The global SOUL trial of oral semaglutide on cardiovascular outcomes in people living with type 2 diabetes and high cardiovascular disease (CVD) risk showed a 14% reduction in major adverse cardiovascular events (MACE) compared to placebo. Oral semaglutide improved each of the composite measures, death from cardiovascular causes, nonfatal stroke, and nonfatal myocardial infarction.

“Early separation of the curves demonstrates the role of oral semaglutide in people with type 2 diabetes and high cardiovascular risk,” said Rodica Pop-Busui, MD, PhD, the Jordan Schnitzer Endowed Chair in Diabetes, Professor and Head of Endocrinology and Diabetes, and Director of the Harold Schnitzer Diabetes Center at Oregon Health & Sciences University, during the Sunday, June 22, symposium, SOUL Trial—Effects of Oral Semaglutide on Cardiovascular (and Other) Outcomes in People with Type 2 Diabetes at High CV Risk.

Oral semaglutide also showed a nonsignificant numerical superiority for a composite kidney outcome. Components included cardiovascular-related death, kidney-related death, persistent ≥50% estimated glomerular filtration rate (eGFR) reduction, persistent eGFR ≤15 mL/min/1.73m², and chronic kidney replacement therapy.

There was also a significant improvement in a composite of major adverse limb events, including hospitalization for acute or chronic limb ischemia.

“This was the first time PAD (peripheral artery disease) has been prioritized in a glucagon-like peptide-1 receptor agonist (GLP-1 RA) trial,” said Darren K. McGuire, MD, MHSc, Distinguished Teaching Professor and the Jere H. Mitchell, MD Distinguished Chair in Cardiovascular Science, University of Texas Southwestern Medical Center.

SOUL randomized 4,825 individuals to oral semaglutide and 4,825 to placebo. Nearly all participants, 98%, completed the trial despite the COVID-19 pandemic and other global events, Dr. McGuire noted.

The median age of patients was 66 years, 29% were female, and 69% were white with a body mass index (BMI) of 31. The median duration of type 2 diabetes was 15 years, and virtually all participants had CVD, chronic kidney disease (CKD), or both, at baseline. Other medications were allowed other than GLP-1 RAs.

SOUL is the largest GLP-1 trial to include a prespecified secondary analysis of outcomes by concomitant sodium-glucose cotransporter-2 (SGLT2) inhibitor use, noted Nikolaus Marx, MD, Professor of Cardiology and Head of Internal Medicine, University Hospital Aachen, Germany.  About a quarter of participants (26.9%) were using SGLT2 inhibitors at baseline, and 48.9% used an SGLT2 inhibitor during SOUL.

Oral semaglutide reduced MACE outcomes independent of any SGLT2 inhibitor use, Dr. Marx reported. These findings support current guideline recommendations from the American Diabetes Association^® (ADA) and the European Society of Cardiology endorsing GLP-1 RAs and/or SGLT2 inhibitors as first-line therapies for patients with type 2 diabetes and established CVD.

“These findings underscore current guidelines for the additive use of both agents in people with type 2 diabetes and cardiovascular disease,” Dr. Marx said.

Subgroup analyses show consistent cardiovascular benefits for oral semaglutide regardless of baseline BMI and greater benefit for baseline A1C levels >8%.

“Patients with A1C above and below 8% contributed to the positive primary outcome, but it appears to be more pronounced at higher A1C levels at baseline,” said John B. Buse, MD, PhD, the Verne S. Caviness Distinguished Professor and Director of the Diabetes Care Center, University of North Carolina School of Medicine.

SOUL showed a nonsignificant benefit for stroke, but some subgroups may benefit.

“Subgroup analyses suggest that younger patients and those without hypertension may experience a stroke benefit from oral semaglutide,” said Silvio E. Inzucchi, MD, Professor and Clinical Chief of Endocrinology at Yale School of Medicine and Medical Director of the Yale Diabetes Center. “But overall, the relative risk ratios for nonfatal stroke and fatal/nonfatal stroke were not statistically significant.”

Current guidelines from the ADA and American Stroke Association recommend GLP-1 RAs for secondary ischemic stroke prevention. The addition of an SGLT2 inhibitor is recommended if the risk for heart failure or CKD predominate.

The results of SOUL will likely extend well beyond diabetology and cardiology, said John Deanfield, MB, BChir, Professor of Cardiology, University College London, United Kingdom. Medicine is siloed, he explained, but patients are not.

“All of us see patients with the malignant triad—type 2 diabetes, cardiovascular disease, and chronic kidney disease,” Dr. Deanfield said. “One of these is bad enough, but if you have more than one, it worsens outcomes for the others. This is a truly disruptive moment in health care. SOUL represents clinical benefits consistent with injectable formulations of GLP-1 receptor agonists. It harmonizes and facilitates cardiology, endocrinology, and nephrology practices … which will have wide implications for population health.”

On-demand access to presentations from the 85^th Scientific Session will be available to registered participants following the conclusion of the meeting in Chicago, from June 25–August 25.