Orforglipron, Eli Lilly’s once-daily GLP-1 pill, did not raise the risk of heart attack, stroke or cardiovascular death compared with insulin glargine in 2,749 adults with type 2 diabetes and established heart or kidney disease, according to the ACHIEVE-4 trial published in The Lancet on 30 September. It is the first cardiovascular-outcomes trial of a non-peptide GLP-1 drug. For anyone weighing an oral GLP-1, the result is about safety measured against insulin, not a proven heart benefit.
What the trial compared
ACHIEVE-4 (NCT05803421) ran at 317 sites in 16 countries and territories. Adults with type 2 diabetes, an HbA1c between 7.0% and 10.5%, a BMI of 25 or more and established cardiovascular or chronic kidney disease were randomly assigned to once-daily oral orforglipron, titrated to the highest tolerated dose up to 36 mg as a capsule (which the paper says is equivalent to a 17.2 mg tablet), or to once-daily injected insulin glargine. The trial was open-label: participants and their doctors knew which treatment was being given. Average age was 63.1, HbA1c 8.2% and BMI 33; 85.9% had established cardiovascular disease and 37.6% chronic kidney disease.
The primary outcome was a four-part composite of cardiovascular death, non-fatal heart attack, non-fatal stroke and hospitalisation for unstable angina. Over a median of two years it occurred in 57 of 1,358 people on orforglipron (4.2%) and 67 of 1,343 on glargine (5.0%), a hazard ratio of 0.84 with a 95% confidence interval of 0.59 to 1.20. The pre-set test was whether the upper end of that interval fell below 1.8. It did, comfortably: the data rule out an increase in risk of more than about 20%. Because the interval also crosses 1, they do not show that orforglipron lowers risk.
Gastrointestinal adverse events were reported by 62.1% of people on orforglipron and 14.2% on glargine, and were the most common reason for stopping the pill. Clinically significant or severe hypoglycaemia, a blood glucose below 54 mg/dL, was far less common on orforglipron: 6.8% against 19.2%. There were 19 deaths (1.4%) on orforglipron and 43 (3.2%) on glargine; the investigators judged all but one, in the glargine group, unrelated to treatment.
Why the comparator matters
Injectable GLP-1 drugs such as semaglutide have trials showing they reduce cardiovascular events compared with placebo. ACHIEVE-4 was built to answer a narrower question: whether orforglipron does harm. Insulin glargine was the comparator, so the trial measures orforglipron against another glucose-lowering treatment rather than against nothing, and the 0.84 hazard ratio should not be read as a 16% heart benefit.
The death figures will draw attention, and they are the part of the result most open to misreading. Deaths were not the primary endpoint, the trial was not designed to compare them, and in an open-label trial the two groups may have been managed differently in ways that affect outcomes. They are a reason to look for the full mortality breakdown, not a finding in themselves.
The paper adds to earlier results on the drug, including ACHIEVE-3, in which orforglipron beat oral semaglutide on blood sugar and weight over 52 weeks. Our orforglipron page covers what is known about the drug overall. Separately, Lilly posted results for ACHIEVE-5, a 546-person trial of orforglipron added to insulin glargine, to ClinicalTrials.gov on 1 October; those registry results are not peer-reviewed and are not covered here.
What is not yet known. The trial was funded by Lilly, seven of its eleven authors are Lilly employees and shareholders, and it was open-label. It enrolled people with type 2 diabetes and established heart or kidney disease, so it does not directly address people taking orforglipron for weight alone. Two years is a median follow-up, not a lifetime. Because the comparator was insulin, it cannot say whether orforglipron protects the heart the way injectable semaglutide has been shown to; that would take a placebo-controlled outcomes trial. This report is based on the published abstract.
Sources: Klein KR, Wysham C, Tuttle KR, et al. Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial. Lancet, published online 30 September 2026 (NCT05803421). ClinicalTrials.gov, NCT06109311 (ACHIEVE-5), results first posted 1 October 2026.
