semaglutide · Event-driven
SELECT
With a mean follow-up of 39.8 months, a major cardiovascular event occurred in 6.5% of patients on semaglutide 2.4 mg once weekly and in 8.0% on placebo.
Randomized controlled trial
SOUL: oral semaglutide (Rybelsus) and heart outcomes in diabetes
Over a mean follow-up of 47.5 months, a major cardiovascular event occurred in 12.0% of participants on oral semaglutide and 13.8% on placebo (hazard ratio 0.86; 95% CI, 0.77 to 0.96; p = 0.006).
McGuire DK et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. New England Journal of Medicine, 2025. DOI: 10.1056/NEJMoa2501006
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- Alex Gonzalez
- Last updated
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Key facts
- Drug
- semaglutide
- Design
- Randomized controlled trial
- Participants
- 9,650
- Duration
- Event-driven (follow-up is given in the results)
- Funding
- Novo Nordisk
- Registry
- NCT03914326
- Population
- 9,650 adults aged 50 or older with type 2 diabetes (HbA1c of 6.5 to 10.0%) and atherosclerotic cardiovascular disease, chronic kidney disease or both, randomized to oral semaglutide or placebo (4,825 per group), on top of standard care.
- Primary outcome
- First major cardiovascular event (cardiovascular death, nonfatal heart attack or nonfatal stroke) with once-daily oral semaglutide (maximum dose 14 mg) versus placebo, with a superiority hypothesis; major kidney events were a confirmatory secondary objective.
What it found
Over a mean follow-up of 47.5 months, a major cardiovascular event occurred in 12.0% of participants on oral semaglutide and 13.8% on placebo (hazard ratio 0.86; 95% CI, 0.77 to 0.96; p = 0.006). That equals 3.1 versus 3.7 events per 100 person-years. The confirmatory secondary objectives, including major kidney events, did not differ significantly between groups. Serious adverse effects occurred in 47.9% on oral semaglutide and 50.3% on placebo.
Limitations
Funded by Novo Nordisk, which makes semaglutide. It only included people with type 2 diabetes and cardiovascular or kidney disease, so it says nothing about people without diabetes. It studied oral semaglutide at doses of up to 14 mg a day, not the injectable form or the doses used for obesity.
What it means for you
SOUL is not a weight-loss trial: in people with type 2 diabetes and cardiovascular or kidney disease, semaglutide as a pill (Rybelsus) reduced the risk of heart attack, stroke or cardiovascular death compared with placebo (12.0% versus 13.8% over a mean follow-up of almost four years). It showed no significant difference in major kidney events, and it says nothing about people without diabetes or about the doses used for obesity. If you have diabetes and a history of heart disease, it is a useful finding to discuss with your doctor.
Further reading
- How Much Weight Do People Lose on Ozempic, Wegovy or Zepbound? Trial Data
- Ozempic vs Mounjaro (and Zepbound): Real Differences From the Trials and Labels
- What Happens When You Stop Ozempic, Wegovy or Zepbound: Weight Regain, Explained
- GLP-1 drug pages
- All study summaries
- Original paper: doi.org/10.1056/NEJMoa2501006
Sources
The original paper and the records consulted for this summary, with the date they were accessed.
- New England Journal of Medicine.McGuire DK, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025;392(20):2001-2012.accessed .
- National Library of Medicine (PubMed).PubMed record PMID 40162642 (abstract).accessed .
- ClinicalTrials.gov (National Library of Medicine).ClinicalTrials.gov record NCT03914326 (registration and primary outcome).accessed .