Novo Nordisk says oral semaglutide cut cardiovascular events by 14% in SOUL trial

Novo Nordisk said Oct. 21 that its oral semaglutide tablet, Rybelsus, reduced the risk of major adverse cardiovascular events by 14% versus placebo in a Phase III study called SOUL ^[2]. The company plans to take the data to regulators near the end of 2024 as it seeks a label expansion for the pill ^[2].

SOUL enrolled 9,650 people age 50 and older who had type 2 diabetes plus established cardiovascular disease, chronic kidney disease, or both ^[2]. It was a multicenter, international, randomized, double-blind, placebo-controlled trial: participants took 14 mg of oral semaglutide once daily or a placebo on top of their existing standard of care ^[2]. The primary measure was whether the drug lowered the risk of MACE, or major adverse cardiovascular events, and the trial met that goal ^[2]. The results also appeared in the journal Diabetes, Obesity and Metabolism ^[2].

Martin Holst Lange, Novo Nordisk's executive vice president and head of Development, said the drug's benefits came "on top of standard of care," and noted that about one in three adults with type 2 diabetes also has cardiovascular disease ^[2].

Semaglutide is a GLP-1 receptor agonist. The FDA has approved it both as a once-weekly injection, sold as Ozempic for diabetes and Wegovy for weight management, and as a daily tablet, Rybelsus ^[2]. Wegovy already picked up a cardiovascular indication in March 2024, for adults with known heart disease who also have obesity or overweight, to be used with a reduced-calorie diet and more activity ^[2].

The SOUL investigators wrote that trials pushing for tighter blood sugar control have not convincingly improved cardiovascular outcomes, while some drugs in the GLP-1 receptor agonist and SGLT2 inhibitor classes have, and those effects appeared largely separate from glucose lowering ^[2]. Across at least nine outcomes trials with 60,080 participants combined, GLP-1 receptor agonists have shown benefit for cardiovascular death and kidney outcomes in people with type 2 diabetes who have or are at high risk of cardiovascular disease, the authors wrote ^[2].

Several specifics were not in the announcement. Absolute event rates in each group, statistical details such as a p-value, and which particular events accounted for the 14% difference have not been reported ^[2]. A 2025 scientific conference will present the detailed findings; it has not been named ^[2]. Novo Nordisk has not disclosed a timeline for any regulatory decision ^[2].

Why it matters for patients

SOUL studied exactly the group where cardiovascular risk is the main worry: adults with type 2 diabetes who already have heart or kidney disease ^[2]. Injectable semaglutide carries cardiovascular outcome evidence; a pill would offer the same molecule without shots ^[2]. The study authors pointed to a survey of 113 physicians and 1,096 patients that found prescribing and dose increases were delayed even when blood sugar was poorly controlled, mostly because of the injectable route, inconvenience and perceived injection burden ^[2]. They suggested that an oral GLP-1 with proven cardiovascular benefit might help overcome hesitancy among patients and doctors alike ^[2].

Two limits are worth noting. The 14% figure is a relative reduction, and without absolute event rates the size of the benefit for any one person has not been reported ^[2]. And the trial tested one drug, oral semaglutide 14 mg, in a specific population, so the results do not automatically carry over to weight-loss-only use or to other GLP-1 medicines or drug classes ^[2].

What happens next

Novo Nordisk expects to submit the SOUL data to regulators around the end of 2024 ^[2]. Detailed results are scheduled for a scientific conference in 2025 ^[2]. No date has been given for a decision on expanding the Rybelsus label ^[2].