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March 29, 2025
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Key takeaways:
Oral semaglutide reduced risk for cardiovascular events in people with type 2 diabetes, atherosclerotic CVD and kidney disease.
It is now the first and only oral GLP-1 receptor agonist with proven CV benefit.
CHICAGO — Oral semaglutide reduced risk for major adverse CV events by 14% in high-risk adults with type 2 diabetes regardless of SGLT2 inhibitor use, according to data presented at the American College of Cardiology Scientific Session.
Researchers presenting findings from the SOUL trial, simultaneously published in The New England Journal of Medicine, also found that the overall safety profile of oral semaglutide 14 mg (Rybelsus, Novo Nordisk), a GLP-1 receptor agonist approved for people with type 2 diabetes, was similar to what has been observed in previous semaglutide trials, adding to the favorable risk-benefit profile for the class and making this the first oral GLP-1 to show CV benefit.
Oral semaglutide reduced risk for cardiovascular events in people with type 2 diabetes, atherosclerotic CVD and kidney disease. Image: Adobe Stock
“The study design for SOUL was not terribly different from the other CV outcomes trials that have focused on high-risk ASCVD patients; however, we amplified it with prevalent, diagnosed ASCVD, making it a true secondary prevention population, while also adding to it a chronic kidney disease cohort,” Healio | Cardiology Today Editorial Board Member Darren K. McGuire, MD, MHSc, professor of medicine in the division of cardiology, Dallas Heart Ball Chair for Research on Heart Disease in Women and Distinguished Teaching Professor at the University of Texas Southwestern Medical Center, said during an interview. “We hit the target we were anticipating. These findings bring us back to center and support the fact that oral semaglutide will generate the same CV benefits as the rest of the class of GLP-1 receptor agonists.”
SOUL was a double-blind, event-driven, superiority trial including 9,650 adults aged 50 years or older with longstanding type 2 diabetes, known ASCVD, CKD or both, followed for a mean of 49.5 months. Researchers randomly assigned patients to receive oral semaglutide gradually titrated to the maximal, 14-mg dose or placebo on top of standard care. Despite some having CKD, kidney function was well-preserved in this cohort, with a mean estimated glomerular filtration rate of 74 mL/min/1.73 m2; more than half of participants were also taking SGLT2 inhibitors at some point during the trial.
The primary outcome was a composite of CV death, nonfatal MI or nonfatal stroke; confirmatory secondary outcomes included major renal events.
At follow-up, 12% of participants in the semaglutide group (incidence rate, 3.1 events per 100 person-years) and 13.8% of participants in the placebo group (incidence rate, 3.7 events per 100 person-years) experienced a primary outcome event, for an HR of 0.86 (95% CI, 0.77-0.96; P = .0006).
Darren K. McGuire
“Importantly, at 3 years that was an absolute difference of 2%, yielding a number needed to treat of 50,” McGuire said during the presentation.
The first confirmatory secondary outcome — a kidney-related composite of CV death, kidney death, persistent eGFR reduction of at least 50%, persistent eGFR of less than 15 mL/min/1.73 m2 and chronic kidney replacement therapy — did not differ between groups.
Because of that, the other two confirmatory secondary outcomes — CV death (HR = 0.93; 95% CI, 0.8-1.09) and major adverse limb events (HR = 0.71; 95% CI, 0.52-0.96) — were not tested for significance, McGuire said.
Serious adverse events did not differ between the groups.
In a prespecified analysis simultaneously published in Circulation, researchers found the SOUL results remained consistent regardless of background SGLT2 therapy (P for interaction = .66), suggesting an independent treatment benefit with oral semaglutide, McGuire said.
“Delivery of this tablet is more complicated than usual,” McGuire told Healio. “Because of the mechanism of its delivery, oral semaglutide must stick to the gastric mucosa. It must be taken in a fasting state with minimal liquid intake — 4 oz of water and then nothing else orally while the tablet is delivering the medicine. We were not sure if a large population could follow these rules. What this study shows is, on average, people got the medicine. That makes these data very generalizable and prescribable.”
Reference:
For more information:
Darren K. McGuire, MD, MHSc, can be reached at darren.mcguire@utsouthwestern.edu.
Perspective
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Data from SOUL are further testament to the benefits of GLP-1s, particularly semaglutide, in patients with CV risk, namely those with diabetes and renal disease. This study demonstrated an important reduction in a combined three-point MACE endpoint of cardiac death, nonfatal MI and stroke. I am not surprised with the level of impact. The authors did a good job explaining why their first hierarchical variable — renal disease — did not meet statistical significance. These patients, despite having kidney disease, had a eGFR in the normal range, as opposed to participants from the FLOW trial, which enrolled fewer patients who also had worse renal function and a much lower eGFR. We know that sicker people generally derive better benefits with an intervention, and this is something that has plagued primary prevention trials for years. However, if one looks at the data for nonfatal MI, there is not a patient out there that would not like to prevent that type of event. This is also what we might have anticipated considering what we know about the bioavailability of oral semaglutide vs. the injectable version.
Does this study damper my enthusiasm for GLP-1s, or for semaglutide specifically? The answer is no. The SUSTAIN and SELECT studies drove a lot of my clinical activity and the way I treat patients as a cardiologist. If there is a patient who fits the phenotype of this study and they just will not take an injectable version of this drug, I would have no hesitation prescribing the oral medication.
There is still work to do. We must make sure this information is disseminated to physicians of all specialties, namely primary care physicians, nephrologists and cardiologists. We must make sure they understand the data as well as the limitations.
Howard Weintraub, MD
Clinical Director
Center for the Prevention of Cardiovascular Disease
NYU Langone Heart
Clinical Professor
Department of Medicine
Leon H. Charney Division of Cardiology
NYU Grossman School of Medicine
Disclosures: Weintraub reports receiving consultant fees from Novo Nordisk and serving as a clinical investigator for the SELECT trial.
Published by:
Sources/DisclosuresCollapse
Source:
McGuire DK, et al. Joint American College of Cardiology/Journal of the American Heart Association late-breaking clinical trials III. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).
Disclosures:
McGuire reports receiving consultant fees from Altimmune, Alveus Pharma, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Intercept Pharmaceuticals, Kailera, Lexicon, Metsera, Neurotronics, NewAmsterdam, Novo Nordisk, Pfizer and Ventyx Pharmaceuticals.
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