What the indication says
Section 1 of the label lists two uses for Rybelsus® and Ozempic® tablets in adults with type 2 diabetes. The first is improving blood sugar control alongside diet and exercise. The second is reducing the risk of major adverse cardiovascular events, often shortened to MACE: death from a cardiovascular cause, a heart attack that is not fatal, or a stroke that is not fatal [1].
It applies to adults at high risk for these events; the Recent Major Changes box dates the change to 10/2025 [1]. Ozempic® injection has its own, older cardiovascular indication, worded for adults with established cardiovascular disease and based on a different trial, SUSTAIN 6 [2].
How the US, EU and Canadian documents compare
The same SOUL data appear in all three regulators’ documents, but with different wording. The table summarises what we found on 20 October 2026.
| Document | Cardiovascular wording | Where |
|---|---|---|
| Rybelsus® and Ozempic® tablets, US prescribing information, revised 1/2026 [1] | Reduce the risk of cardiovascular death, non-fatal heart attack or non-fatal stroke in adults with type 2 diabetes at high risk of these events | Section 1; SOUL as Trial 7 in 14.4 |
| Rybelsus®, EU product information [4] | No separate cardiovascular indication; the diabetes indication points to section 5.1, where SOUL and PIONEER 6 are described | Sections 4.1 and 5.1 |
| Rybelsus®, Canadian product monograph, authorized 13 July 2026 [5] | Reduce the risk of the same three events in adults with type 2 diabetes who have established cardiovascular disease or are at high risk | Section 1; SOUL in section 14 |
Two tablet products and one trial dose
The US label now covers two tablet products with different strengths: Rybelsus® at 3, 7 and 14 mg and Ozempic® tablets at 1.5, 4 and 9 mg. It states that they are not substitutable on a milligram-to-milligram basis, and its switching table pairs Rybelsus® 14 mg with Ozempic® tablets 9 mg [1]. The EU product information describes the 14 mg tablet used in SOUL as bioequivalent to its own 9 mg strength [4].
Wegovy® tablets are a separate semaglutide product with a different dose and their own heart indication, written for adults with established cardiovascular disease and obesity or overweight [6]. Numbers from SOUL cannot be moved across to another product or strength, and which product and dose fit you is your prescriber’s decision.
Who took part
The label calls the study Trial 7 and gives its registry number, NCT03914326. On ClinicalTrials.gov, the public trial registry of the US National Library of Medicine, the same study is listed as a phase 3 trial with the acronym SOUL [1][7].
Everyone enrolled had type 2 diabetes, was at least 50 years old and had established cardiovascular disease, chronic kidney disease (an eGFR below 60), or both. Just over half (56.7%) had heart or vessel disease without kidney disease, 13% had kidney disease only and 27% had both [1]. The published summary adds that HbA1c had to be between 6.5% and 10.0% at entry [3].
The average participant was 66 years old, with diabetes for 15.4 years; 71% were men. Mean HbA1c was 8%, mean BMI 31.1 and mean eGFR 73.8. Many had other serious conditions: 91% high blood pressure, 40% a previous heart attack, 23% heart failure and 16% peripheral artery disease. Nearly all used other diabetes medicines, including metformin (76%), insulin (51%) and SGLT2 inhibitors (27%), and most took cholesterol-lowering drugs (89%) and platelet inhibitors such as aspirin (77%) [1].
How the trial was run
Participants were randomly assigned, double-blind, to one 14 mg semaglutide tablet a day or a placebo tablet, on top of their usual care [1].
The main question was how long it took until a first MACE event. Median follow-up was about 49 months in both groups; the summary gives a mean of 47.5 months [1][3]. The label reports that 98.4% completed the trial and that vital status was known for 99.5% at the end, which matters because people lost to follow-up can blur an outcome trial [1].
The main result
A first MACE event occurred in 579 of 4,825 people on semaglutide tablets (12%) and in 668 of 4,825 on placebo (13.8%). The label reports a hazard ratio of 0.86, with a 95% confidence interval of 0.77 to 0.96, and says the tablets significantly reduced MACE [1]. Expressed per year, the summary gives 3.1 first events per 100 person-years on the tablets and 3.7 on placebo [3].
