Semaglutide Cardiovascular Outcomes Trial - SOUL

Mar 29, 2025
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Author/Summarized by Author:
William Schuyler Jones, MD, FACC
Summary Reviewer:
Fred M. Kusumoto, MD, FACC
Trial Sponsor:
Novo Nordisk
Date Presented:
03/29/2025
Date Published:
03/29/2025
Date Updated:
03/29/2025
Original Posted Date:
03/29/2025
References

Contribution To Literature:

The SOUL trial showed that in patients with T2DM and ASCVD, CKD, or both, use of oral semaglutide was associated with a significantly lower risk of MACE vs. placebo, without an increase in serious adverse events.

Description:

The goal of the phase 3b trial was to assess the cardiovascular efficacy of oral semaglutide, a GLP-1 receptor agonist, and to determine the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both.

Study Design

Participants at 444 sites in 33 countries were randomly assigned in a 1:1 ratio to receive either once-daily oral semaglutide or matching placebo, in addition to standard care (n=4,825 for both semaglutide and placebo groups). The dose was started at 3 mg and was escalated to 7 mg and then 14 mg. Standard care included glucose-lowering and cardiovascular risk–reducing therapies, per guidelines.

  • Total number of enrollees: 9,650
  • Duration of follow-up: median 49.5 months
  • Mean patient age: 66.1 years
  • Percentage female: 28.9%

Inclusion criteria:

  • Age ≥50 years
  • Diagnosed with T2DM
  • Hemoglobin A1c 6.5-10%
  • Had at least one of the following: coronary artery disease, cerebrovascular disease, symptomatic peripheral artery disease, or CKD

Exclusion criteria:

  • End-stage kidney disease
  • Received long-term kidney-replacement therapy

Principal Findings:

Primary outcome: The primary outcome was three-point MACE (composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke) in a time-to-event analysis. Over the course of the study, 12.0% of patients in the semaglutide group vs. 13.8% in the placebo group had a primary endpoint (hazard ratio, 0.86; 95% CI, 0.77-0.96; p=0.006).

Secondary outcomes: The confirmatory secondary outcomes, which included major kidney disease events (a five-point composite outcome), major adverse limb events, and serious adverse events, were not significantly different between the two groups.

Interpretation:

In patients with T2DM and ASCVD and/or CKD, the use of oral semaglutide in this trial was associated with a lower risk of three-point MACE when compared with placebo. This trial adds to the beneficial risk-benefit profile of oral semaglutide in patients with T2DM and established ASCVD and/or CKD.

References:

McGuire DK, Marx N, Mulvagh SL, et al., for the SOUL Study Group. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med 2025;Mar 29:[Epub ahead of print].

Presented by Dr. Darren K. McGuire at the American College of Cardiology Annual Scientific Session (ACC.25), Chicago, IL, March 29, 2025.

Clinical Topics: Prevention

Keywords: ACC25, ACC Annual Scientific Session, Atherosclerosis, Diabetes Mellitus, Type 2, Kidney Failure, Chronic, Primary Prevention


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