Don't Miss a Beat: STRIDE and SOUL Trials at ACC.25

In this on-site episode of Don't Miss a Beat from the American College of Cardiology (ACC) 2025 Annual Scientific Sessions, hosts Muthiah Vaduganathan, MD, MPH, a cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, and Steve Greene, MD, an advanced heart failure specialist at Duke University School of Medicine, break down a pair of trials from the meeting: STRIDE and SOUL.

STRIDE Trial

The STRIDE trial, funded by Novo Nordisk, was a double-blind, randomized, placebo-controlled study initiated in 2020 to evaluate the effects of semaglutide 1.0 mg (Ozempic) on walking distance in patients with type 2 diabetes (T2D) and peripheral artery disease (PAD). Conducted across 112 sites in 20 countries, the trial enrolled 792 patients, who were randomized 1:1 to receive semaglutide or placebo for 52 weeks.

Participants assigned to semaglutide received an escalating dose regimen (0.25 mg to 1.0 mg). The primary endpoint, the ratio from baseline in maximum walking distance at 52 weeks, favored semaglutide (1.21 [interquartile range, 0.95–1.55] vs 1.08 [0.86–1.36]), with an estimated treatment ratio (ETR) of 1.13 (95% CI, 1.06–1.21; P = .0004).

Secondary outcomes further supported semaglutide’s benefit. At week 57, the improvement in walking distance was greater with semaglutide (ETR, 1.08; P = .038). Quality-of-life scores (VascuQoL-6) at week 52 were significantly higher in the semaglutide group (median difference, 1.00; P = .011). Pain-free walking distance also improved more with semaglutide than with placebo (ETR, 1.11; P = .0046).

SOUL Trial

The SOUL trial was a double-blind, placebo-controlled, event-driven study designed to assess the cardiovascular effects of oral semaglutide (Rybelsus) in patients with T2D and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD). The trial enrolled 9650 patients aged ≥50 years and was conducted across 450 centers in 44 countries. Participants were randomized 1:1 to receive semaglutide or placebo, with a mean follow-up of 47.5 months.

Primary outcome events occurred in 12.0% of participants receiving semaglutide (3.1 events per 100 person-years) compared with 13.8% in the placebo group (3.7 events per 100 person-years), resulting in a hazard ratio (HR) of 0.86 (95% CI, 0.77–0.96; P = .006). The primary driver of benefit was a 26% reduction in nonfatal myocardial infarction, with additional reductions in nonfatal stroke (12%) and cardiovascular death (7%). No significant improvements in kidney function were observed.

Serious adverse events occurred slightly less frequently in the semaglutide group compared with placebo (47.9% vs 50.3%; P = .02). However, gastrointestinal adverse events, including nausea, diarrhea, constipation, and flatulence, were more common in the semaglutide group (5.0% vs 4.4%). Benefits were consistent across subgroups, including participants receiving sodium-glucose cotransporter-2 inhibitors.

Relevant disclosures for Vaduganathan include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others. Relevant disclosures for Greene include Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, and others.

References:

1. Bonaca MP, Catarig A-M, Houlind K, et al. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): A phase 3B, double-blind, randomised, placebo-controlled trial. The Lancet. Published online March 29, 2025. doi:10.1016/s0140-6736(25)00509-4

2. McGuire DK, Marx N, Mulvagh SL, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. New England Journal of Medicine. Published online March 29, 2025. Doi: 10.1056/nejmoa2501006