Efficacy and Safety of Semaglutide According to Frailty Status: A Post Hoc Analysis of the SELECT Randomized Clinical Trial
- Design
- Randomized trial · 5432 participants · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different population[Auto] Participants had obesity/overweight without diabetes (mean age 61.6); effects may be mediated by weight loss.
- Could weight loss explain it?
- Possibly[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.
- Study tier
- Study tier 1[Auto] Large randomized trial with clinical outcomes (auto-provisional; risk of bias and consistency not yet assessed).
- Assessment
- Version 1 · automatic, not yet reviewed by a person · Sep 20, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
[Auto, unreviewed; quoted from abstract conclusions] This study found that semaglutide demonstrated beneficial effects on a broad range of clinical outcomes in SELECT, without detectable heterogeneity by baseline FI. Benefits of semaglutide on health-related quality of life appeared greater with higher FI.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 2.4 mg
- Comparator
- placebo
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- Not stated
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Mean age
- 61.6
- Obesity status
- obesity/overweight present (all or most)
- Diabetes status
- excluded (no diabetes)
- Cvd status
- cardiovascular disease present in population (see abstract)
- Sample size
- 5432
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 5432
- Randomization
- yes
- Blinding
- not stated
- Comparator
- placebo
- Follow up duration
- not stated
- Outcome type
- hard
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI, 0
- Risk of bias
- not assessed (auto)
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- None identified
- Sponsor role
- not reported in abstract
- Author conflicts
- not available in metadata
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[IMPORTANCE] Whether frailty influences the benefit-risk balance of glucagon-like peptide-1 receptor agonists (GLP-1 RA) is uncertain. [OBJECTIVE] To evaluate whether frailty modifies the efficacy and safety of the GLP-1 RA semaglutide in adults with cardiovascular disease and overweight/obesity. [DESIGN, SETTING, AND PARTICIPANTS] In this secondary analysis of a randomized clinical trial, participants were adults with a body mass index of 27 or higher and established cardiovascular disease without diabetes. A 31-item frailty index (FI) was constructed using the Rockwood cumulative deficit approach; participants were categorized as not frail (FI ≤0.210), more frail (FI 0.211-0.310), and most frail (FI ≥0.311). [INTERVENTIONS] Semaglutide, 2.4 mg, once weekly or placebo. [MAIN OUTCOMES AND MEASURES] The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Key secondary clinical outcomes, health-related quality-of-life (assessed by EuroQol 5-Dimension 5-Level [EQ-5D-5L] score), and safety events were additionally examined. [RESULTS] Of 17 604 participants, the mean (SD) age was 61.6 (8.9) years; 12 732 patients (72.3%) were male and 4872 were female (27.7%). A total of 5432 patients (31%) had an FI up to 0.210, 8349 (47%) had an FI of 0.211 to 0.310, and 3823 (22%) had an FI 0.311 or higher. The incidence of the primary outcome increased with higher baseline FI. Benefits of semaglutide vs placebo on the primary outcome appeared consistent across the FI categories (hazard ratio [HR], 0.84; 95% CI, 0.65-1.07, if the FI was ≤0.210; HR, 0.70; 95% CI, 0.59-0.82, if the FI was 0.211-0.310; HR, 0.92; 95% CI, 0.76-1.10, if the FI was ≥0.311; P = .09 for interaction). Similar findings were observed when the FI was examined continuously (P = .30 for interaction). Semaglutide additionally reduced the composite heart failure outcome (P = .82 for interaction), all-cause hospitalization (P = .71 for interaction), and all-cause mortality (P = .28 for interaction) regardless of FI category. Benefits of semaglutide on EQ-5D-5L scores appeared larger with higher FI (P = .02 for interaction). Between baseline and week 104, FI category was more likely to improve (odds ratio [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. The HRs for adverse events leading to permanent discontinuation of semaglutide vs placebo appeared lower among participants with higher baseline FI (P < .001 for interaction). [CONCLUSIONS AND RELEVANCE] This study found that semaglutide demonstrated beneficial effects on a broad range of clinical outcomes in SELECT, without detectable heterogeneity by baseline FI. Benefits of semaglutide on health-related quality of life appeared greater with higher FI. [TRIAL REGISTRATION] ClinicalTrials.gov Identifier: NCT03574597.