{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T15:49:31Z","timestamp":1793202571066,"version":"4.5.0"},"reference-count":36,"publisher":"American Medical Association (AMA)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"abstract":"\n Importance<\/jats:title>\n Whether frailty influences the benefit-risk balance of glucagon-like peptide-1 receptor agonists (GLP-1 RA) is uncertain.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate whether frailty modifies the efficacy and safety of the GLP-1 RA semaglutide in adults with cardiovascular disease and overweight\/obesity.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n 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 \u22640.210), more frail (FI 0.211-0.310), and most frail (FI \u22650.311).<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Semaglutide, 2.4 mg, once weekly or placebo.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of 17\u202f604 participants, the mean (SD) age was 61.6 (8.9) years; 12\u202f732 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 \u22640.210; 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 \u22650.311;\n P<\/jats:italic>\n \u2009=\u2009.09 for interaction). Similar findings were observed when the FI was examined continuously (\n P<\/jats:italic>\n \u2009=\u2009.30 for interaction). Semaglutide additionally reduced the composite heart failure outcome (\n P<\/jats:italic>\n \u2009=\u2009.82 for interaction), all-cause hospitalization (\n P<\/jats:italic>\n \u2009=\u2009.71 for interaction), and all-cause mortality (\n P<\/jats:italic>\n \u2009=\u2009.28 for interaction) regardless of FI category. Benefits of semaglutide on EQ-5D-5L scores appeared larger with higher FI (\n P<\/jats:italic>\n \u2009=\u2009.02 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 (\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001 for interaction).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT03574597<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamacardio.2026.3566","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T15:01:14Z","timestamp":1789570874000},"source":"Crossref","is-referenced-by-count":2,"title":["Efficacy and Safety of Semaglutide According to Frailty Status"],"prefix":"10.1001","author":[{"given":"John W.","family":"Ostrominski","sequence":"first","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"},{"name":"Division of Endocrinology, Diabetes and Hypertension, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Plutzky","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M.","family":"Scirica","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Kees","family":"Hovingh","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"},{"name":"Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole Kleist","family":"Jeppesen","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Michael","family":"Lincoff","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildiko","family":"Lingvay","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\/Endocrinology and Peter O\u2019 Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hoffmann Morville","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Quiroga","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, 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