Efficacy and Safety of Semaglutide According to Frailty Status: A Post Hoc Analysis of the SELECT Randomized Clinical Trial
- Design
- Randomized trial · 17604 participants · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had BMI 27 or higher and established cardiovascular disease (no diabetes); mean age 61.6 years, within the target range.
- Could weight loss explain it?
- PossiblyThe abstract reports no weight change, HbA1c change or mediation analysis; frailty-category comparisons are not a weight separation.
- Study tier
- Study tier 2MODERATE: a post hoc secondary analysis of a large randomized trial (17 604 participants) with hard outcomes; subgroup analyses of this kind sit below the main trial result.
- Assessment
- Version 4 · Two independent AI reviews agreed · Nov 7, 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.
This post hoc analysis of the SELECT trial looked at 17 604 adults with heart disease and a BMI of 27 or higher but no diabetes, grouped by how frail they were. Semaglutide's reduction in heart attack, stroke and cardiovascular death looked similar across frailty groups, though in the least and most frail groups the estimates were uncertain (HR 0.84 and 0.92, with confidence intervals crossing 1). Quality-of-life gains appeared larger in frailer people, and frailty was more likely to improve on semaglutide than on placebo.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 2.4 mg, once weekly
- Comparator
- placebo
- Primary outcome
- composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke (MACE), by frailty category
- Effect
- Primary outcome HR, 0.84 (95% CI, 0.65-1.07) if FI ≤0.210; HR, 0.70 (95% CI, 0.59-0.82) if FI 0.211-0.310; HR, 0.92 (95% CI, 0.76-1.10) if FI ≥0.311; P = .09 for interaction; heart failure composite, all-cause hospitalization and all-cause mortality reduced regardless of FI; FI more likely to improve (OR, 2.46) and less likely to worsen (OR, 0.47) vs placebo
- 95% confidence interval
- 95% CI, 0.65-1.07 (FI ≤0.210); 95% CI, 0.59-0.82 (FI 0.211-0.310); 95% CI, 0.76-1.10 (FI ≥0.311)
- P value
- P = .09 for interaction (primary outcome)
- Follow-up
- Not stated
- Adverse events
- HRs for adverse events leading to permanent discontinuation of semaglutide vs placebo appeared lower with higher baseline frailty (P < .001 for interaction)
- Limitations
- Post hoc subgroup analysis of one trial by a constructed frailty index; for the primary outcome, two of the three frailty-category confidence intervals cross 1.
Who was studied
- Mean age
- mean 61.6 (SD 8.9) years
- Sex distribution
- 72.3% male; 27.7% female
- Bmi min
- 27
- Obesity status
- overweight or obesity required (body mass index of 27 or higher)
- Diabetes status
- excluded
- Cvd status
- established cardiovascular disease required
- Ckd status
- not reported in abstract
- Baseline condition
- established cardiovascular disease with overweight/obesity
- Sample size
- 17604
- Inclusion exclusion
- adults with BMI 27 or higher and established cardiovascular disease, without diabetes
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 17604
- Randomization
- yes
- Blinding
- not stated
- Comparator
- placebo
- Follow up duration
- not stated
- Outcome type
- hard
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI, 0.65-1.07 (FI ≤0.210); 95% CI, 0.59-0.82 (FI 0.211-0.310); 95% CI, 0.76-1.10 (FI ≥0.311)
- Risk of bias
- not assessed
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- not reported in abstract
- 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.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 20, 2026 | 42747817 first ingestion |
| pubmed | Sep 20, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 20, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 20, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 20, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 27, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 27, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 27, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 27, 2026 | 42747817 duplicate matched on doi |
| pubmed | Sep 27, 2026 | 42747817 duplicate matched on doi |
| owner-review | Nov 6, 2026 | reviewed_by set to Carrie Schluter (2026-11-05) on the owner's own confirmation. The assessment is unchanged and still the auto-classifier's, so its extracted values stay withheld under the 2026-10-18 decision. |
| reextract | Nov 6, 2026 | drug_details.dose: '2.4 mg' -> '2.4 mg once weekly'. Q-043: manufacturer, drug_details.dose and the funding fields re-extracted by auto-classifier-v1.2. manufacturer no longer reads companies named only in the authors' conflicts statement (IN-062) and refuses a multi-company roster; dose is tied to the GLP-1 agent by name, never reads a concentration, records a multi-dose design whole and keeps a frequency written beside the amount; industry_funded, sponsor_role and funding_source read the conflicts statement's own sponsor sentences, a supplier counting as partial. Every other value is carried forward unchanged, evidence_level included. Owner decisions IN-064, 2026-11-06. |