Oral Semaglutide Lowers Cardiovascular Events by 14% in Type 2 Diabetes Patients with Heart, Kidney Disease

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Headline data from the Phase III SOUL trial found that oral semaglutide (Rybelsus) lowered major adverse cardiovascular events (MACE) by 14% compared to placebo in patients with type 2 diabetes and cardiovascular (CV) or kidney disease.^1,2 The results of the trial, also published by Diabetes, Obesity and Metabolism, are expected to be submitted to regulatory authorities around the end of the year to support a label expansion, according to Novo Nordisk, who added that detailed data from the trial will also be presented at a scientific conference in 2025.

"We are pleased to see that the results from SOUL demonstrate that oral semaglutide reduces the risk of cardiovascular events and that the benefits of oral semaglutide come on top of standard of care,” Martin Holst Lange, executive vice president and head of Development at Novo Nordisk, said in a press release. “Approximately one in three adults with type 2 diabetes also have cardiovascular disease; therefore, it is crucial to have therapies that can address both conditions.”¹

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA), was initially approved in June 2021 for chronic weight management in those with obesity or overweight and at least one weight-related condition, including high blood pressure, type 2 diabetes, or high cholesterol, in addition to diet and increased exercise.³ Semaglutide has been approved by the FDA in both long-acting injectable (Wegovy and Ozempic) and daily oral tablet (Rybelsus) formulations. In March 2024, Wegovy (semaglutide) was approved by the FDA to reduce the risk of MACE in adults with known heart disease and with obesity or overweight, in addition to a reduced calorie diet and increased physical activity.⁴

The multicenter, international, randomized, double-blind, parallel-group, placebo-controlled, SOUL cardiovascular outcomes trial enrolled 9650 patients aged ≥50 years to evaluate the effect of oral semaglutide (14 mg once daily) on cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease (CVD) and/or chronic kidney disease (CKD). The trial’s primary objective was to show that oral semaglutide reduced the risk of MACE in comparison with placebo, in addition to standard of care, in patients with type 2 diabetes and established CVD and/or CKD.

“Clinical intervention trials evaluating the effectiveness of more versus less intensive glucose control have failed to demonstrate convincing benefits for CV outcomes in type 2 diabetes,” the study authors wrote. “However, results from trials designed specifically to assess CV safety/efficacy of antihyperglycaemic medications in type 2 diabetes have proven that some, but not all agents among the (GLP-1RA) and sodium-glucose cotransporter-2 (SGLT2) inhibitor classes lower CVD risk. Importantly, among those with proven CV efficacy, these effects have been observed to be largely independent of glucose-lowering effects.”²

With Rybelsus achieving the trial’s primary objective, the study authors noted that the safety and efficacy of GLP-1RAs in patients with type 2 diabetes with or at high risk for CVD, have been shown across at least nine outcomes trials to date with a combined total of 60,080 participants. Data from these trials have confirmed the efficacy of GLP-1RAs on CV mortality and kidney outcomes in patients with type 2 diabetes with or at high risk for CVD, according to the trial investigators.

“The results from the SOUL trial will add to the evidence base for the safety and CV efficacy of GLP-1RAs, specifically evaluating safety and efficacy of the first oral GLP-1RA,” the study authors concluded. “If the trial outcome is favourable, the availability of an oral GLP-1RA with proven CV efficacy may help overcome any hesitancy from patients and clinicians alike, in using this category of antihyperglycaemic medication, previously only available in injectable formulations. Indeed, a previous survey conducted with 113 physicians and 1096 patients has shown delays in treatment prescribing and uptitration of GLP-1RAs, despite poor glycaemic control, predominantly due to the injectable mode of administration, lack of convenience and perceived increased injection burden.”²

References

1. Novo Nordisk A/S: Oral semaglutide demonstrates a 14% reduction in risk of major adverse cardiovascular events in adults with type 2 diabetes in the SOUL trial. News release. Novo Nordisk. October 21, 2024. Accessed October 23, 2024. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=171480

2. McGuire DK, Busui RP, Deanfield J, Inzucchi SE, Mann JFE, Marx N, Mulvagh SL, Poulter N, Engelmann MDM, Hovingh GK, Ripa MS, Gislum M, Brown-Frandsen K, Buse JB. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial. Diabetes Obes Metab. 2023 Jul;25(7):1932-1941. doi: 10.1111/dom.15058. Epub 2023 Apr 11. PMID: 36945734.

3. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. News release. June 4, 2021. Accessed October 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014

4. Wegovy® receives FDA approval for cardiovascular risk reduction in adults with known heart disease and overweight or obesity. Novo Nordisk. News release. March 8, 2024. Accessed October 23, 2024. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=167031