Novo Nordisk Details SOUL Trial Behind Rybelsus MACE Approval

Novo Nordisk Canada has detailed the SOUL trial behind Health Canada's expanded indication for Rybelsus (semaglutide tablets) to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes, with the company calling it the first and only approved GLP-1 in pill form in Canada with the new indication [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/].

Trial design and scale

The SOUL trial was a randomized, double-blind, parallel-group, placebo-controlled study evaluating semaglutide tablets in patients aged 50 years or older with type 2 diabetes mellitus and established cardiovascular disease and/or chronic kidney disease [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/]. In total, 9,650 patients were randomized to receive either Rybelsus 14 mg or placebo daily [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/].

The primary endpoint was time to first occurrence of a three-part composite outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/]. The trial results were published in the New England Journal of Medicine online on March 29, 2025 [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/].

Company statement

Announcing the Mississauga, Ontario approval, Vince Lamanna, President of Novo Nordisk Canada Inc., said: “This approval marks an important milestone for type 2 diabetes patients in Canada, who are at higher risk of cardiovascular events due to the chronic disease” [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/]. Lamanna added that Rybelsus “is the first and only approved GLP-1 in pill form in Canada that improves glycemic control and offers cardiovascular protection” [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/].

Novo Nordisk noted that Health Canada originally approved Rybelsus in April 2020 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/].

Indication specifics

The expanded indication permits the use of semaglutide tablets to reduce the risk of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in adults with type 2 diabetes mellitus who have established cardiovascular disease or are at high risk for these events [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/].

According to Novo Nordisk's announcement, an estimated 9 in 10 Canadians have at least one risk factor for stroke, heart disease, or vascular cognitive impairment, including sex, age, diabetes, family history, and Indigenous, South Asian, and African family heritage [Source: lifesciencesbc.ca/members/health-canada-approves-rybelsus-semaglutide-tablets-to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-in-adults-with-type-2-diabetes/].

Context: shifting Canadian GLP-1 landscape

The Rybelsus indication expansion lands in a Canadian market that is in flux. On April 28, 2026, Health Canada authorized the first generic semaglutide injection, filed by Dr. Reddy's Laboratories as a generic version of brand-name Ozempic, making Canada the first G7 country to approve a generic version of semaglutide [Source: canada.ca/en/health-canada/news/2026/04/canada-becomes-the-first-g7-country-to-approve-a-generic-version-of-semaglutide.html]. Health Canada said it was concurrently reviewing eight other submissions for generic semaglutide from different companies, with decisions expected in the coming weeks and months [Source: canada.ca/en/health-canada/news/2026/04/canada-becomes-the-first-g7-country-to-approve-a-generic-version-of-semaglutide.html].

Obesity Canada's Scientific Director, Dr. Sanjeev Sockalingam, noted that fewer than 20 per cent of Canadians with private drug benefit plans have access to Health Canada-approved obesity treatment medications [Source: obesitycanada.ca/news/health-canada-generic-semaglutide-approval/]. Coverage variability across Canadian plans has been an ongoing focus for patients comparing brand-name semaglutide and tirzepatide products including Wegovy, Mounjaro, and Zepbound. Patients can check current plan rules using the insurance coverage checker and follow regulatory developments via the generic semaglutide tracker, with additional background available on the FAQ.

This article is for informational purposes only and does not constitute medical advice.