Eli Lilly and Company announced detailed results on September 30, 2026, from the Phase 3 ACHIEVE-4 trial, showing that the oral once-daily GLP-1 receptor agonist Foundayo (orforglipron) demonstrated a non-inferior risk of major adverse cardiovascular events compared to titrated insulin glargine in adults with type 2 diabetes and obesity or overweight.
ACHIEVE-4 Trial Design and Primary Endpoint Results
The ACHIEVE-4 trial represents the most extensive and longest-running investigation of orforglipron in type 2 diabetes to date, having been simultaneously published in The Lancet and unveiled in Milan, Italy, at the 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD). The trial evaluated adults with type 2 diabetes and obesity or overweight who faced an increased cardiovascular risk.
Participants taking Foundayo experienced a 16% lower risk of MACE-4—defined as cardiovascular death, heart attack, stroke, or hospitalization for unstable sudden chest pain—with a hazard ratio of 0.84 (95.0% CI: 0.59 to 1.20), successfully meeting prespecified criteria for non-inferiority compared to insulin glargine. For MACE-3, encompassing cardiovascular death, heart attack, or stroke, patients taking Foundayo saw a 23% lower risk with a hazard ratio of 0.77 (95.0% CI: 0.52 to 1.13).
“For people living with type 2 diabetes, protecting the heart is as important as controlling blood sugar,” said Klara Klein, M.D., Ph.D., Assistant Professor of Medicine at the University of North Carolina School of Medicine. “ACHIEVE-4 reaffirmed the safety of orforglipron and demonstrated an association with a lower risk of major cardiovascular events and death. These results, paired with the simple administration of a once-daily pill, taken without fasting or water restrictions, could make orforglipron a compelling potential option across the globe.”
Pre-Planned Survival and Cardiometabolic Analyses
In pre-planned analyses, the trial tracked deeper mortality and health metrics against the insulin glargine control group. Foundayo showed a 53% lower risk of cardiovascular death (hazard ratio: 0.47; 95.0% CI: 0.25 to 0.90) and a 57% lower risk of all-cause death (hazard ratio: 0.43; 95.0% CI: 0.25 to 0.75).
Beyond survival markers, patients treated with Foundayo experienced measurable improvements across multiple secondary cardiometabolic risk factors at week 52:
- Waist Circumference: Reduced by 7.0 cm.
- Systolic Blood Pressure: Decreased by 4.4 mmHg.
- Triglycerides: Lowered by 18.9%.
- Non-HDL Cholesterol: Reduced by 6.6%.
- hsCRP (Inflammation Marker): Decreased by 38.9%.
Individuals treated with Foundayo showed a 27.1% greater decrease in albuminuria alongside an eGFR decline that was 2.8 mL/min/1.73 m² less severe than the decline observed in patients given insulin glargine.
Glycemic Control and Weight Metrics
At 52 weeks, patients on Foundayo achieved an average A1C reduction of -1.6% from a mean baseline of 8.22%, compared to a -1.0% reduction for insulin glargine. Body weight changes showed a divergence as well: participants taking Foundayo lost an average of 8.8% (-8.1 kg / -17.9 lbs) from a mean baseline weight of 90.9 kg, whereas the insulin glargine group gained an average of 1.7% (+1.4 kg / +3.1 lbs).
By 104 weeks, 54.6% of participants taking Foundayo achieved an A1C of 6.5% or lower, compared to 23.8% of those on insulin glargine. Also, 35.9% of Foundayo-treated participants reached a body weight reduction of 10% or greater, versus 3.4% in the comparator arm.
“Foundayo has consistently delivered strong efficacy in type 2 diabetes across our Phase 3 ACHIEVE program,” said Thomas Seck, M.D., senior vice president of product development for Lilly Cardiometabolic Health.
Earlier Efficacy Findings in Obesity Trials
The cardiovascular findings build on prior Phase 3 evaluations of orforglipron in non-diabetic populations. Complete results from the ATTAIN-1 trial, published previously in The New England Journal of Medicine and presented at the EASD Annual Meeting 2025, evaluated adults with obesity or overweight without diabetes. In that 72-week study led by Sean Wharton, M.D., director at Wharton Medical Clinic, the highest 36 mg dose of orforglipron achieved an average weight loss of 27.3 lbs (12.4%) using the efficacy estimand. