Orforglipron Meets MACE Noninferiority vs Insulin Glargine in Phase 3 ACHIEVE-4

Orforglipron (Eli Lilly and Company), an oral, non-peptide GLP-1 receptor agonist, was noninferior to insulin glargine for major adverse cardiovascular events (MACE) in adults with type 2 diabetes at increased cardiovascular risk, according to results of the phase 3 ACHIEVE-4 trial published in The Lancet.

The investigators noted that while some peptide GLP-1 receptor agonists have established cardiovascular benefit, the cardiovascular safety of non-peptide agents had not been studied. Noninferiority would be declared if the upper limit of the 95% CI for the hazard ratio was below 1.8, a margin aligned with regulatory guidance.

The open-label, event-driven trial randomly assigned 2749 adults at 317 sites in 16 countries and territories to once-daily oral orforglipron at the maximum tolerated dose (up to a 36mg capsule, equivalent to a 17.2mg tablet) or titrated once-daily insulin glargine. Participants had a glycated hemoglobin (HbA1c) level of 7.0% to 10.5%, a BMI of 25 kg/m² or more,  established cardiovascular disease or chronic kidney disease and were taking up to three glucose-lowering medications. Over a median follow-up of 2 years, the primary four-component MACE outcome occurred in 4.2% of the orforglipron group and 5.0% of the insulin glargine group (hazard ratio, 0.84; 95% CI, 0.59-1.20; P<0.0001 for noninferiority). Orforglipron did not achieve superiority for three-component MACE.

At week 52, the estimated treatment differences vs insulin glargine were −0.50% for HbA1c and −8.9% for body weight. Gastrointestinal adverse events occurred in 62.1% of orforglipron recipients vs 14.2% of insulin glargine recipients and were the most common reason for orforglipron discontinuation. Clinically significant or severe hypoglycemia occurred in 6.8% vs 19.2%, respectively.

The authors noted that the open-label design might have introduced bias and that the trial was not powered for superiority and used a comparator chosen for cardiovascular neutrality, precluding conclusions about cardiovascular risk reduction. Because most participants had established cardiovascular disease, the results may not generalize to broader populations. Eli Lilly and Company funded, designed, and oversaw the trial.

Source: 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. The Lancet. Published online September 30, 2026. doi:10.1016/S0140-6736(26)01865-9