Oral semaglutide and cardiovascular risk: what the SOUL trial actually found

What did @drdavidalfery actually say?

The creator claims a new NEJM study shows oral semaglutide (Rybelsus) reduces serious cardiovascular events in high-risk type 2 diabetics, reporting a hazard ratio of 0.86 and a p-value of 0.006 from a randomized double-blind placebo-controlled trial. He frames this as evidence that oral GLP-1 agonists can "be really effective in preventing complications."

Specifically, he says patients had to be over 50, have an A1c between 6.5 and 10, and carry either established atherosclerotic cardiovascular disease or chronic kidney disease. The trial ran "just over four years." He also notes oral semaglutide is not particularly effective for weight loss compared to injectable forms, which is a fair caveat that a lot of GLP-1 hype merchants skip over entirely.

Does the science back this up?

Yes, largely. The trial he is describing is the SOUL trial, published in the New England Journal of Medicine in 2024 (McGuire et al., 2024, NEJM). The numbers he cites check out. The hazard ratio for the primary composite endpoint, which was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, was 0.86, with a 95% confidence interval of 0.77 to 0.96, and a p-value of 0.006.

That is a statistically significant 14% relative risk reduction. The trial enrolled over 9,600 patients across more than 40 countries and followed them for a median of roughly 49.5 months, which lines up with his "just over four years" description. The inclusion criteria he described match the published protocol. This is real, and the effect size is clinically meaningful for a high-risk population.

One important nuance he does not mention: the absolute risk reduction was more modest than the relative numbers suggest. The event rate difference between groups was a few percentage points, meaning you would need to treat a meaningful number of patients to prevent one event. That does not make the finding less real, but it changes how a clinician should communicate benefit to a patient.

What did they get wrong (or right)?

He gets the core trial facts right. The journal, the study design, the inclusion criteria, the hazard ratio, and the p-value are all accurate. Credit where it is due: he correctly identifies this as a prospective randomized double-blind placebo-controlled trial, which is exactly what it was.

A few things are worth flagging. First, he defines the composite endpoint as "non-fatal heart attack, non-fatal stroke, or death," but that last component is specifically cardiovascular death, not all-cause mortality. That distinction matters. All-cause mortality was not significantly different between groups in SOUL, which is a finding he omits entirely.

Second, his claim that Rybelsus is "not terribly effective" for weight loss is directionally correct but slightly reductive. Oral semaglutide at 14 mg does produce weight loss, just less than injectable semaglutide. The PIONEER trials showed roughly 4-5 kg weight loss at the approved dose, which is not nothing, but is meaningfully less than Ozempic or Wegovy doses.

Third, he misspells and mispronounces "Wegovy" and "Novo Nordisk" and refers to the drug as "rebelsis" instead of Rybelsus throughout, which is a minor but repeated error in a video that is ostensibly educating patients on a specific medication name.

What should you actually know?

The SOUL trial is a genuinely important result. Before SOUL, the cardiovascular benefit of GLP-1 receptor agonists had been established primarily for injectable formulations, specifically liraglutide in LEADER (Marso et al., 2016, NEJM) and injectable semaglutide in SUSTAIN-6 (Marso et al., 2016, NEJM). SOUL extends that evidence to the oral form, which is a meaningful gap to close.

That said, context matters here. Rybelsus is approved at doses of 3 mg, 7 mg, and 14 mg. The SOUL trial used 14 mg as the target dose. Not every patient tolerates that dose or absorbs it consistently. Oral semaglutide requires specific administration conditions, taken on an empty stomach with a small amount of water and waiting 30 minutes before eating, which affects real-world adherence in ways a clinical trial does not fully capture.

The cardiovascular benefit also appeared primarily in patients with established atherosclerotic cardiovascular disease, not those with only chronic kidney disease, according to subgroup analyses. That is a clinically relevant detail for prescribers deciding who benefits most. If you or a patient are managing type 2 diabetes with cardiovascular risk, this is a conversation worth having with a physician, not a reason to self-prescribe or switch medications without guidance.