Lilly ACHIEVE‑4 confirms Foundayo cardiovascular safety and cardiometabolic benefits

Trial design

ACHIEVE‑4 was a Phase 3, event‑driven, randomized, open‑label study that enrolled 2,749 adults with type 2 diabetes and BMI ≥25 kg/m2 across 15 countries, comparing escalating‑dose oral orforglipron (Foundayo) with insulin glargine; participants had A1C 7.0–10.5% (7.5–10.5% if on a sulfonylurea) and were on 1–3 oral antihyperglycemic agents.

Cardiovascular outcomes

Foundayo met the pre‑specified non‑inferiority criterion versus insulin glargine for time to first MACE‑4 (CV death, MI, stroke, hospitalization for unstable/sudden chest pain) with HR 0.84 (95% CI 0.59–1.20); MACE‑3 HR was 0.77 (95% CI 0.52–1.13); a preplanned analysis showed lower all‑cause mortality (HR 0.43; 95% CI 0.25–0.75), noting these analyses were not controlled for multiplicity.

Glycemic and weight outcomes

At 52 weeks Foundayo reduced A1C by 1.6% versus 1.0% for insulin glargine (treatment difference −0.66%; 95% CI −0.74 to −0.58; p<0.001) and produced mean weight change −8.8% (−8.1 kg) versus +1.7% (+1.4 kg) for insulin glargine (treatment difference −10.42%; 95% CI −10.92 to −9.93; p<0.001); A1C and weight benefits persisted through 104 weeks.

Safety

Safety findings were consistent with the GLP‑1 class: common adverse events included nausea, vomiting, diarrhea, decreased appetite and constipation; 10.6% of patients on Foundayo discontinued due to adverse events; dedicated analyses found no hepatic safety signal.

Regulatory

Lilly plans to submit Foundayo for the treatment of type 2 diabetes to the U.S. FDA by the end of Q2 under the Commissioner’s National Priority Review Voucher.