Key result
Oral semaglutide reduces total 3-point major cardiovascular events by ~14% compared with placebo.
Why the study?
Oral semaglutide reduced first 3-point MACE in the SOUL trial, but its effects on subsequent events and total cardiovascular event burden were unknown.
Does once-daily oral semaglutide reduce total (first and subsequent) 3-point major adverse cardiovascular events compared with placebo in patients with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease?
RCT (n=9,650)
Double-blind
1:1
Yes
Does once-daily oral semaglutide reduce total (first and subsequent) 3-point major adverse cardiovascular events compared with placebo in patients with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease?
Answers are grounded in this paper and cite their sources.
Oral semaglutide reduces not only first but also subsequent major adverse cardiovascular events in patients with high-risk type 2 diabetes, lowering the total burden of cardiovascular morbidity and mortality.
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
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Marx et al. (2026) conducted an RCT in Type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease (n=9,650). Oral semaglutide vs. Placebo in addition to standard of care was evaluated on Occurrence of total (first and subsequent) 3-point major adverse cardiovascular events (3-P MACE: nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) (Mean ratio 0.86, 95% CI 0.76-0.97, p=0.01). Oral semaglutide reduced total (first and subsequent) 3-point major cardiovascular events compared with placebo.
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