First and Subsequent Major Cardiovascular Events With Oral Semaglutide in High-Risk Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial

Importance In the Semaglutide Cardiovascular Outcomes Trial (SOUL), oral semaglutide reduced the risk of a first 3-point major adverse cardiovascular event (3-P MACE; including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular [CV] death). Total event analyses, assessing both first and subsequent events, can contribute to a better understanding of the impact of interventions on the total burden of disease; however, the effects of oral semaglutide on subsequent events are unknown. Objective To evaluate the effect of oral semaglutide vs placebo on total 3-P MACE. Design, Setting, and Participants This was a prespecified secondary analysis of the double-blind, placebo-controlled, event-driven, phase 3b SOUL randomized clinical trial, conducted from June 2019 to September 2024 with a median (IQR) follow-up of 49.5 (44.0-54.9) months at 444 centers in 33 countries. Participants had type 2 diabetes and atherosclerotic CV disease and/or chronic kidney disease. Data were analyzed from December 2024 to August 2025. Interventions Once-daily oral semaglutide (maximal dose 14 mg) or placebo, in addition standard of care. Main Outcomes and Measures Occurrence of total (first and subsequent) 3-P MACE. Results Overall, 9650 participants (median [IQR] age, 66.0 [61.0-72.0] years; 6860 [71.1%] male) were randomized 1:1. In the oral semaglutide group, fewer first and subsequent 3-P MACE occurred (683 total; 579 first and 104 subsequent events) compared with placebo (791 total; 668 first and 123 subsequent events) (mean ratio, 0.86; 95% CI, 0.76-0.97; P = .01). For the end point of 3-P MACE plus non-CV death, there were 138 fewer total events with oral semaglutide (910 events) compared with placebo (1048 events) (mean ratio, 0.87; 95% CI, 0.79-0.95; P = .004). As previously reported, adverse events led to treatment discontinuation in 749 (15.5%) and 559 (11.6%) participants receiving oral semaglutide and placebo, respectively. Conclusions Oral semaglutide reduced the risk of first plus subsequent 3-P MACE vs placebo, highlighting the benefit of oral semaglutide in reducing the total burden of clinical morbidity and mortality in this high-risk population. Trial Registration ClinicalTrials.gov Identifier: NCT03914326

Authors

Institutions

Publication Details

Journal
JAMA Cardiology
Published
2026-11-11
DOI
https://doi.org/10.1001/jamacardio.2026.4944
Primary Topic
Diabetes Treatment and Management
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
article

First and Subsequent Major Cardiovascular Events With Oral Semaglutide in High-Risk Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial

G. Kees Hovingh, Bruno Lapauw, Silvio E. Inzucchi, Naresh Aggarwal et al.
JAMA Cardiology
Diabetes Treatment and Management
article

First and Subsequent Major Cardiovascular Events With Oral Semaglutide in High-Risk Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial

G. Kees Hovingh, Bruno Lapauw, Silvio E. Inzucchi, Naresh Aggarwal, Mariano I. Chahin, José Francisco Kerr Saraiva, Richard H. Tytus, Robert Schlosser, Guy Tellier, Andreas L. Birkenfeld, Linong Ji, Zubin Punthakee, Eder A. Hernández-Ruiz, Francis Duyck, Srecko Tusek, Pardeep S. Jhund, Rodica Pop‐Busui, Nikolaus Marx, Srečko Marušić, Martin Haluzı́k, Žaklina Davicevic-Elez, Sharon L. Mulvagh, Gabriela Román, Ignacio J. Mackinnon, Sorin G. Beca, Robinson Sánchez García, Silvija Canecki-Varžić, Christophe E.M. De Block, Rudolf Prager, João Eduardo Nunes Salles, Monika Kellerer, John Eric Deanfield, John B. Buse, Federico Pérez Manghi, Johannes F.E. Mann, Hirotaka Watada, Luiz Alberto Andreotti Turatti, Jelena Vučak Lončar, Thomas van Bemmel, Evelyn Fließer-Görzer, SUE PEDERSEN, Virginia Esther Visco, John Weisnagel, Cecilia Luquez, Borys Mankovsky, Daniel Leonardo Piskorz, Silmara Oliveira Leite, Kim Alexander Connelly, Alex N. Videmark, P Schelde, Alberto J. Lorenzatti, José M Pozzi, HARPREET SINGH BAJAJ, Guoyue Yuan, Carolyn S.P. Lam, Aslam Amod, Maria Helena Vidotti, Christoph F. Ebenbichler, Darren K. McGuire, Neil R Poulter, Shih‐Te Tu, Juan José Gorgojo Martínez, Cyrus V Desouza, Michael A. Tsoukas, Luis Noronha, Matthew Aaron Cavender, Vesna Šimegi-Đekić, D Rahelić, Kun Ho Yoon, Denise R. Franco, John G. B. Mancini, Mansoor Husain, Rosangela Roginski Rea, Søren Gregersen, Francis C. C. Chow, Hugo R. Kurtz Lisboa, Thomas P. P. Ransom, Miguel H Bustamante Labarta, Alberto Gomes Taques Fonseca, Mads D.M. Engelmann, Derrick Musinga, Peter Fasching, A. Angelo Cadena Bonfanti, Lucrecia Nardone, Ivan D. Hernandez Erazo, José Francisco, SOUL Study Group, Xinhua Ye, Fang Bian, Ellen Heyns, Hani Alasaad, Thomas Pieber, Rosario Arechavaleta, Jun Liu, Juan E. Gómez Mesa, Chantal Mathieu, Tina Ticinovic Kurir, Xiaolin Dong
article en

