Late Breaking Clinical Trial

Debra L. Beck, MSc, and Eugene Braunwald, MD

Date Published: March 29, 2025

Oral semaglutide, a combination of the GLP-1 receptor agonist semaglutide and an absorption enhancer, has been shown to reduce HbA1c and body weight and has demonstrated cardiovascular safety, but its cardiovascular efficacy remains uncertain in patients with established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both. The international, randomized SOUL trial was designed to assess whether oral semaglutide could reduce major adverse cardiovascular events (MACE) in this high-risk population.

A total of 9,650 adults (mean age, 66 years; 71% male) with type 2 diabetes (HbA1c 6.5–10.0%) and a history of ASCVD, CKD (eGFR <60), or both were randomly assigned to semaglutide (target dose 14 mg daily) or placebo, in addition to standard care. Mean follow-up was 47.5 months.

For the primary MACE endpoint, a composite of cardiovascular death, nonfatal MI, or nonfatal stroke, oral semaglutide was associated with a 14% relative reduction in risk (12.0% for semaglutide vs. 13.8% for placebo, hazard ratio (HR), 0.86 (95% CI, 0.77–0.96); p=0.006), with a 2% absolute risk reduction over 3 years and a number needed to treat of 50.

When the individual components of the primary endpoint were looked at independently, only nonfatal MI was reduced significantly with semaglutide (HR, 0.74; 95% CI, 0.61–0.89). Nonfatal stroke (HR 0.88; 95% CI, 0.70–1.11) and cardiovascular death (HR 0.93; 95% CI, 0.80–1.09) were not significantly reduced.

There was no significant difference between groups in terms of outcomes related to kidney function CV-related death (a 5-point composite including kidney-related death, persistent ≥50% eGFR reduction, persistent eGFR <15 mL/min/1.73 m2, and chronic kidney replacement therapy; HR, 0.91; p=0.09).

Patients treated with semaglutide had greater reductions in HbA1c at 104 weeks (–0.56% vs. placebo) and greater weight loss (–2.95 kg vs. placebo), and lower CRP levels.

Serious adverse events were seen in 47.9% of the study arm and in 50.3% of the placebo arm; 15.5% and 11.6% of each group, respectively, discontinued their medications due to adverse events. No new safety signals were identified.

Summary

Daily oral semaglutide significantly reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes and high cardiovascular or renal risk, without increasing serious adverse events. The primary benefit was a reduction in nonfatal myocardial infarction. The trial supports the use of oral semaglutide as an effective cardioprotective therapy in high-risk diabetic populations.

“We found that the oral formulation looks just like the rest of the class of GLP-1 inhibitors,” said Dr. DK McGuire, in his presentation of the study. “The same cardiovascular benefits can be derived from the tablet that we’ve seen from the injectables before.”

SGLT2 inhibitor subanalysis: In a prespecified subanalysis, participants were analyzed according to SGLT2 inhibitor use. At baseline, 26.9% of participants were taking SGLT2 inhibitors; 48.9% used them at some point during the trial.

Over a mean follow-up of 47.5 months, the risk of the primary outcome in those taking SGLT2 inhibitors at baseline was similar to that seen in those not taking SGLT2 inhibitors (p for interaction=0.66). An analysis of MACE by any in-trial SGLT2 inhibitors use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2 inhibitors were similar, as were reductions seen in HbA1c, weight, body mass index and high-sensitivity C-reactive protein.

“There’s been a huge [open] question among clinicians about whether these drugs are complementary and whether we should use one or the other or both,” McGuire said. “The results showed no significant difference in outcomes between patients who took SGLT-2 inhibitors, who were likely to have more advanced disease, and those who did not, suggesting that the drugs can be safely used together and are complementary in their ability to reduce cardiovascular risk.”

References

ACC 2025 Late-Breaking Clinical Trial: SOUL: Oral semaglutide and CV outcomes in high-risk type 2 diabetes. Presenter, D McGuire.

https://pubmed.ncbi.nlm.nih.gov/40162642/
https://pubmed.ncbi.nlm.nih.gov/40156843/

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