CHICAGO -- Semaglutide further solidified its efficacy for diabetes-associated cardiovascular conditions, this time building its positions in peripheral artery disease (PAD) and with an oral formulation, based on two major studies.
In the randomized STRIDE trial, a year of semaglutide (Ozempic, Wegovy) injections increased the walking ability of people with type 2 diabetes (T2D) and lower limb PAD by 21%, a significant improvement over placebo's 8% improvement. This between-group difference produced an estimated treatment ratio of 1.13 for semaglutide (95% CI 1.06-1.21), corresponding, in absolute terms, to a median 26.4-meter improvement in maximum walking distance over placebo, reported Marc Bonaca, MD, MPH, of CPC Clinical Research and University of Colorado School of Medicine in Aurora, at the American College of Cardiology (ACC) annual meeting.
This makes semaglutide the first drug to show benefits in both cardiovascular outcomes and walking function, Bonaca said.
Separately, in the SOUL trial of people with T2D who also had atherosclerotic cardiovascular disease and/or chronic kidney disease (CKD), several years of oral semaglutide (Rybelsus) reduced one's risk of major adverse cardiovascular events (MACE) by the end of year 4 (12.0% vs 13.8% with placebo, HR 0.86, 95% CI 0.77-0.96), a positive result driven by the reduction of nonfatal myocardial infarctions (MIs) in particular (HR 0.74, 95% CI 0.61-0.89), according to Darren McGuire, MD, of UT Southwestern in Dallas.
Despite no improvement in cardiovascular mortality and adverse kidney events, SOUL suggested that oral semaglutide may keep up with its injectable cousins when it comes to cardiovascular efficacy, especially in a population already using other protective drugs like SGLT2 inhibitors. This is important because, unlike the GLP-1 receptor agonist injectables, oral semaglutide is still limited to one FDA approved indication: adjunctive glycemic control in people with T2D.
Semaglutide is well-known as being among the highly sought-after GLP-1 receptor agonist injectables, a drug class that has had its cardiovascular efficacy established in heart failure patients and people with T2D and cardiovascular disease, high risk of cardiovascular disease, or CKD. Having outgrown their initial development for glycemic control, these GLP-1 injectables now count cardioprotective and weight loss applications among their FDA approved indications.
"Many patients hesitate at the use of injectable semaglutide, so a study [SOUL] demonstrating the cardiovascular benefit of an oral formulation of semaglutide is important and will likely be attractive to patients," said Chiadi Ndumele, MD, PhD, MS, of Johns Hopkins University in Baltimore, who was not involved in the trial.
STRIDE and SOUL together now take semaglutide's cardiovascular efficacy to new dimensions and have implications for clinical practice, Ndumele and others agreed.
"I think both are well done and practice-changing trials. They add to the growing amount of data regarding GLP-1 agonists in general and semaglutide specifically. Use has already been increasing and will now further accelerate. Multiple trials are ongoing with other agents in this class of drugs, and these are eagerly awaited," commented Deepak Bhatt, MD, MPH, MBA, of Mount Sinai Fuster Heart Hospital in New York City.
STRIDE: A Big Step Forward
"We haven't had a new therapy for function in PAD in 25 years," Bonaca said at an ACC press conference. In current practice, PAD patients have few medical therapies to help their walking -- the only guideline-recommended one being cilostazol, which has no proven cardiovascular benefits and is used infrequently due to side effects.
In STRIDE, published simultaneously inThe Lancet, the functional benefit of injectable semaglutide was apparent as early as 26 weeks and was still widening by 52 weeks, suggestive of even greater long-term effects if the trial had kept going.
"STRIDE is very important as it improved functional capacity and quality of life among patients with diabetes and symptomatic PAD. Such quality-of-life improvement is very important for patients and seemed to increase over time. It would be great to see an impact on vascular events in this population for a change in practice," Ndumele commented. "However, it seems clear that the benefits are not very weight dependent, suggesting that semaglutide has direct vascular benefits, as prior studies have indicated."
Additionally, an exploratory analysis showed semaglutide's near-halving of risk of combined rescue therapy or all-cause death (4% vs 8%, HR 0.46, 95% CI 0.24-0.85), as highlighted by Eugenia Gianos, MD, from Lenox Hill Hospital of Northwell Health, New York City, who was not involved in the trial.
Though this finding needs confirmation in further trials, it is "really exciting for us in the field of preventive cardiology ... that this is another therapy that we can add to this group of patients" who, at the end of the day, die not from not being able to walk but from heart attacks and strokes, Gianos suggested at the press conference.
STRIDE was a double-blind randomized trial conducted in North America, Asia, and Europe from 2020-2024. Included were adults with T2D and PAD with intermittent claudication (Fontaine stage IIa, able to walk >200 m without pain) and an ankle-brachial index ≤0.90 or toe-brachial index ≤0.70.
Out of 1,363 screened candidates, 792 participants were selected and randomized 1:1 to subcutaneous semaglutide (1.0 mg once weekly) or placebo for 52 weeks.
This cohort was 25% women and had a median age of 68. At baseline, the median maximum walking distance was 185 m. Concomitant therapies used by these patients included metformin in about 80%, SGLT2 inhibitors in about 35%, aspirin in 52%, and cilostazol in 11%. Median follow-up reached 13.2 months.
