ACHIEVE-4: orforglipron and heart safety in type 2 diabetes

Why this study matters

As of October 2026, orforglipron is not authorized in Canada, and this study is research for Canadian readers. Health Canada has been reviewing it since January 2026. The US FDA approved it on 1 April 2026 as Foundayo for weight management. Orforglipron is a GLP-1 receptor agonist taken as a daily pill. It is a small molecule, not a peptide (a protein-like molecule). The authors note that the heart safety of non-peptide GLP-1 medicines like orforglipron had not been studied before. ACHIEVE-4 was designed to check that orforglipron does not raise the risk of heart attacks, strokes and related events in people at higher risk.

Who was in the study

The trial randomized 2749 adults at 317 sites in 16 countries and territories. Everyone had type 2 diabetes, an HbA1c between 7.0% and 10.5%, and a BMI of 25 or higher. HbA1c is a blood test that reflects average blood sugar over the past few months. BMI, or body mass index, is weight in kilograms divided by height in metres squared. Everyone was taking up to three diabetes medicines (metformin, a sulfonylurea or an SGLT2 inhibitor) and had established heart or blood vessel disease or chronic kidney disease.

Of the 2749 people, 1032 (38%) were female and 1717 (62.5%) were male. In all, 2362 (85.9%) had heart or blood vessel disease and 1033 (37.6%) had chronic kidney disease. The average age was 63.1 years, the average HbA1c was 8.2% and the average BMI was 33.

What the researchers did

People were randomized, meaning assigned by chance, in equal numbers to one of two treatments. One group took orforglipron by mouth once a day, at the highest dose they could tolerate, up to 36 mg as a capsule (which the authors say is equivalent to a 17.2 mg tablet). The other group injected insulin glargine, a long-acting insulin, once a day, with the dose adjusted over time. The trial was open-label, meaning everyone knew which treatment they were getting. It was event-driven, meaning it continued until a set number of heart events had happened.

The main result was the time until a first major heart event, called MACE-4. This counted death from heart or blood vessel causes, a non-fatal heart attack, a non-fatal stroke, or a hospital stay for unstable angina (chest pain from reduced blood flow to the heart).

This was a non-inferiority trial. Its goal was to show orforglipron is not worse than the comparison, not to show it is better. The result was summed up as a hazard ratio, which compares how often events happened in the two groups over time. A hazard ratio of 1 means no difference. Orforglipron would count as not worse if the top of the 95% confidence interval for the hazard ratio was below 1.8. A confidence interval, or CI, is the range of values the data are reasonably consistent with. The analysis included everyone who took at least one dose, whether or not they kept taking it.

What they found

Over a median follow-up of 2 years, a major heart event happened in 57 of 1358 people (4.2%) on orforglipron and 67 of 1343 people (5.0%) on insulin glargine. The hazard ratio was 0.84 (95% CI 0.59 to 1.20). The top of that range, 1.20, is below 1.8, so orforglipron met the test for being no worse than insulin glargine (P below 0.0001 for non-inferiority) (R33-C09).

Because the range includes 1, the trial did not show that orforglipron lowered heart events compared with insulin glargine. The published summary we reviewed does not report changes in weight or HbA1c.

Side effects and people who stopped

Stomach and bowel side effects were the most common side effects with orforglipron and the most common reason people stopped taking it (R33-C10). Low blood sugar was less common with orforglipron than with insulin glargine. The published summary we reviewed does not give the number of people who stopped treatment.

There were 62 deaths in total. All but one, in the insulin glargine group, were judged unrelated to treatment (R33-C11). The published summary we reviewed does not report a statistical comparison of deaths, so this difference should not be read as a proven benefit.

What this study does not tell you

• The comparison was insulin glargine, not placebo or another GLP-1 medicine, and the trial was open-label, which can affect how side effects are reported.
• The non-inferiority limit of 1.8 was set to rule out a large increase in risk. The result's range, 0.59 to 1.20, still allows for anything from a lower risk to a somewhat higher risk with orforglipron.
• The doses were given as capsules. The authors say the 36 mg capsule is equivalent to a 17.2 mg tablet, so capsule and tablet doses are not labelled the same way.
• Everyone had type 2 diabetes and heart or kidney disease, so the results may not apply to people without diabetes.
• The trial was funded by Eli Lilly and Company, which makes orforglipron, and several authors work for the company.

What it means in Canada

As of October 2026, orforglipron is not authorized in Canada and has been under Health Canada review since January 2026. ACHIEVE-4 adds heart safety evidence in people with type 2 diabetes, but it does not change the Canadian status. You can follow emerging medicines on our medicines page. For medicines available in Canada, see semaglutide in Canada, tirzepatide in Canada and public drug coverage by province.

Related reading

Other studies in this library that bear on the same question.

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