- ACHIEVE-4 randomized 2,749 adults with type 2 diabetes and overweight/obesity across 15 countries comparing oral GLP-1 agonist orforglipron (Foundayo) versus insulin glargine.
- Foundayo met non-inferiority for MACE‑4 (HR 0.84; 95% CI 0.59–1.20), showed lower MACE‑3 risk (HR 0.77) and a 57% lower all‑cause death in a preplanned analysis (HR 0.43; 95% CI 0.25–0.75).
- At 52 weeks Foundayo reduced A1C by 1.6% vs 1.0% for insulin glargine (treatment difference −0.66) and produced mean weight change −8.8% (−8.1 kg) vs +1.7% (+1.4 kg) (treatment difference −10.42%).
- Lilly plans to submit Foundayo to the FDA for type 2 diabetes by end of Q2; common GI adverse events were reported, 10.6% discontinued for AEs, and DILI analyses showed no hepatic safety signal.
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.