Total serious adverse events (AEs) came out to 19% versus 20% between semaglutide and placebo groups, respectively, though treatment-related ones were limited to 1% and 2%. These were most frequently gastrointestinal AEs in both groups. The proportion of people permanently discontinuing their study treatment reached 14% versus 11%, respectively. "Overall, safety aligned with previous semaglutide trials," study authors noted.
"In the context of concerns about sarcopenia from weight loss with GLP-1 receptor agonist therapy, improved function on a graded treadmill suggests that no substantial detrimental effects occurred in the muscle in a highly vulnerable population," they added.
A major limitation of STRIDE was that it did not study people with PAD without T2D, Bonaca's team acknowledged.
And as for semaglutide's effect on major adverse limb events, the study's low event rates precluded such an analysis.
SOUL: Oral Approach Shines
In SOUL, simultaneously published in the New England Journal of Medicine, a significant improvement in major adverse limb events (HR 0.71, 95% CI 0.52-0.96) did accompany oral semaglutide's demonstrated efficacy for the primary endpoint of MACE.
Ndumele highlighted the surprise in SOUL's lack of impact on cardiovascular mortality, which had been suggested in the FLOW trial on injectable semaglutide in people with more severe CKD.
McGuire and colleagues had conducted the study in several dozen countries enrolling from 2019-2021. There were 9,650 individuals who reached the randomization phase; all had to be ages 50 or older with an HbA1c of 6.5-10.0% and at least one out of coronary artery disease, cerebrovascular disease, symptomatic PAD, and CKD.
The cohort averaged age 66.1, with 28.9% women, nearly 70% white, and nearly 25% Asian. Most participants had a history of cardiovascular disease (most commonly coronary artery disease in 70.7%) and 42.4% had a history of CKD. Baseline eGFR was 73.8 ml/minute/1.73 m2. Nearly 27% of participants were already on SGLT2 inhibitors at baseline.
The SOUL protocol had participants randomized 1:1 to oral semaglutide (starting at 3 mg and escalated to 14 mg for the rest of the study) or placebo. Participants were told to take their assigned tablet in the morning, with a little water and no food or other medications until at least 30 minutes later.
Participants averaged 47.5 months of follow-up (median 49.5 months). About 88% in both groups stayed on their assigned treatment for the duration of the trial.
MACE was defined as a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.
A secondary endpoint, major kidney disease events, came out no different between groups.
Serious AEs came out to 47.9% with oral semaglutide versus 50.3% with placebo. These were most commonly cardiac disorders (17.8% vs 19.8%) and infections (15.0% vs 16.5%), neither of which favored either group; only GI events occurred numerically in excess with semaglutide (5.0% vs 4.4%).
Despite randomization, McGuire's team noted that high-sensitivity C-reactive protein levels had been lower in the oral semaglutide group than in the placebo group at baseline, and the difference persisted over time.
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Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow
Disclosures
STRIDE and SOUL were funded by Novo Nordisk.
Bonaca is the Executive Director of the Colorado Prevention Center, a non-profit academic research organization supported by Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma, Alnylam Pharmaceuticals, Amgen, Angionetics, Anthos Therapeutics, Array BioPharma, AstraZeneca and Affiliates, Atentiv, Audentes Therapeutics, Bayer and Affiliates, Bristol Myers Squibb, Cambrian Biopharma, Cardiol Therapeutics, CellResearch, Cleerly, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading, Epizon Pharma, Esperion Therapeutics, Everly Well, Exicon Consulting, Faraday Pharmaceuticals, Foresee Pharmaceuticals, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, Janssen and Affiliates, Kowa Research Institute, Lexicon Pharmaceuticals, Medimmune, Merck and Affiliates, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Prairie Education and Research Cooperative, Prothena Biosciences, Regeneron Pharmaceuticals, Regio Biosciences, Sanofi-Aventis Group, Silence Therapeutics, Smith & Nephew, Stealth BioTherapeutics, VarmX, and Virta Health Corporation.
McGuire disclosed various personal relationships with AbbVie, Afimmune, Alnylam, Altimmune, Alveus Therapeutics, the American Heart Association, Amgen, Applied Therapeutics, Arena Pharmaceuticals, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Beren Pharmaceutical, Boehringer Ingelheim, CSL Behring, Dynavax, Eidos Pharmaceuticals, Eli Lilly, Esperion, GlaxoSmithKline, Intercept Pharmaceuticals, Ipsen Bioscience, Kailera, Lexicon Pharmaceuticals, Merck, Metavant, Metsera, Neurotronics, New Amsterdam, Novo Nordisk, Otsuka Pharmaceutical, Pfizer, Sage Publications, Sarepta Therapeutics, and Ventyx.
Bhatt reported research funding from Novo Nordisk and Eli Lilly.
Gianos disclosed consultant fees/honoraria from Kaneka and Med-IQ; and research funding from Amgen, AstraZeneca, DCRI, Eli Lilly, and Novartis.
Chiadi had no disclosures.
Primary Source
Lancet
Source Reference: Bonaca MP, 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" Lancet 2025; DOI: 10.1016/S0140-6736(25)00509-4.
Secondary Source
New England Journal of Medicine
Source Reference: McGuire DK, et al "Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes" N Engl J Med 2025; DOI: 10.1056/NEJMoa2415120.