A hazard ratio compares how often first events happened in each group over time. A value below 1 means first events happened less often in the tablet group; the EU and Canadian documents describe 0.86 as a 14% lower relative risk [4][5]. In raw numbers, 12% of people on the tablets and 13.8% on placebo had an event over about four years. Both readings are useful when you talk it over with your clinician.
| Outcome | Placebo (n = 4,825) | Semaglutide 14 mg (n = 4,825) | Hazard ratio (95% CI) |
|---|---|---|---|
| MACE (main outcome) [1] | 668 (13.8%) | 579 (12%) | 0.86 (0.77 to 0.96) |
| Cardiovascular death | 320 (6.6%) | 301 (6.2%) | 0.93 (0.8 to 1.09) |
| Non-fatal heart attack | 253 (5.2%) | 191 (4%) | 0.74 (0.61 to 0.89) |
| Non-fatal stroke | 161 (3.3%) | 144 (3%) | 0.88 (0.7 to 1.11) |
Reading the three parts and the next outcomes
The label shows the three components of MACE separately and notes that they are listed descriptively, as support for the main result. They were not tested as separate claims [1].
The largest difference was in non-fatal heart attacks. For cardiovascular death and non-fatal stroke the confidence intervals include 1, so the trial alone cannot tell whether those parts differed. That is common in outcome trials.
SOUL also tested further outcomes in a fixed order. The first was a composite of serious kidney events, which gave a hazard ratio of 0.91 (0.80 to 1.05) in the EU product information, and the published summary says none of the confirmatory secondary outcomes differed significantly from placebo [3][4]. The Canadian monograph notes that its secondary results were not controlled for multiple testing [5].
An earlier, shorter safety trial
The label also describes Trial 8, registered as PIONEER 6 (NCT02692716): 3,183 adults with type 2 diabetes and heart or vessel disease or other risk factors, followed for a median of 16 months [1][8]. The EU text calls it a pre-approval trial meant to establish cardiovascular safety [4].
It was designed to rule out an unacceptable rise in risk, using a margin of 1.3, not to prove a reduction. That aim was met: MACE occurred in 3.8% of the tablet group and 4.8% on placebo, a hazard ratio of 0.79 with an interval (0.57 to 1.11) that crossed 1 [1].
Safety findings from the long trial
In Trial 7 the label says safety data collection was limited to serious adverse events, events that led to stopping and events of special interest. The study drug was stopped permanently because of an adverse event by 15.5% of the tablet group and 11.6% of the placebo group [1]. The summary reports serious adverse events in 47.9% on the tablets and 50.3% on placebo [3].
Gallbladder events appear in the warnings: gallstones in 1.1% versus 0.9%, and gallbladder inflammation in 1.1% versus 0.7% [1]. Adjudicated acute pancreatitis was 0.4% in both groups, according to the EU text [4]. The diabetic eye warning in the tablet label draws on a two-year outcome trial of semaglutide injection, and asks that people with a history of diabetic retinopathy be monitored [1].
Where this sits among semaglutide heart indications
Three separate US semaglutide labels now carry a heart indication, each based on a different trial and population: Ozempic® injection for adults with type 2 diabetes and established cardiovascular disease, Rybelsus® and Ozempic® tablets for adults with type 2 diabetes at high risk, and Wegovy® injection and tablets for adults with established cardiovascular disease and obesity or overweight [1][2][6].
Each indication rests on its own trial, and the Wegovy® Medication Guide says Wegovy® should not be used together with other semaglutide-containing products or other GLP-1 receptor agonists [6]. Which medicine, which form and whether any of these indications applies to you are for your prescriber to decide.
Rybelsus®, Ozempic® and Wegovy® are registered trademarks of Novo Nordisk A/S. PepLabo is not affiliated with or endorsed by Novo Nordisk.
When to get help
The signs and contact information below come from this article’s sourced guidance.
Emergency
- Chest pressure, squeezing or pain lasting more than a few minutes, or sudden shortness of breath
Contact: Emergency services (911 or your local number), even if unsure
MedlinePlus [9]
- Sudden numbness or weakness on one side, confusion, trouble speaking or seeing, or a sudden severe headache
Contact: Emergency services (911 or your local number)
MedlinePlus [10]
- Strong belly pain that keeps going, sometimes reaching the back, whether or not you feel sick or vomit
Contact: Stop the tablets and call your prescriber right away, as the guide says
Medication Guide [1]
Today
At your next appointment
- Questions about whether the heart indication applies to you, or how a tablet fits with your other heart medicines
Contact: Your prescriber or cardiologist
US label, section 1 [1]