SOUL
Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes
Clinical Question
In persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, is treatment with oral semaglutide superior to placebo for reducing major adverse cardiovascular events?
Study Overview
Objective
Semaglutide once-daily oral pills vs placebo in patients with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both.
Study Summary
Oral semaglutide significantly reduced major adverse cardiovascular events (MACE) compared to placebo (HR 0.86; P=0.006), mainly driven by a reduction in nonfatal myocardial infarction with favorable safety profile.
Intervention
Oral semaglutide (max 14 mg/day) vs. placebo, in addition to standard of care, among patients with type 2 diabetes and ASCVD and/or CKD.
Patients per Arm
Semaglutide: 4825, Placebo: 4825
Bottom Line
Among high-risk patients with type 2 diabetes, once-daily oral semaglutide was superior to placebo in reducing the risk of major adverse cardiovascular events over a median follow-up of 49.5 months. Serious adverse events were also lower in the semaglutide group.
Major Points
- Largest and longest GLP-1 RA cardiovascular outcomes trial: 9,650 patients with T2DM and established ASCVD, CKD, or both, followed for median 49.5 months across 444 centers in 33 countries.
- Oral semaglutide reduced 3-point MACE by 14% vs placebo (12.0% vs 13.8%, HR 0.86, 95% CI 0.77–0.96, P=0.006) — first oral GLP-1 RA to demonstrate cardiovascular superiority.
- Builds on injectable semaglutide results (SUSTAIN 6, SELECT) — confirms the GLP-1 RA class effect extends to oral formulation, expanding access for injection-averse patients.
- NNT of 50 over 3 years (95% CI 31–125) to prevent one MACE event — clinically meaningful absolute risk reduction of 1.8%.
- First confirmatory secondary endpoint (major kidney disease events) did not reach significance (HR 0.91, P=0.19), halting the hierarchical testing procedure — kidney benefit remains unproven.
- CV death not significantly reduced (HR 0.93, P not tested due to hierarchical failure) — the MACE benefit was driven by nonfatal MI and nonfatal stroke reduction rather than mortality.
- All-cause mortality showed a favorable trend (HR 0.91, 95% CI 0.80–1.02) but was not formally tested — tantalizing but not conclusive for a mortality benefit.
- Higher discontinuation in semaglutide group (15.5% vs 11.6%) due to GI side effects — raises concern about real-world adherence and durability of benefit.
- Substantial SGLT2 inhibitor co-use at baseline (26.9%) — results demonstrate additive benefit on top of modern diabetes therapy including SGLT2i.
- Underrepresentation of women (28.9%) and Black patients (2.6%) limits generalizability — the trial population was predominantly white and male with established CVD.
Design
Study Type: International, double-blind, randomized, placebo-controlled, event-driven, superiority phase 3b trial.
Randomization: 1
Blinding: Double-blind.
Enrollment Period: June 2019 through March 2021.
Follow-up Duration: Median of 49.5 months.
Centers: 444
Countries: 33 countries
Sample Size: 9650
Analysis: Intention-to-treat.
Inclusion Criteria
- Age ≥50 years.
- Type 2 diabetes with glycated hemoglobin (HbA1c) 6.5% to 10.0%.
- Established atherosclerotic cardiovascular disease (prior MI, stroke, PAD, or coronary/carotid revascularization).
- Chronic kidney disease (eGFR 15–59 mL/min/1.73 m²) with or without ASCVD.
- Stable diabetes therapy for ≥90 days before screening.
Exclusion Criteria
- End-stage kidney disease (eGFR <15) or receiving long-term kidney-replacement therapy (dialysis or transplant).
- Type 1 diabetes or history of diabetic ketoacidosis.
- Current or prior use of GLP-1 receptor agonist within 90 days.
- History of pancreatitis or medullary thyroid carcinoma/MEN2.
- NYHA class IV heart failure.
- Planned coronary or carotid revascularization.
- Active malignancy (excluding non-melanoma skin cancer).
- Pregnancy, breastfeeding, or planned pregnancy.
Arms
| Field | Control | Oral Semaglutide |
|---|---|---|
| Intervention | Once-daily matching placebo, in addition to standard care for diabetes and cardiovascular disease. | Once-daily oral semaglutide, escalated from 3 mg to 14 mg, in addition to standard care. |
| Duration | Median of 49.5 months | Median of 49.5 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Major adverse cardiovascular events (a three-point composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). | Primary | 13.8% (668/4825) | 12.0% (579/4825) | 0.86 | 0.006 |
| Major kidney disease events (five-point composite) | Secondary | 9.0% (435/4825) | 8.4% (403/4825) | HR 0.91 (95% CI, 0.80 to 1.05) | 0.19 |
| Death from cardiovascular causes | Secondary | 6.6% (320/4825) | 6.2% (301/4825) | HR 0.93 (95% CI, 0.80 to 1.09) | Not tested (hierarchical testing stopped) |
| Death from any cause | Secondary | 12.0% (577/4825) | 10.9% (528/4825) | HR 0.91 (95% CI, 0.80 to 1.02) | |
| Serious adverse events | Adverse | 50.3% | 47.9% | 0.02 | |
| Adverse events leading to permanent discontinuation of trial product | Adverse | 11.6% | 15.5% | ||
| Discontinuation due to gastrointestinal disorders | Adverse | 2.0% | 6.4% | ||
| Acute pancreatitis | Adverse | 0.4% | 0.4% |
Criticisms
- Limited generalizability — enrolled only patients with established ASCVD, CKD, or both; results do not apply to primary prevention or lower-risk T2DM populations.
- Severe underrepresentation of women (28.9%) and Black patients (2.6%) — cardiovascular outcomes may differ in these populations.
- Failure of the kidney endpoint (HR 0.91, P=0.19) halted hierarchical testing — CV death and all-cause mortality benefits cannot be formally claimed despite favorable trends.
- Higher discontinuation in semaglutide group (15.5% vs 11.6%) primarily due to GI side effects — real-world adherence may be lower than trial setting, attenuating benefit.
- Industry-sponsored by Novo Nordisk (semaglutide manufacturer) — potential bias in trial design, conduct, and interpretation.
- 14% relative risk reduction (HR 0.86) is modest compared to other CV interventions — clinical significance debated given the cost of oral semaglutide and the NNT of 50.
- Cannot distinguish whether the CV benefit is mediated by glucose lowering, weight loss, anti-inflammatory effects, or direct vascular mechanisms — the mechanism remains unclear.
- Substantial background therapy including SGLT2i (26.9%) and statins — the incremental benefit of adding semaglutide to optimized modern therapy is relatively small.
- Oral formulation requires fasting administration (30 minutes before first food/drink) — practical adherence challenges not captured in the trial's supervised setting.
Funding
Novo Nordisk
Based on: SOUL (The New England Journal of Medicine, 2025)
Authors: D.K. McGuire, N. Marx, S.L. Mulvagh, ..., and J.B. Buse
Citation: N Engl J Med 2025;392:2001-2012
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