Key Points
- Injectable semaglutide, a GLP-1 receptor agonist, reduces CV events in patients with T2DM, however whether the oral form of semaglutide confers the same CV risk reduction is uncertain.
- The SOUL trial randomized 9650 participants age ≥50 with T2DM and established CAD, cerebrovascular disease, symptomatic PAD, or CKD to oral semaglutide or placebo. The primary outcome was 3-point MACE (CV death, nonfatal MI, and nonfatal stroke).
- Oral semaglutide was associated with a significant 14% relative reduction in MACE compared to placebo (HR 0.86 [95% CI: 0.77 – 0.96]), primarily driven by reduction in non-fatal MI. At 3 years, the absolute risk reduction with semaglutide was 2.0 percentage points, for number needed to treat of 50 persons. Serous adverse events were higher in the placebo group, but GI events were more common with semaglutide.
- Oral semaglutide is the first and only oral GLP-1 receptor agonist with proven CV benefits, demonstrating a risk reduction comparable to injectable GLP-1 agents, with no new safety signals identified.
Cardiovascular (CV) disease is a leading cause of death and disability in patients with type 2 diabetes mellitus (T2DM). Injectable formulations of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been shown to reduce CV risk in patients with T2DM, but whether oral formulations confer a similar benefit is unknown. This is important because many patients are hesitant or unable to perform weekly injections. If effective, an oral formulation could improve access to this class of medications for purposes of CV risk reduction.
On March 29th 2025, findings from “Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes” trial were presented at ACC Scientific Sessions 2025 on behalf of the Semaglutide Cardiovascular Outcomes Trial (SOUL) study group, with simultaneous publication in the New England Joal of urnMedicine. The purpose of this investigation was to evaluate whether oral semaglutide reduces CV events among high-risk patients with T2DM.
This was a double-blind, placebo-controlled, event-driven, superiority trial which randomized 9650 participants age ≥ 50 years with T2DM, a hemoglobin A1c of 6.5-10%, and either coronary artery disease (CAD), cerebrovascular disease, symptomatic peripheral artery disease (PAD), or chronic kidney disease (CKD; defined as an eGFR <60 mL/min/1.73 m2) to oral semaglutide or placebo in a 1:1 fashion on top of standard of care. The dose was escalated from 3mg to 14mg, with dose reductions and treatment pauses allowed. The primary outcome was 3-point MACE, including CV death, non-fatal myocardial infarction (MI) and non-fatal stroke, over an estimated 5 year study period. Secondary outcomes included 5-point composite kidney outcome, CV death, and major adverse limb events.
A total of 4825 patients were randomized from 450 medical centers in 44 countries to each arm, with <2% drop out. Overall, ~29% were female, with an average age of 66.1, average A1c of 8%, and average BMI of 31.0 kg/m2; more than half of participants had established ASCVD. At 54 months, 579 patients in the semaglutide group and 688 patients in the placebo group experienced the primary outcome for an event rate of 3.1 and 3.7 per 100 person-years, respectively. Oral semaglutide was associated with a significant 14% relative risk reduction in 3-point MACE compared to placebo (HR 0.86 [95% CI: 0.77, 0.96]; p=0.0028 for superiority). The absolute risk reduction was 2% over three years, representing a number needed to treat of 50 patients (95% CI: 31 to 125). There was a consistent trend towards benefit for oral semaglutide vs. placebo in each of the individual components: CV death (6.2% vs. 6.6%, HR 0.93 [95% CI: 0.80, 1.09]), non-fatal MI (4.0% vs. 5.2%, HR 0.74 [95% CI: 0.61, 0.89]), and nonfatal stroke (3.0% vs. 3.3%, HR 0.88 [95% CI: 0.70, 1.11]). Major adverse limb events were also lower in the semaglutide group (HR 0.71 [95% CI: 0.52, 0.96]). There was no differences between the groups for major kidney disease events. No heterogenous treatment effects for the primary outcome were observed across the subgroup analyses, with similar efficacy by age, sex, BMI, eGFR, and concomitant SGLT2i use, suggesting a complimentary role for these medications in the management of high-risk patients with T2DM.
Serious adverse events were significantly higher in the placebo group (50.3% vs. 47.9%; p=0.02), the majority of which were defined cardiac disorders and infections. Gastrointestinal disorders were more common with semaglutide than placebo (5.0% vs. 4.4%, respectively), and discontinuation of the study drug was more common on the oral semaglutide group (15.5%) than in the placebo group (11.6%), driven by gastrointestinal side effects (6.4% vs. 2.0%, respectively). However, rates of acute pancreatitis (0.4%) and eye disorders (2.0%) were similar for both groups.
This trial was funded by Novo Nordisk; Black patients were under-represented due to low enrollment at non-North American sites.
The risk reduction observed in this study aligns with pooled results of eight previous trials of injectable GLP-1 receptor agonists, according to the researchers. Darren K. McGuire, M.D., MHSc, from the University of Texas Southwestern Medical Center, and Parkland Health System, Dallas, Texas, concluded: “We found that the oral formulation looks just like the rest of the class of GLP-1 inhibitors. The same cardiovascular benefits can be derived from the tablet that we’ve seen from the injectables before…Oral semaglutide is the first and only oral GLP-1 RA with proven CV benefits.”