Eli Lilly's once-daily GLP-1 pill orforglipron, sold for weight management as Foundayo, was not worse for the heart than insulin glargine in ACHIEVE-4, a trial of 2,749 adults with type 2 diabetes at high heart risk. Over a median of 2 years, 4.2% on orforglipron and 5.0% on insulin had a major heart event. The results were published in The Lancet on 30 September 2026 and presented at the EASD meeting in Milan.
What happened
ACHIEVE-4 (PubMed 42815506) ran at 317 sites in 16 countries and territories. Everyone had type 2 diabetes with an A1C of 7.0% to 10.5%, a BMI of 25 or more, and established heart disease or chronic kidney disease. They were randomly assigned to orforglipron once a day, up to the highest dose they tolerated, or insulin glargine injections once a day. It was open label, so everyone knew which they were taking. Lilly funded it.
The main question was whether orforglipron was safe for the heart, measured as heart-related death, heart attack, stroke or hospital stay for unstable angina. Orforglipron counted as safe if the upper end of the confidence interval stayed under 1.8.
| Orforglipron | Insulin glargine | |
|---|---|---|
| Major heart event, median 2 years | 4.2% | 5.0% |
| Hazard ratio (95% CI) | 0.84 (0.59 to 1.20) | |
| Deaths from any cause | 1.4% | 3.2% |
| A1C change at 52 weeks (Lilly) | 1.6 lower | 1.0 lower |
| Weight change at 52 weeks (Lilly) | 8.8% lower | 1.7% higher |
| Lost 10% or more at 104 weeks (Lilly) | 35.9% | 3.4% |
| Gastrointestinal side effects | 62.1% | 14.2% |
| Serious low blood sugar | 6.8% | 19.2% |
Lilly reported that 10.6% of people on orforglipron stopped because of side effects over 52 weeks, and that kidney function declined more slowly than on insulin.
What it does not tell us
- That the pill protects the heart. The trial was built to show orforglipron was not worse than insulin, and it did. The confidence interval includes no difference, so it does not show a benefit.
- What the lower death rate means. Lilly highlights 57% fewer deaths from any cause, but that was not the trial's main question, the trial was open label, and the comparison was insulin, not placebo.
- Anything about people without diabetes. Everyone here had type 2 diabetes and heart or kidney disease. Whether the result applies to people taking Foundayo for weight alone is not tested here.
What it means for you
If you take Foundayo for weight, or are considering it, this is reassuring. The first heart safety trial of a non-peptide GLP-1 pill found no sign of harm in people at high risk, and the lower rate of low blood sugar against insulin is useful if you have diabetes. As of October 2026, Lilly's own release still describes orforglipron for type 2 diabetes as under investigation.
Six in ten people had gut side effects. If that is you, our guide to what to eat on orforglipron covers eating around them, and the news of Foundayo's approval explains how the pill is taken. Talk to your prescriber before changing any diabetes medicine.
What to do with this
An 8.8% loss in a year is real weight, and some of it is muscle. Eating to a protein target on a smaller appetite is the part you control.