3 Key Takeaways
Plain English Summary- 01Core Finding
Data were analyzed from December 2024 to August 2025.
- 02Study Evidence
Tested in a randomized controlled trial (9650 participants) at the randomized clinical trial stage.
- 03Practical Meaning
Controlled trial findings show causal benefit under protocol rules; real-world effectiveness can vary across patients.
What This Means for You
Oral semaglutide reduced the risk of first plus subsequent 3-P MACE vs placebo (inactive comparison treatment), highlighting the benefit of oral semaglutide in reducing the total burden of clinical morbidity and mortality in this high-risk population.
The Discovery
To evaluate the effect of oral semaglutide vs placebo (inactive comparison treatment) on total 3-P MACE. 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. Occurrence of total (first and subsequent) 3-P MACE. 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 and 559 participants receiving oral semaglutide and placebo, respectively.
How It Works, Simply
This cardiology research focuses on cardiovascular hemodynamic & lipid pathway modulation. Researchers evaluated it using a randomized controlled trial (9650 participants) at the randomized clinical trial stage of medical research.
3 Key Takeaways
Clinical Takeaways- 01Core Finding
Data were analyzed from December 2024 to August 2025.
- 02Study Evidence
Tested in a randomized controlled trial (9650 participants) at the randomized clinical trial stage.
- 03Practical Meaning
Controlled trial findings show causal benefit under protocol rules; real-world effectiveness can vary across patients.
Key Numbers
Biological Mechanism & Study Design
Study Design & Cohort
Randomized controlled trial
Randomized controlled trial (9650 participants) · Randomized Clinical Trial
Biological Pathway & Modality
Cardiovascular hemodynamic & lipid pathway modulation
Intervention: First and Subsequent Major Cardiovascular Events With Oral Semaglutide in High-Risk
Experimental Findings & Endpoints
To evaluate the effect of oral semaglutide vs placebo on total 3-P MACE.
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. Occurrence of total (first and subsequent) 3-P MACE.
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 and 559 participants receiving oral semaglutide and placebo, respectively.
Clinical Translation & Practice Context
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.
The Bottom Line · Clinical Pearl
“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.”
Published in JAMA Cardiology · Current Stage: Randomized Clinical Trial
