ACHIEVE-4 Phase 3 Trial Finds Oral Orforglipron Non-Inferior to Insulin Glargine on Cardiovascular Safety, Published in The Lancet

Results from ACHIEVE-4, a Phase 3 cardiovascular outcomes trial of Eli Lilly's oral GLP-1 receptor agonist orforglipron, were published online September 30, 2026 in The Lancet, reporting the first cardiovascular safety data for a non-peptide, small-molecule GLP-1 receptor agonist in adults with type 2 diabetes at increased cardiovascular risk.

The trial, registered on ClinicalTrials.gov as NCT05803421 and titled "A Phase 3, Open-Label Study of Once Daily LY3502970 Compared With Insulin Glargine in Adult Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk," was an event-driven, multicenter, randomized, open-label, active-comparator, parallel-group study conducted at 317 sites across 16 countries between May 1, 2023 and September 5, 2024 enrollment, with the study completing in March 2026. Eligible participants were adults with type 2 diabetes, an HbA1c between 7.0 percent and 10.5 percent, a BMI of 25 kg/m2 or higher, treated with up to three glucose-lowering medications, and established cardiovascular or chronic kidney disease.

A total of 2,749 participants were randomized roughly 1:1 to once-daily oral orforglipron at a maximum tolerated dose up to 36 mg, or once-daily injectable insulin glargine, titrated per standard practice. Mean baseline age was 63.1 years, mean HbA1c was 8.2 percent, and mean BMI was 33 kg/m2; 85.9 percent of participants had established cardiovascular disease and 37.6 percent had chronic kidney disease.

The primary endpoint was time to a four-component major adverse cardiovascular event, or MACE-4, defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Non-inferiority of orforglipron to insulin glargine required the upper bound of the two-sided 95% confidence interval for the hazard ratio to fall below 1.8. Over a median follow-up of 2 years, MACE-4 occurred in 57 of 1,358 orforglipron participants (4.2 percent) versus 67 of 1,343 insulin glargine participants (5.0 percent), a hazard ratio of 0.84 (95% CI 0.59-1.20), meeting the pre-specified non-inferiority margin (p<0.0001 for non-inferiority).

Gastrointestinal adverse events were reported in 851 of 1,371 orforglipron participants (62.1 percent) compared with 193 of 1,355 insulin glargine participants (14.2 percent), and were the most common reason for treatment discontinuation in the orforglipron group. Clinically significant or severe hypoglycemia, defined as blood glucose below 54 mg/dL, occurred less often with orforglipron, in 93 of 1,371 participants (6.8 percent), than with insulin glargine, in 260 of 1,355 participants (19.2 percent). Sixty-two deaths were reported during the study, 19 of 1,371 participants on orforglipron (1.4 percent) and 43 of 1,355 on insulin glargine (3.2 percent); the study authors reported that all deaths except one, in the insulin glargine group, were deemed unrelated to treatment.

The study authors concluded that the cardiovascular safety of orforglipron was confirmed by its non-inferiority to insulin glargine for MACE-4, writing that the findings "support orforglipron as a potential once-daily, oral treatment option with established cardiovascular safety in people with type 2 diabetes and increased cardiovascular risk." The trial was funded by Eli Lilly and Company, and several authors are Lilly employees and shareholders.

Orforglipron, a non-peptide, small-molecule GLP-1 receptor agonist taken as a once-daily tablet, received FDA approval under the brand name Foundayo on April 1, 2026 for chronic weight management in adults with obesity, or overweight with weight-related conditions. It is not yet FDA-approved for type 2 diabetes, the population ACHIEVE-4 enrolled, nor authorized by the European Medicines Agency or Australia's Therapeutic Goods Administration for any indication. Lilly has said its diabetes-specific regulatory submissions draw on the separate ACHIEVE Phase 3 trial program, of which ACHIEVE-4 is a part, alongside previously reported trials including ACHIEVE-2 and ACHIEVE-3. This report describes trial-level cardiovascular outcomes data and does not constitute treatment or dosing guidance.