Eli Lilly (NYSE: LLY) reported that orforglipron (Foundayo) met its primary cardiovascular safety endpoint in the Phase III ACHIEVE-4 trial, demonstrating non-inferiority in risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes. Lilly says the data will support an FDA submission for the type 2 diabetes indication by end of Q2 2026.
Trial specifics
ACHIEVE-4 (NCT05803421) is a Phase III, event-driven, randomized, open-label trial enrolling adults with type 2 diabetes and overweight or obesity at increased cardiovascular risk, which randomized 2,749 participants across 15 countries.
The primary endpoint — time to first occurrence of MACE-4, encompassing cardiovascular death, heart attack, stroke, or hospitalization for unstable chest pain — showed a hazard ratio of 0.84 (95% CI: 0.59 to 1.20) for orforglipron versus insulin glargine, satisfying the prespecified non-inferiority margin. On the narrower MACE-3 composite, the hazard ratio was 0.77 (95% CI: 0.52 to 1.13). Neither endpoint reached nominal statistical superiority. In a pre-specified but multiplicity-uncontrolled analysis, all-cause mortality was 57% lower with orforglipron (HR: 0.43; 95% CI: 0.25 to 0.75; nominal p = 0.002), a finding that warrants cautious interpretation but is likely to feature prominently in regulatory discussions. On glycemic and weight endpoints, orforglipron produced a 1.6% reduction in A1C from a mean baseline of 8.22% at 52 weeks versus 1.0% for insulin glargine, and an 8.8% reduction in body weight compared to a 1.7% gain in the insulin glargine arm.
The safety profile was consistent with the GLP-1 receptor agonist class. Nausea, vomiting, diarrhea, decreased appetite, and constipation were the most common adverse events. Approximately 10.6% of orforglipron patients discontinued treatment due to adverse events over the 52-week minimum treatment period. A pre-specified analysis of drug-induced liver injury found no hepatic safety signal, consistent with earlier trials in the ACHIEVE and ATTAIN programs.