FDA adds a cardiovascular indication to the oral GLP-1 Rybelsus

The FDA approved Rybelsus (semaglutide) on October 17, 2025 for a new use: lowering the risk of major adverse cardiovascular events in adults with type 2 diabetes who face a high risk of those events. No other GLP-1 medicine taken by mouth carries that indication ^[5][6].

The indication covers cardiovascular death, nonfatal heart attack and nonfatal stroke, the three parts of the composite endpoint used in the trial ^[5]. Novo Nordisk said it applies whether or not a person has already had a cardiovascular event, covering what the company calls primary and secondary prevention ^[5]. The cardiovascular use applies to the 7 mg and 14 mg tablets, taken once daily ^[5].

SOUL, the trial behind the decision, enrolled 9,650 adults with type 2 diabetes and high cardiovascular risk. Participants were randomly assigned to oral semaglutide at a maximum dose of 14 mg or to placebo, both added to standard care, and were followed for a mean of about four years ^[5][6]. A first MACE occurred in 579 of 4,825 people on semaglutide, or 12.0%, and in 668 of 4,825 on placebo, or 13.8%. That is a hazard ratio of 0.86 (95% CI, 0.77-0.96; p=0.006) ^[5]. Novo Nordisk described the result as a 14% relative reduction in risk over four years and a 2% absolute reduction at three years, with the benefit driven mainly by fewer nonfatal heart attacks ^[5][6].

Serious adverse events were reported in 47.9% of the semaglutide group and 50.3% of the placebo group. Serious cardiac problems were less frequent with the drug (17.8% versus 19.8%), while serious gastrointestinal problems were slightly more frequent (5.0% versus 4.4%). About 15% of people on semaglutide stopped treatment because of an adverse event, compared with 11.6% on placebo, mostly for gastrointestinal problems or infections ^[5]. The label lists nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation among the common side effects, and carries warnings about pancreatitis, diabetic retinopathy complications, low blood sugar when the drug is used with insulin or sulfonylureas, kidney injury from dehydration, and thyroid C-cell tumors seen in rodents ^[1][5].

“Even in the absence of a previous heart attack or stroke, adults with type 2 diabetes face an increased risk of cardiovascular events, underscoring the need for therapies that go beyond managing blood sugar,” said John B. Buse, MD, PhD, of the UNC School of Medicine and a co-chair of the SOUL steering committee ^[5].

Rybelsus was first cleared on September 20, 2019 as the first oral GLP-1 for blood sugar control in adults with type 2 diabetes ^[1][5]. Novo Nordisk says the medicine is sold in 45 countries and has been prescribed to 2.4 million people worldwide ^[5].

Why it matters for patients

People who would rather swallow a tablet than give themselves an injection now have a cardiovascular option. The semaglutide injection Ozempic already carries a MACE risk-reduction indication, so this adds a delivery method rather than a new kind of benefit ^[1].

The size of the benefit depends on how it is measured. SOUL showed 14% fewer events in relative terms and a 2% absolute risk reduction at three years, meaning the absolute difference between groups was small even though the relative change was statistically significant ^[5].

The trial tested semaglutide on top of standard care, so the results reflect the drug as an addition to other treatments, not a replacement for them ^[5]. The approval is limited to type 2 diabetes with high cardiovascular risk. It is not an obesity approval, and the label states it is not known whether Rybelsus is safe and effective in children ^[5]. Whether the new indication changes what patients pay for the drug has not been reported.

What has happened since

The same molecule has moved into other labels. On December 22, 2025, the FDA approved a once-daily semaglutide pill under the Wegovy brand for weight loss in adults with obesity, or with overweight plus a weight-related condition, also indicated to reduce MACE risk in adults with overweight or obesity who have established cardiovascular disease ^[4].

On January 30, 2026, the FDA approved a labeling update renaming the Rybelsus R2 formulation as Ozempic tablets, and a February 4, 2026 company announcement said the Ozempic pill would reach the US market in the second quarter of 2026 ^[1].