In nearly 10,000 people with type 2 diabetes and cardiovascular or kidney disease, daily oral semaglutide reduced the risk of major cardiovascular events by 14% compared to placebo over about 4 years.
14% reduction in MACEOral semaglutide reduced the composite of cardiovascular death, heart attack, and stroke vs. placebo (HR 0.86, P=0.006) in the SOUL trial
What the researchers found
Among 9,650 randomized participants with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both:
- **Primary outcome (MACE)**: 12.0% in the oral semaglutide group vs. 13.8% in the placebo group (HR 0.86; 95% CI 0.77-0.96; P = 0.006)
- Incidence rates: 3.1 vs. 3.7 events per 100 person-years
- Mean follow-up: 47.5 months (median 49.5 months)
- The confirmatory secondary outcome of major kidney disease events did not differ significantly between groups
- Serious adverse events: 47.9% vs. 50.3% (numerically lower with semaglutide)
- Gastrointestinal disorders: 5.0% vs. 4.4% (slightly higher with semaglutide, as expected)
Why it matters
While injectable semaglutide had already shown cardiovascular benefits, this is the first large-scale trial proving the oral formulation also protects the heart. For the millions of patients who prefer pills over injections, this is a game-changer — they can now get cardiovascular protection from an oral GLP-1 drug. Published in the NEJM with nearly 10,000 participants and 4 years of follow-up, this represents the highest tier of clinical evidence.
How the study worked
This was a double-blind, placebo-controlled, event-driven, superiority trial (SOUL). Participants aged 50+ with type 2 diabetes (HbA1c 6.5-10.0%) and established atherosclerotic cardiovascular disease, chronic kidney disease, or both were randomized to once-daily oral semaglutide (up to 14 mg) or placebo, added to standard care. The primary outcome was time to first major adverse cardiovascular event (MACE: cardiovascular death, nonfatal MI, or nonfatal stroke).
What this study cannot tell us
The confirmatory secondary outcome for kidney disease events was not significantly different, so oral semaglutide's renal benefits remain unproven. The trial population was predominantly high-risk with established cardiovascular or kidney disease, so results may not generalize to lower-risk patients. The maximum oral dose of 14 mg is lower than injectable semaglutide doses used for weight loss, and the cardiovascular benefit may be partially driven by weight loss and metabolic improvements rather than direct cardiac effects. The trial was funded by Novo Nordisk, the manufacturer.
How to read the evidence
This is a large, double-blind, placebo-controlled, randomized superiority trial published in the New England Journal of Medicine — the gold standard for clinical evidence. With 9,650 participants and nearly 4 years of follow-up, it provides robust evidence for oral semaglutide's cardiovascular efficacy.
When this study was published
Published in 2025, this is a landmark contemporary trial that will likely influence clinical practice guidelines for type 2 diabetes management going forward.
The bigger picture
The SOUL trial is a milestone in GLP-1 therapeutics. It establishes oral semaglutide not just as a glucose-lowering agent but as a cardiovascular protective therapy for high-risk diabetic patients. Combined with the SELECT trial (injectable semaglutide in obesity) and FLOW trial (semaglutide in kidney disease), this further cements GLP-1 receptor agonists as multi-benefit therapies spanning metabolic, cardiovascular, and potentially renal disease — now available in an oral formulation.
Questions still open
- Would higher doses of oral semaglutide (beyond 14 mg) produce even greater cardiovascular benefit?
- Why did the kidney disease outcomes not reach significance, and would a longer follow-up period change that result?
- How does the cardiovascular benefit of oral semaglutide compare head-to-head with SGLT2 inhibitors in this patient population?
Common questions
Is this the same semaglutide used for weight loss?
Should all people with type 2 diabetes take oral semaglutide?
Read the original research
Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.
The New England journal of medicine, 392(20), 2001-2012
Citation
McGuire, Darren K; Marx, Nikolaus; Mulvagh, Sharon L; Deanfield, John E; Inzucchi, Silvio E; Pop-Busui, Rodica; Mann, Johannes F E; Emerson, Scott S; Poulter, Neil R; Engelmann, Mads D M; Ripa, Maria Sejersten; Hovingh, G Kees; Brown-Frandsen, Kirstine; Bain, Stephen C; Cavender, Matthew A; Gislum, Mette; David, Jens-Peter; Buse, John B. (2025). Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.. The New England journal of medicine, 392(20), 2001-2012. https://doi.org/10.1056/NEJMoa2501006