9,650 people. Four years. The first GLP-1 tablet shown to prevent heart attacks and strokes. It only gets absorbed if you take it on an empty stomach.
Every GLP-1 with a proven cardiovascular benefit until now has been an injection. SOUL asked whether the same molecule, delivered as a daily tablet, does the same job.
SOUL was a double-blind, placebo-controlled, event-driven superiority trial. It randomized 9,650 adults aged 50 or older who had type 2 diabetes with an HbA1c between 6.5% and 10.0%, plus established atherosclerotic cardiovascular disease, chronic kidney disease, or both. Half received once-daily oral semaglutide titrated to a maximum of 14mg; half received matching placebo. Both groups continued standard care, including whatever statins, blood pressure drugs and glucose-lowering therapy they were already on.
This was a long trial by GLP-1 standards. Mean follow-up was 47.5 months and median follow-up 49.5 months — roughly four years, or about 1,500 consecutive tablets per participant.
The primary outcome was the standard three-part composite known as MACE: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, measured as time to first event. A five-part kidney composite was the main confirmatory secondary outcome.
A 14% relative reduction, and a 1.8 percentage point absolute one. Both framings describe the same result. Over four years, 579 of 4,825 people on oral semaglutide had a major cardiac event, compared with 668 of 4,825 on placebo. Event rates were 3.1 versus 3.7 per 100 person-years.
Reported analyses attribute most of the benefit to fewer nonfatal heart attacks, with smaller and statistically non-significant contributions from stroke and cardiovascular death. That pattern is worth holding loosely: individual components of a composite endpoint are not powered to stand on their own, and a trial that shows a significant composite can easily show nothing significant in any single piece of it.
The kidney result was negative. The five-point kidney composite did not differ significantly between groups. This is where SOUL diverges from the injectable semaglutide story — the FLOW trial, run in people with type 2 diabetes and chronic kidney disease, did show a kidney benefit with weekly injections. Different population, different dose, different formulation, different answer. SOUL is not evidence for or against kidney protection in the FLOW population.
Safety was unremarkable. Serious adverse events were slightly less common on oral semaglutide than on placebo (47.9% versus 50.3%), and serious gastrointestinal disorders occurred in 5.0% versus 4.4%. Nausea, vomiting, diarrhea and constipation remain the ordinary complaints with this drug class, most concentrated around dose increases.
In adults with type 2 diabetes and established cardiovascular or kidney disease, once-daily oral semaglutide reduced major adverse cardiovascular events by 14% over roughly four years — 12.0% versus 13.8% on placebo — without an increase in serious adverse events. The kidney endpoint was not met.
Sources: McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. New England Journal of Medicine 2025;392:2001-2012 (doi:10.1056/NEJMoa2501006) · FDA-approved prescribing information for RYBELSUS (semaglutide) tablets · FDA cardiovascular indication approval, 17 October 2025. NEJM abstract · FDA label (PDF) · ACC trial summary · NCT03914326.
Semaglutide is a peptide. Swallowed on its own it would be digested before it reached the bloodstream. The tablet works around this by co-formulating the drug with an absorption enhancer, salcaprozate sodium, that lets a small fraction cross the stomach lining. Small is the operative word: the label puts absolute bioavailability at roughly 0.4% to 1%.
That margin is why the dosing instructions are so specific. The prescribing information says to take the tablet at least 30 minutes before the first food, beverage, or other oral medication of the day, with no more than 4 ounces of plain water. Not coffee. Not with breakfast. Not alongside the morning blood pressure tablet.
The label is explicit about what happens otherwise: waiting less than 30 minutes, or taking it with food, other beverages, or other oral medicines, reduces absorption and lessens the drug's effect. Waiting longer than 30 minutes can increase absorption instead. Steady-state exposure takes four to five weeks to establish.
No other GLP-1 has a failure mode like this. A weekly injection either happened or it did not. An oral semaglutide tablet can be swallowed exactly as prescribed and still deliver a fraction of the intended dose, with nothing to signal that anything went wrong. The person taking it feels compliant, the pill count is correct, and the exposure is not what the trial delivered.
This is the practical reason a daily oral GLP-1 needs a different kind of tracking than a weekly injection: not just did I take it, but did I take it correctly, and how long until I could eat.
This one did change the label. On 17 October 2025 the FDA approved a cardiovascular risk-reduction indication for oral semaglutide 7mg and 14mg in adults with type 2 diabetes at high cardiovascular risk, making it the first oral GLP-1 to carry one. SOUL was the basis for that decision.
The population matters. Everyone in SOUL was 50 or older, had type 2 diabetes, and already had atherosclerotic cardiovascular disease, chronic kidney disease, or both. The result does not transfer automatically to people taking a GLP-1 for weight management without diabetes, and it says nothing about the higher-dose oral semaglutide formulations being developed for obesity.
Four years of daily tablets is the exposure that produced this. Cardiovascular benefit in these trials accrues slowly and invisibly. There is no felt difference between a well-absorbed dose and a badly absorbed one, which is exactly what makes a daily routine easy to erode and worth defending.
Talk to a prescriber before changing anything. Switching between an injectable and an oral GLP-1 is not a like-for-like swap in dose or in schedule, and neither the trial nor this summary is a basis for making that switch on your own.
This article summarizes published clinical trial results and FDA-approved prescribing information for general education. It is not medical advice. Individual results vary, and any decision about starting, switching, adjusting, or stopping any GLP-1 medication should be made with a prescriber.