Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes

McGuire DK, Marx N, Mulvagh SL, Deanfield JE, Inzucchi SE, Pop-Busui R, Mann JF, Emerson SS, Poulter NR, Engelmann MD, Ripa MS, Hovingh GK, Brown-Frandsen K, Bain SC, Cavender MA, Gislum M, David JP, Buse JB (2025)

Publication Type: Journal article

Publication year: 2025

Journal

New England Journal of Medicine Massachusetts Medical Society

Book Volume: 392

Pages Range: 2001-2012

Journal Issue: 20

DOI: 10.1056/NEJMoa2501006

Abstract

Background The cardiovascular safety of oral semaglutide, a glucagon-like peptide 1 receptor agonist, has been established in persons with type 2 diabetes and high cardiovascular risk. An assessment of the cardiovascular efficacy of oral semaglutide in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both is needed. Methods In this double-blind, placebo-controlled, event-driven, superiority trial, we randomly assigned participants who were 50 years of age or older, had type 2 diabetes with a glycated hemoglobin level of 6.5 to 10.0%, and had known atherosclerotic cardiovascular disease, chronic kidney disease, or both to receive either once-daily oral semaglutide (maximal dose, 14 mg) or placebo, in addition to standard care. The primary outcome was major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis. The confirmatory secondary outcomes included major kidney disease events (a five-point composite outcome). Results Among the 9650 participants who had undergone randomization, the mean (±SD) follow-up was 47.5±10.9 months, and the median follow-up was 49.5 months. A primary-outcome event occurred in 579 of the 4825 participants (12.0%; incidence, 3.1 events per 100 person-years) in the oral semaglutide group, as compared with 668 of the 4825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P=0.006). The results for the confirmatory secondary outcomes did not differ significantly between the two groups. The incidence of serious adverse events was 47.9% in the oral semaglutide group and 50.3% in the placebo group; the incidence of gastrointestinal disorders was 5.0% and 4.4%, respectively. Conclusions Among persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the use of oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo, without an increase in the incidence of serious adverse events.

Involved external institutions

Novo Nordisk A/S DK Denmark (DK) University of North Carolina at Chapel Hill US United States (USA) (US) University of Texas Southwestern Medical Center (UT Southwestern) US United States (USA) (US) Universitätsklinikum Aachen (UKA) DE Germany (DE) Dalhousie University CA Canada (CA) University College London (UCL) GB United Kingdom (GB) Yale School of Medicine US United States (USA) (US) Oregon Health and Science University (OSHU) US United States (USA) (US) LMU Klinikum DE Germany (DE) University of Washington US United States (USA) (US) Imperial College London / The Imperial College of Science, Technology and Medicine GB United Kingdom (GB) Swansea University GB United Kingdom (GB)

How to cite

APA:

McGuire, D.K., Marx, N., Mulvagh, S.L., Deanfield, J.E., Inzucchi, S.E., Pop-Busui, R.,... Buse, J.B. (2025). Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. New England Journal of Medicine, 392(20), 2001-2012. https://doi.org/10.1056/NEJMoa2501006

MLA:

McGuire, Darren K., et al. "Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes." New England Journal of Medicine 392.20 (2025): 2001-2012.

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