Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes (SOUL)

Authors, Journal, Affiliations, Type, DOI

• Authors: McGuire DK, Marx N, Mulvagh SL, Deanfield JE, Inzucchi SE, Pop-Busui R, Mann JFE, Emerson SS, Poulter NR, Engelmann MDM, Ripa MS, Hovingh GK, Brown-Frandsen K, Bain SC, Cavender MA, Gislum M, David J-P, Buse JB; for the SOUL Study Group
• Journal: New England Journal of Medicine
• Affiliations: University of Texas Southwestern Medical Center; Novo Nordisk (Søborg, Denmark); 444 sites across 33 countries
• Type: International double-blind, randomised, placebo-controlled, event-driven, superiority phase 3b trial
• DOI: https://doi.org/10.1056/NEJMoa2501006

Overview

The SOUL trial randomised 9,650 adults (≥50 years) with type 2 diabetes (HbA1c 6.5–10%) and established ASCVD, CKD, or both to once-daily oral semaglutide (14mg maximum) or placebo over a median 49.5 months. Oral semaglutide reduced the 3-point MACE primary endpoint by 14% (HR 0.86; 95% CI 0.77–0.96; P=0.006), driven primarily by a 26% reduction in nonfatal MI (HR 0.74). Major kidney disease events did not reach statistical significance (HR 0.91; P=0.19), halting the confirmatory secondary hierarchy. This is the first oral GLP-1 receptor agonist to demonstrate cardiovascular superiority over placebo.

Keywords

Oral semaglutide, SOUL trial, type 2 diabetes, MACE, cardiovascular outcomes, GLP-1 receptor agonist, atherosclerotic cardiovascular disease, chronic kidney disease, nonfatal myocardial infarction, PIONEER 6

Key Takeaways

Trial Design

• Double-blind, placebo-controlled, event-driven, superiority phase 3b RCT; 444 sites, 33 countries; enrollment June 2019–March 2021
• Eligibility: age ≥50; T2DM (HbA1c 6.5–10%); ≥1 of coronary artery disease, cerebrovascular disease, symptomatic PAD, or CKD (eGFR <60 ml/min/1.73 m²)
• Oral semaglutide dose-escalated: 3mg → 7mg → 14mg once daily; taken fasting with ≤120 ml water; ≥30 min before food or other medications
• Funded by Novo Nordisk; academic-led steering committee; independent statistical verification by Statogen Consulting
• Powered at 90% to detect 17% lower MACE risk; target ≥1,225 primary-outcome events; one prespecified interim analysis (at 2/3 of events)

Participants

• n=9,650 (4,825 per group); mean age 66.1±7.6 years; 28.9% women; 2.6% Black
• History: CAD 70.7%; heart failure 23.1%; cerebrovascular disease 21.2%; PAD 15.7%; CKD 42.4%
• 26.9% receiving SGLT2 inhibitors at baseline in both groups
• Mean follow-up 47.5±10.9 months; median 49.5 months; 98.4% completed trial; vital status available for 99.5%
• Treatment received for 87.4% of possible duration (86.5% semaglutide vs 88.4% placebo)

Primary Outcome — 3-Point MACE

• 579/4,825 (12.0%; 3.1 events/100 person-years) semaglutide vs 668/4,825 (13.8%; 3.7 events/100 person-years) placebo
• HR 0.86 (95% CI 0.77–0.96; P=0.006) — superiority established
• Absolute risk reduction at 3 years: 2.0 percentage points; NNT=50 (95% CI 31–125)
• CV death: HR 0.93 (95% CI 0.80–1.09) — not individually significant
• Nonfatal MI: HR 0.74 (95% CI 0.61–0.89) — dominant benefit; 4.0% vs 5.2%
• Nonfatal stroke: HR 0.88 (95% CI 0.70–1.11) — not individually significant; 3.0% vs 3.3%
• Consistent effect across prespecified subgroups (age, sex, BMI, CVD/CKD history, eGFR, medication use)

