Clinical Report: Frailty may not limit semaglutide benefits

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

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.

Related Resources & Content

1. SELECT investigators, JAMA Cardiology, Year not provided — Efficacy and Safety of Semaglutide According to Frailty Status: A Post Hoc Analysis of the SELECT Randomized Clinical Trial
2. Lincoff et al., New England Journal of Medicine, 2023 — Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
3. U.S. Food and Drug Administration, 2024 — FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight
4. MDSpire News — Waist Loss Only Part of Semaglutide’s Power
5. MDSpire News — Semaglutide Users Face Increased Gastroparesis Risk
6. mdspire news — Semaglutide Study of COVID-19 Mortality
7. JAMA Ophthalmology — Data and Timing-Related Concerns About Semaglutide and NAION Risk
8. Efficacy and Safety of Semaglutide According to Frailty Status: A Post Hoc Analysis of the SELECT Randomized Clinical Trial
9. FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight
10. American College of Cardiology Issues Guidance on Weight Management Drugs - American College of Cardiology
11. 2023 Guideline for the Management of Patients With Chronic Coronary Disease - Professional Heart Daily | American Heart Association
12. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association
13. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
14. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial - PMC
15. Effect of Semaglutide on Regression and Progression of Glycemia in People With Overweight or Obesity but Without Diabetes in the SELECT Trial - PMC
16. Effect of semaglutide on mortality and cardiovascular events in patients at high cardiovascular risk: an updated systematic review and meta-analysis | European Journal of Preventive Cardiology | Oxford Academic
17. Glucagon‐Like Peptide‐1 Receptor Agonists and Major Adverse Cardiovascular Events in Patients With and Without Diabetes: A Meta‐Analysis of Randomized‐Controlled Trials - PMC
18. Cardiovascular benefits of semaglutide: a systematic review and meta-analysis of randomized controlled trials | BMC Cardiovascular Disorders | Springer Nature Link