Summary: In 9650 adults aged 50 years or older with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both, once-daily oral semaglutide 14 mg reduced major adverse cardiovascular events compared with placebo over a median 49.5 months (12.0% vs 13.8%; hazard ratio 0.86; 95% CI 0.77 to 0.96; P=0.006). Confirmatory kidney outcomes did not differ significantly, and serious adverse events were not increased.
PICO Summary
| Element | Detail |
|---|---|
| Population | 9650 adults aged 50 years or older with type 2 diabetes (HbA1c 6.5 to 10.0%) and known atherosclerotic cardiovascular disease, chronic kidney disease, or both; double-blind, placebo-controlled, event-driven, multinational superiority randomised controlled trial (SOUL) |
| Intervention | Once-daily oral semaglutide, maximal dose 14 mg, plus standard care (n=4825) |
| Comparison | Matching placebo plus standard care (n=4825) |
| Outcome | Primary three-point MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke): 579/4825 (12.0%; 3.1 per 100 person-years) vs 668/4825 (13.8%; 3.7 per 100 person-years); hazard ratio 0.86; 95% CI 0.77 to 0.96; P=0.006. Absolute risk reduction 1.8 percentage points over a median 49.5 months (approximate NNT 56). Confirmatory secondary major kidney disease events did not differ significantly. Serious adverse events 47.9% vs 50.3%; gastrointestinal disorders 5.0% vs 4.4% |
Oral Semaglutide & CV Outcomes (SOUL)
RCT · T2D + CVD/CKD · 49.5 months
Once-daily oral semaglutide cut 3-point MACE by 14% (HR 0.86) versus placebo in high-risk type 2 diabetes. Benefit was confined to the primary endpoint; confirmatory kidney outcomes were not significantly reduced.
Expert Commentary
This is a positive, well-powered cardiovascular outcome trial, and the verdict is that oral semaglutide meaningfully lowers ischaemic risk in high-risk type 2 diabetes. The design is robust: double-blind, placebo-controlled, event-driven, and adequately sized, so the result is not readily explained by bias. The effect size is modest and biologically plausible rather than implausibly large, with a hazard ratio of 0.86 and an upper confidence bound of 0.96 that sits close to unity. The principal limitation is that benefit was confined to the composite primary endpoint; the confirmatory kidney outcome was not significantly reduced, so the hierarchical testing structure means downstream secondary claims are exploratory only, and no cardiorenal protection should be inferred. The absolute risk reduction was 1.8 percentage points over roughly four years, equating to a number needed to treat near 56, which is clinically worthwhile but not transformative. The trial was funded by the manufacturer, Novo Nordisk, and several authors are employees, which warrants the usual caution. Can I use this with my patients? Yes, for a patient like those enrolled, namely someone aged 50 or older with type 2 diabetes and established atherosclerotic disease who prefers or requires an oral agent. Clinicians should weigh gastrointestinal tolerability and cost, and reserve injectable agents where greater metabolic effect is needed.
References
McGuire DK, Marx N, Mulvagh SL, Deanfield JE, Inzucchi SE, Pop-Busui R, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025;392(20):2001-2012. doi:10.1056/NEJMoa2501006