Abstract

Importance In the Semaglutide Cardiovascular Outcomes Trial (SOUL), oral semaglutide reduced the risk of a first 3-point major adverse cardiovascular event (3-P MACE; including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular [CV] death). Total event analyses, assessing both first and subsequent events, can contribute to a better understanding of the impact of interventions on the total burden of disease; however, the effects of oral semaglutide on subsequent events are unknown. Objective To evaluate the effect of oral semaglutide vs placebo on total 3-P MACE. Design, Setting, and Participants This was a prespecified secondary analysis of the double-blind, placebo-controlled, event-driven, phase 3b SOUL randomized clinical trial, conducted from June 2019 to September 2024 with a median (IQR) follow-up of 49.5 (44.0-54.9) months at 444 centers in 33 countries. Participants had type 2 diabetes and atherosclerotic CV disease and/or chronic kidney disease. Data were analyzed from December 2024 to August 2025. Interventions Once-daily oral semaglutide (maximal dose 14 mg) or placebo, in addition standard of care. Main Outcomes and Measures Occurrence of total (first and subsequent) 3-P MACE. Results Overall, 9650 participants (median [IQR] age, 66.0 [61.0-72.0] years; 6860 [71.1%] male) were randomized 1:1. In the oral semaglutide group, fewer first and subsequent 3-P MACE occurred (683 total; 579 first and 104 subsequent events) compared with placebo (791 total; 668 first and 123 subsequent events) (mean ratio, 0.86; 95% CI, 0.76-0.97; P = .01). For the end point of 3-P MACE plus non-CV death, there were 138 fewer total events with oral semaglutide (910 events) compared with placebo (1048 events) (mean ratio, 0.87; 95% CI, 0.79-0.95; P = .004). As previously reported, adverse events led to treatment discontinuation in 749 (15.5%) and 559 (11.6%) participants receiving oral semaglutide and placebo, respectively. Conclusions Oral semaglutide reduced the risk of first plus subsequent 3-P MACE vs placebo, highlighting the benefit of oral semaglutide in reducing the total burden of clinical morbidity and mortality in this high-risk population. Trial Registration ClinicalTrials.gov Identifier: NCT03914326

JAMA Cardiology
University of North Carolina at Chapel Hill (US), Parkland Health & Hospital System (US), Dalhousie University (CA), Oregon Health & Science University (US), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Novo Nordisk (Denmark) (DK), Iuliu Hațieganu University of Medicine and Pharmacy (RO), Universitair Ziekenhuis Leuven (BE), Gelre Hospitals (NL), Yale University (US), Juntendo University (JP), Universitätsklinikum Aachen (DE), Institute of Clinical and Experimental Medicine (CZ), University College London (GB), Imperial College London (GB), Universidade Federal do Paraná (BR), The University of Texas Southwestern Medical Center (US), RWTH Aachen University (DE)
Diabetes Treatment and Management
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon