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Efficacy and Safety of Semaglutide According to Frailty Status
John W. OstrominskiJorge PlutzkyBenjamin M. SciricaG. Kees HovinghOle Kleist JeppesenA. Michael LincoffIldiko LingvayThomas MorvilleMaria QuirogaYael SoferMiguel Urina-TrianaVanita R. ArodaSELECT Trial InvestigatorsDjamel E. NiboucheMohamed ChettibiNaima HammoudiAlejandro PortoAlejandra OviedoHugo D. SanabriaMarcelo CasasEduardo FariasErnesto DurontoCarolina ChaconAdriana VillarinoJavier M. FariasCésar J. ZaidmanClaire MorbeyDavid M. ColquhounElif I. EkinciMelissa LeungMaged WilliamKaram KostnerMitra ShiraziDavid CrossJohn AmerenaPeter PurnellMargaret ArstallWalter P. AbhayaratnaHermann ToplakR. PragerBernhard LudvikALEXANDRA KAUTZKY-WILLERUrsula HanuschElmar AignerSusanne KäserMichel De PauwPhilippe VanduynhovenPhilippe Van De BorneChris VercammenJan VerwerftMathias VrolixLuiz A. TurattiJose F. SaraivaCíntia CercatoAdrian P. KormannSilmara O. LeitePaulo RossiFlávia B. ArantesLilia N. MaiaSergio E. KaiserAlberto G. FonsecaHugo LisboaDENISE FRANCOJosé C. NicolauPedro S. FarskyLuiz E. RittAssen GoudevDobrin VassilevNikolay RunevB. GeorgievTzvetana KatovaIvo PetrovВалери ГелевMaria MilanovaArman PostadzhiyanMariya TokmakovaY. YotovSnezhanka Tisheva- GospodinovaDotska MinkovaZhulieta R. Prakova-TenevaSvetla VasilevaAlan EganGeorge TsoukasSubodh VermaRonald BourgeoisPierre FilteauRam VijayaraghavanMichael HartleibTamara SpaicJohn StewartAmritanshu- S. PandeyRemi Rabasa-LhoretFrançois St-MauriceJames Y. ChaSue PedersenRoy AllisonPaul PoirierMarie‐France LangloisDavid LauY. Robitaille
Key result
Semaglutide consistently reduces major cardiovascular events across all frailty categories.
- n=17,604
Why the study?
Whether frailty influences the benefit-risk balance of GLP-1 receptor agonists like semaglutide in adults with cardiovascular disease and overweight/obesity was uncertain.
Does semaglutide 2.4 mg once weekly reduce cardiovascular events in adults with cardiovascular disease and overweight/obesity regardless of frailty status?
Key Points
- To determine whether baseline frailty status modifies the clinical efficacy and safety of semaglutide in adults with cardiovascular disease and overweight or obesity without diabetes.
- Secondary analysis of the SELECT randomized clinical trial (NCT03574597) evaluating 17,604 adults with BMI ≥27 and established cardiovascular disease assigned to once-weekly semaglutide 2.4 mg or placebo.
- Frailty was assessed using a 31-item cumulative deficit frailty index (FI) categorizing participants as not frail (FI ≤0.210; n=5,432), more frail (FI 0.211–0.310; n=8,349), or most frail (FI ≥0.311; n=3,823).
- Semaglutide reduced the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke consistently across frailty categories: FI ≤0.210 (HR 0.84, 95% CI 0.65–1.07), FI 0.211–0.310 (HR 0.70, 95% CI 0.59–0.82), and FI ≥0.311 (HR 0.92, 95% CI 0.76–1.10; P = .09 for interaction; continuous FI interaction P = .30).
- Reductions in heart failure outcomes (interaction P = .82), all-cause hospitalization (interaction P = .71), and all-cause mortality (interaction P = .28) were consistent across all frailty strata.
- Semaglutide was associated with greater improvements in EQ-5D-5L quality-of-life scores in higher FI groups (interaction P = .02), increased odds of FI category improvement by week 104 (OR 2.46, 95% CI 1.80–3.37), and decreased odds of worsening frailty (OR 0.47, 95% CI 0.34–0.65).
Study Design
Type
RCT (n=17,604)
Randomization
randomized
Structured PICO
Does semaglutide 2.4 mg once weekly reduce cardiovascular events in adults with cardiovascular disease and overweight/obesity regardless of frailty status?
P
Population
17,604 adults with established cardiovascular disease, overweight/obesity, and no diabetes, evaluated by baseline frailty index.
I
Intervention
Semaglutide 2.4 mg once weekly
C
Comparator
Placebo
O
Outcome
Composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal strokecomposite
Semaglutide 2.4 mg once weekly provides consistent cardiovascular benefits and improves quality of life across varying levels of frailty in patients with established cardiovascular disease and overweight or obesity.
Ask about this paper
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“There are persistent concerns around the balance of risk and benefit with GLP-1 receptor agonist–based medications, such as semaglutide, in this population. As a result, some healthcare providers are hesitant to prescribe GLP-1s for older adults.”
KGKelley GregorovicRN, nurse practitioner
“Frailty is something we absolutely need to consider when we're treating older adults. But I don't want frailty alone to become a reason that patients can't access these medications, particularly when we know the benefits can extend well beyond weight loss.”
Implication
Supports semaglutide use across frailty levels in CVD; extends SELECT benefits to frail subgroups without heterogeneity.
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
JAMA Cardiology · RCT. Semaglutide's CV benefit was consistent across frailty levels, without detectable heterogeneity Efficacy and Safety of Semaglutide According to Frailty Status 17,604 adults: Established CVD, overweight or obesity, no diabetes. Analysed by frailty index category: Semaglutide 2.4 mg weekly vs Placebo. 0.70 to 0.92 Hazard ratios across frailty strata. CV death, MI, stroke: consistent across frailty levels. 2.46 odds ratio: Higher odds of frailty improving by week 104. Dr. John W. Ostrominski (obesity medicine specialist · Brigham and Women's Hospital and Harvard Medical School): “There are persistent concerns around the balance of risk and benefit with GLP-1 receptor agonist–based medications, such as semaglutide, in this population.” From their public comments on the paper Bottom line: Supports semaglutide use across frailty levels in CVD with overweight or obesity.
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Cite This Study
Ostrominski et al. (2026) conducted an RCT in cardiovascular disease and overweight/obesity (n=17,604). Semaglutide vs. placebo was evaluated on cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Semaglutide consistently reduced cardiovascular death, nonfatal MI, and nonfatal stroke across frailty categories (HRs 0.70 to 0.92; P=0.09 for interaction) without detectable heterogeneity.