Confirmatory Secondary Outcomes (Hierarchical Testing)

• Major kidney disease events (5-point composite): HR 0.91 (95% CI 0.80–1.05; P=0.19) — not significant; testing hierarchy stopped
  • Components: CV death, renal death, eGFR reduction ≥50%, eGFR <15 ml/min/1.73 m², or dialysis/transplantation
  • CV death accounted for 71.2% of events in this composite
• CV death (2nd in hierarchy): HR 0.93 (95% CI 0.80–1.09) — not formally tested
• Major adverse limb events (3rd; 2-point composite): HR 0.71 (95% CI 0.52–0.96) — directionally positive; not formally tested

Supportive Secondary Outcomes

• Heart failure events (3-point composite): HR 0.90 (95% CI 0.79–1.03)
• All-cause mortality: HR 0.91 (95% CI 0.80–1.02)
• Fatal or nonfatal MI: HR 0.73 (95% CI 0.61–0.88)
• Fatal or nonfatal stroke: HR 0.95 (95% CI 0.76–1.17)
• Severe hypoglycemia: HR 0.90 (95% CI 0.66–1.22) — no significant difference; 1.6% vs 1.7%

Metabolic and Inflammatory Effects (Week 104)

• HbA1c: −0.71 pp (semaglutide) vs −0.15 pp (placebo); estimated difference −0.56 pp (95% CI −0.61 to −0.52)
• Body weight: −4.22 kg vs −1.27 kg; estimated difference −2.95 kg (95% CI −3.18 to −2.73)
• hsCRP geometric mean: 1.56 vs 2.01 mg/L — persistent reduction with oral semaglutide

Safety

• Serious adverse events: 47.9% (semaglutide) vs 50.3% (placebo); P=0.02 — fewer serious AEs with semaglutide
• Most common serious AEs: cardiac disorders (17.8% vs 19.8%), infections/infestations (15.0% vs 16.5%)
• GI disorders leading to permanent discontinuation: 6.4% semaglutide vs 2.0% placebo
• GI disorders (any): 5.0% vs 4.4%
• Gallbladder disorders, retinal disorders, malignant neoplasms: 0.4–0.8 pp difference
• Acute pancreatitis: 0.4% in both groups
• Death from noncardiovascular causes: 4.7% vs 5.3%

Limitations of the document

• Exclusively high-risk population (ASCVD/CKD required) — not representative of general T2DM; 32% of T2DM have CVD; 25–40% have CKD
• Low representation of women (28.9%) and Black participants (2.6%) despite their higher cardiovascular risk
• Industry-funded (Novo Nordisk) — data analysis performed by sponsor (independently verified by Statogen Consulting)
• Very low oral bioavailability (0.4–1%) vs injectable semaglutide (89%) — limits direct comparison between formulations
• Kidney outcomes not clarified — underpowered for CKD endpoints; higher baseline eGFR (73.8 ml/min) than FLOW (47.0 ml/min)
• Trial not powered to compare treatment effects across subgroups

Key Concepts Mentioned

• concepts/GLP-1-Receptor-Agonists — oral semaglutide as an example; class cardiovascular outcomes data
• concepts/Cardiorenal-Syndrome — kidney outcomes with oral vs injectable semaglutide

Key Entities Mentioned

• entities/Semaglutide — oral formulation (Rybelsus/14mg); SOUL trial cardiovascular outcomes
• entities/Peripheral-Artery-Disease — major adverse limb events endpoint; HR 0.71 (0.52–0.96)
• entities/Tirzepatide — class context (dual GIP/GLP-1 RA)

Wiki Pages Updated

• wiki/sources/oral-semaglutide-soul-nejm-2025.md — created
• wiki/entities/Semaglutide.md — added SOUL trial to cardiovascular outcomes; updated contradictions
• wiki/concepts/GLP-1-Receptor-Agonists.md — created new concept page
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated