in the randomized, double-blind, placebo-controlled SELECT trial.
Frailty assessment: A 31-item deficit-accumulation index classified participants as not frail (31%), intermediate frailty (47%), or greatest frailty (22%).
Outcomes: The primary outcome was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Researchers also assessed other clinical outcomes, quality of life, frailty changes over 104 weeks, and treatment discontinuation.

Key Findings:

The primary cardiovascular outcome occurred in 4.1% vs 4.9% of participants without frailty, 5.7% vs 8.1% with intermediate frailty, and 11.3% vs 12.2% with the greatest frailty, for semaglutide vs placebo, respectively.
Estimated relative hazard reductions were 16%, 30%, and 8% across the three frailty groups; there was no statistically significant interaction between baseline frailty and treatment.
Semaglutide’s favorable effects on heart failure outcomes, all-cause hospitalization, and all-cause mortality did not vary significantly by frailty category.
Quality-of-life improvements were larger among participants with greater frailty, mainly in mobility, self-care, and usual activities.
Frailty category improved in 34% of semaglutide recipients vs 18% of placebo recipients and worsened in 10% vs 19%, respectively.
Serious adverse events were less frequent with semaglutide across frailty groups, but permanent treatment discontinuation was more frequent; gastrointestinal events were the most common reason.

Interpretation:

The analysis found no definitive evidence that baseline frailty modified semaglutide’s cardiovascular effects. The authors described the findings as hypothesis-generating; cardiovascular benefit was not independently established in the least- and most-frail subgroups.

Limitations:

SELECT was not designed specifically to test whether frailty modified treatment effects, and subgroup analyses may have been underpowered.
Frailty was measured using accumulated health deficits; physical measures such as muscle weakness, gait speed, and falls were not systematically collected.
The analysis did not account for multiple comparisons.
Exclusion of people with diabetes, end-stage kidney disease, no established cardiovascular disease, or BMI below 27 limits generalizability.

Conclusion:

The researchers stated that baseline frailty should not necessarily preclude consideration of semaglutide in otherwise eligible patients with cardiovascular disease and overweight or obesity.