In high-risk type 2 diabetes, adding oral semaglutide to standard care reduced MACE at a mean 48 mo

A manufacturer trial found that semaglutide reduced major adverse cardiovascular (CV) events in type 2 diabetes patients who had CV disease, chronic kidney disease, or both at baseline. The SOUL trial, funded by Novo Nordisk, randomized 9,650 patients ages 50 years or older to daily semaglutide or placebo and showed a 13.8% lower rate of CV events in the former group versus the latter over a follow-up of about four years.

The study was published on March 29 by the New England Journal of Medicine. The following commentary by Satya Sai Sri Bandi, MBBS, and Victor M. Montori, MD, was published in the ACP Journal Club section of Annals of Internal Medicine on July 1.

Subcutaneous glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly used to reduce weight and long-term diabetes complications and to improve glycemic control in patients with type 2 diabetes. Limited direct evidence is available for oral formulations. The SOUL trial contributes evidence about the efficacy of oral semaglutide (vs. placebo) for reducing major adverse CV events, mostly nonfatal myocardial infarction, in patients with diabetes and CV or renal disease.

SOUL findings—both safety and CV efficacy—are consistent with the results of placebo-controlled trials evaluating subcutaneous GLP-1 receptor agonists, including liraglutide, dulaglutide, and semaglutide, in patients with and without diabetes. Although the effect of oral semaglutide on kidney outcomes was also consistent, the SOUL estimate was imprecise. Oral semaglutide typically offers less glycemic control and weight loss than the subcutaneous formulation. SOUL also adds to evidence supporting the use of GLP-1 receptor agonists in patients with peripheral artery disease and limb ischemia, including evidence linking liraglutide with a lower risk for amputations and subcutaneous semaglutide vs. placebo increasing walking distance in patients with intermittent claudication.

This evidence can support clinicians and patients in determining whether to use a GLP-1 receptor agonist and which one to use. SOUL findings invite consideration of oral semaglutide in patients at high risk for CV complications, provided patients can take the medication daily while fasting, which some may find burdensome. Patients who prefer to discontinue subcutaneous semaglutide may switch to the oral form to continue to prevent CV complications while potentially mitigating weight regain.