SOUL trial: oral semaglutide cuts cardiovascular events by 14%

Novo Nordisk announced on October 21, 2024 that its Phase 3 SOUL trial met its primary goal: oral semaglutide, sold as Rybelsus, lowered major adverse cardiovascular events (MACE) by 14% compared with placebo in adults with type 2 diabetes who also had cardiovascular disease, chronic kidney disease, or both ^[2]. The company said it planned to submit the results to regulators around the end of the year to support a label expansion ^[2].

SOUL was a multicenter, international, randomized, double-blind, placebo-controlled cardiovascular outcomes trial that enrolled 9,650 patients aged 50 and older ^[2]. Participants took oral semaglutide 14 mg once daily or placebo, on top of standard care, and the trial was designed to test whether the drug reduced MACE risk in people with type 2 diabetes and established cardiovascular disease and/or chronic kidney disease ^[2].

"We are pleased to see that the results from SOUL demonstrate that oral semaglutide reduces the risk of cardiovascular events and that the benefits of oral semaglutide come on top of standard of care," said Martin Holst Lange, executive vice president and head of Development at Novo Nordisk ^[2]. "Approximately one in three adults with type 2 diabetes also have cardiovascular disease; therefore, it is crucial to have therapies that can address both conditions" ^[2].

What the announcement did and did not include

The October 2024 release was headline data. Novo Nordisk said detailed results would be presented at a scientific conference in 2025 ^[2]. That means several numbers patients and clinicians usually want are not in the available sources: the absolute number of heart attacks, strokes and cardiovascular deaths in each group, the confidence interval around the 14% figure, how the individual parts of the MACE endpoint performed, and the full side-effect profile seen in SOUL. Those details are not yet known from these sources.

The trial investigators had earlier written that GLP-1 receptor agonists and SGLT2 inhibitors have been studied for cardiovascular safety and benefit, and that "some, but not all" agents in those classes lower cardiovascular disease risk — with the benefits largely independent of how much they lower blood sugar ^[2]. They also noted that safety and efficacy of GLP-1 drugs in type 2 diabetes have been examined across at least nine outcomes trials with a combined 60,080 participants ^[2].

Why it matters for patients

Semaglutide is sold in the U.S. as a weekly injection (Ozempic and Wegovy) and as a daily tablet (Rybelsus) ^[2]. Until now, the semaglutide product with a cardiovascular risk-reduction indication was the injection: in March 2024, the FDA approved Wegovy to reduce the risk of MACE in adults with known heart disease who also have overweight or obesity, alongside a reduced-calorie diet and more physical activity ^[2]. SOUL is aimed at extending that kind of claim to the pill, in a different population — people with type 2 diabetes and established heart or kidney disease ^[2].

That distinction matters for coverage and prescribing. Insurers and clinicians often look at what an FDA label formally supports. If regulators accept the SOUL data, Rybelsus would become an oral GLP-1 option with a proven cardiovascular benefit in its label, rather than a blood-sugar drug alone.

The trial authors argued a pill could also change uptake. They cited a survey of 113 physicians and 1,096 patients showing delays in prescribing and dose increases of GLP-1 drugs despite poor blood sugar control, "predominantly due to the injectable mode of administration, lack of convenience and perceived increased injection burden" ^[2]. Their view was that an oral GLP-1 with proven cardiovascular efficacy "may help overcome any hesitancy from patients and clinicians alike" ^[2].

A 14% relative reduction is a relative number. Without the absolute event rates, it is not possible from these sources to say how many people would need to take the drug to prevent one heart attack, stroke or cardiovascular death.

What happens next

• October 21, 2024: Novo Nordisk released SOUL headline results ^[2].
• Around the end of 2024: The company said it expected to submit the data to regulatory authorities to support a label expansion ^[2].
• 2025: Detailed SOUL results are due to be presented at a scientific conference ^[2].

The sources do not give a date for an FDA decision, and any change to the Rybelsus label would depend on that review.