By Dr. Asnat Raziel, bariatric surgeon specializing in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal, Tel Aviv
Foundayo heart safety: the bottom line first
Foundayo heart safety is the focus of the ACHIEVE-4 trial, published in September 2026. The trial tested the drug in people with type 2 diabetes and increased heart risk. The result: the pill met its heart safety goal against insulin. In addition, there were fewer deaths. However, it is important to distinguish between proven safety and heart protection that still needs confirmation.
When we evaluate a treatment for diabetes and obesity, the question is not only how many kilograms come off. We also need to check what happens to the heart and blood vessels. That is why Lilly presented the trial results on September 30, 2026, which appeared at the same time in The Lancet. The trial compared Foundayo, which contains orforglipron, with insulin glargine.
What is Foundayo, and where does it stand today?
Foundayo is a daily pill that activates the GLP-1 receptor. Unlike other drugs in this family, it is a small molecule rather than a protein. You take it once a day, with no fasting and no restrictions on drinking water. The FDA, the US Food and Drug Administration, approved it in April 2026 for weight management, based on trials such as ATTAIN-1. You will find a complete treatment guide in my article on Foundayo treatment.
As for diabetes, the US application for approval is still under review. In Europe, by contrast, the European Medicines Agency’s scientific committee recommended on October 16, 2026, approving it for type 2 diabetes as well. In Israel, the drug has been available since mid-September 2026.
What did the ACHIEVE-4 trial test?
The trial was randomized, phase 3 and open-label. It included 2,749 people with type 2 diabetes and overweight or obesity, at 317 centers in 16 countries. Their average age was 63. Overall, 85.9% had established cardiovascular disease, and 37.6% had chronic kidney disease. Participants received either Foundayo at the highest dose they tolerated, up to 17.2 mg, or insulin glargine. Median follow-up lasted two years.
The main measure was MACE-4. This is a combined measure of four serious events: cardiac death, nonfatal heart attack, nonfatal stroke and hospitalization for unstable angina. Such an event occurred in 57 of 1,358 participants in the Foundayo group (4.2%). By comparison, it occurred in 67 of 1,343 participants in the insulin group (5.0%).
Foundayo heart safety in numbers
These are the hazard ratios versus insulin glargine, with 95% confidence intervals:
- MACE-4, the main measure: 0.84 (0.59-1.20).
- MACE-3, meaning cardiac death, heart attack or stroke: 0.77 (0.52-1.13).
- Cardiac death: 0.47 (0.25-0.90).
- Death from any cause: 0.43 (0.25-0.75).
In absolute numbers, 19 participants in the Foundayo group died during the trial (1.4%). In the insulin group, 43 participants died (3.2%). The researchers judged that all deaths except one in the insulin group were unrelated to treatment.
Foundayo heart safety: what exactly was proven?
These numbers call for careful reading. A hazard ratio of 0.84 reflects an estimated relative reduction of 16% in the main measure. However, the confidence interval includes the value 1. Therefore, the result does not prove a significant reduction in events. This also holds for the 23% relative reduction in MACE-3.
The researchers designed the trial to show non-inferiority, meaning it had to stay within a safety margin set in advance. The margin required the upper end of the confidence interval to fall below 1.8. In practice, it was 1.20. This result supports Foundayo heart safety within the trial. Even so, it does not prove superiority in preventing heart events.
The death data: an encouraging signal, not a promise
These mortality data are especially intriguing. The estimate showed a 53% lower risk of cardiac death, and a 57% lower risk of death from any cause. But these were prespecified analyses without correction for multiple comparisons. When researchers test many measures, the chance of finding a significant result by chance grows. So these data are encouraging for a possible benefit, but they are not a promise that the drug cuts deaths by these rates.
Blood sugar, weight and kidneys
After 52 weeks, HbA1c, the average blood sugar over the past three months, fell by 1.6 percentage points with Foundayo. With insulin, it fell by 1.0 percentage point. At the same time, weight dropped by 8.8%, about 8.1 kg, compared with a 1.7% gain on insulin. After two years, 54.6% of patients on the pill reached an HbA1c of 6.5% or lower, compared with 23.8% on insulin.
In addition, according to Lilly, the decline in kidney function (eGFR) was 2.8 units smaller in the pill group than with insulin. Protein in the urine also fell by 27.1% more than with insulin.
Side effects and hypoglycemia
Heart safety does not cancel out other side effects. Gastrointestinal effects occurred in 62.1% of the pill group, compared with 14.2% on insulin. On the other hand, hypoglycemia, a significant or severe drop in blood sugar, was much less common: 6.8% versus 19.2%. According to Lilly, 10.6% of patients on the pill stopped it because of side effects during the first 52 weeks. According to a conference report, 8.9% stopped because of gastrointestinal effects, compared with 0.2% on insulin.
Who are these data relevant for?
The trial adds important evidence for people with diabetes and increased heart risk. However, we cannot draw direct conclusions from it about people with obesity who do not have diabetes. Also, it does not compare Foundayo with Mounjaro or Wegovy. Both of those injections already have heart protection data, as I describe in my articles on semaglutide and the heart and on Mounjaro and heart disease prevention.
To truly test heart protection, researchers need a different trial. The ATTAIN-Outcomes trial, now under way, is examining heart events in people with overweight or obesity and heart or kidney disease, with or without diabetes.
Bottom line on Foundayo heart safety
We now have a broad research base for a conversation about pill treatment, blood sugar control, weight loss and heart safety. ACHIEVE-4 showed Foundayo heart safety versus insulin, along with improvements in blood sugar and weight. Ultimately, the personal choice should take into account underlying conditions, tolerability, other medications and treatment goals.
The information in this article is general and does not replace personal medical advice.
References
Foundayo noninferior to insulin glargine for CV outcomes in patients with diabetes
Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment
Foundayo – European Medicines Agency
Eli Lilly, the drug’s manufacturer, funded the study.
