First GLP1 in a pill to reduce cardiovascular events in people with type 2 diabetes

We know that several GLP1 receptor agonists reduce cardiovascular events in people with type 2 diabetes – this includes injectables dulaglutide (Trulicity), liraglutide (Victoza), and semaglutide (Ozempic). Semaglutide is also available in an oral (pill) form for type 2 diabetes, called Rybelsus.

In 2019, we published the PIONEER 6 study (disclosure: I was an author), which demonstrated cardiovascular safety of oral semaglutide. This was a smaller and shorter study designed specifically to prove safety, and wasn’t big or long enough to test whether oral semaglutide could reduce cardiovascular events. So, we went on to conduct the SOUL study, which was about 3 times longer and 3 times larger than PIONEER 6, designed to see whether oral semaglutide could reduce cardiovascular events (disclosure: I was an investigator in the SOUL study).

Hot off the presses – here are the results!

The SOUL study included 9650 people aged 50+ with type 2 diabetes and atherosclerotic cardiovascular disease (57% of participants), chronic kidney disease (13% of participants), or both (27% of participants). Participants were randomized to receive either oral semaglutide (max dose 14mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke.

At a median follow up of 50 months, the risk of having a cardiovascular event was reduced by 14% with oral semaglutide vs placebo. This benefit was driven by a 26% reduction in nonfatal heart attack. In a prespecified analysis, 50 people would need to be treated for 3 years to prevent one cardiovascular event.

While we shouldn’t compare across studies directly, one can’t help but consider these results in the context of data with injectable semaglutide (Ozempic). In the SUSTAIN-6 trial, Ozempic 0.5mg or 1mg weekly decreased the risk of cardiovascular events by 26%, driven by a 39% reduction in stroke, and the number needed to treat to prevent one cardiovascular event over 2 years was 45 (disclosure: I was an investigator in this trial).

The SOUL study also looked at a composite kidney outcome which did not show a statistically significant benefit. This is in contrast to the recently published FLOW study, which showed a kidney benefit with injectable semaglutide in people with type 2 diabetes. However, it’s important to point out that kidney health was better at baseline amongst participants in the SOUL study (baseline eGFR 74) than in the FLOW study (baseline eGFR 47); the inclusion criteria for chronic kidney disease were different, the dose of semaglutide was different, and SOUL was not a dedicated kidney outcome study (whereas FLOW was).

The most common side effects with oral semaglutide were gastrointestinal, as expected and already known of semaglutide and the GLP1 class. There were no new safety signals in the study.

BOTTOM LINE: Oral semaglutide is the first and only oral (pill) GLP1 receptor agonist with proven cardiovascular benefits in people living with type 2 diabetes.

Disclaimer: I am/have been an investigator in clinical trials of semaglutide, liraglutide, and dulaglutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide and liraglutide (Novo Nordisk) and dulaglutide (Eli Lilly).

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