PMID-40162642 — SOUL: Oral Semaglutide Cardiovascular Outcomes in High-Risk T2D

[DRAFT — authored 2026-04-18. Requires Medical Director review.]

Citation

McGuire DK, Marx N, Mulvagh SL, Deanfield JE, Inzucchi SE, Pop-Busui R, Sattar N, Bailey CJ, Hoffmann KS, Lingvay I, Mahaffey KW, Mann JFE, Pratley RE, Rosenstock J, Tuttle KR, Schmid BP, Brown-Frandsen K, Gæde P, Gislason G, Hovingh GK, Idorn T, Lunati ME, Lupsa BC, Rossing P. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025;392(20):2001-2012. doi: 10.1056/NEJMoa2501006. PMID: 40162642.

Study Design

Phase: 3a
Design: Multicenter, randomized, double-blind, placebo-controlled, event-driven
Randomization: 1:1 to oral semaglutide 14 mg daily or matching placebo
Duration: Follow-up through accrual of primary endpoint events
N: 9,650 adults
Period: Enrollment June 2019 – March 2021

Population

Age ≥50 years with type 2 diabetes and evidence of atherosclerotic cardiovascular disease (CAD, cerebrovascular, symptomatic PAD) and/or CKD (eGFR <60)
Background standard-of-care diabetes and CV medications continued

Intervention

Oral semaglutide (Rybelsus) 14 mg daily vs. matching placebo
Standard CKD/CVD care maintained; SGLT2i permitted as concomitant therapy

Outcomes

Primary — First MACE (CV death, non-fatal MI, non-fatal stroke)

Oral semaglutide: 12.0% (579/4,825)
Placebo: 13.8% (668/4,825)
HR 0.86 (95% CI 0.77–0.96), P=0.006 — 14% relative reduction in MACE

Secondary

Consistent HR <1 for CV death, MI, stroke individually
Benefit sustained in pre-specified SGLT2i concomitant-use subgroup (no loss of effect when combined)
Adverse events comparable between arms; GI events slightly higher in oral semaglutide arm

Key Findings

SOUL establishes cardiovascular benefit of oral semaglutide (14 mg) in a high-CV-risk T2D population — the first cardiovascular outcomes trial to confirm CV benefit for an oral GLP-1 agent. This extends the CV evidence base beyond PIONEER-6 (non-inferiority) and SELECT (obesity without T2D) to a T2D+CVD/CKD population.

The trial was presented at ACC.25 in March 2025 and simultaneously published in NEJM.

Clinical implications:

Oral semaglutide now has evidence-based CV benefit indication in T2D + established CVD/CKD
Label expansion is anticipated; verify current FDA Prescribing Information at time of reference
Combination with SGLT2i is pharmacologically and clinically compatible

Limitations (Author-acknowledged)

Event-driven design; follow-up duration varied
Oral semaglutide 14 mg is the T2D dose, not the weight-loss dose (25–50 mg in OASIS program)
Population is ASCVD/CKD-selected; generalizability to primary-prevention T2D not established
Non-US demographics predominate; US-specific applicability secondary

Evidence Level

Level Ib (Oxford CEBM) — adequately-powered Phase 3 RCT with pre-specified primary endpoint.

Linked Peptides

Semaglutide

Related Studies

Orchestrator Notes

Funded by Novo Nordisk.
First CV superiority trial for oral GLP-1 class.
Alongside SELECT, FLOW, and STRIDE, forms the contemporary semaglutide CV/kidney/PAD evidence base.
Presented ACC.25 March 29, 2025; simultaneous NEJM publication.

PMID-40162642 – SOUL Oral Semaglutide CV Outcomes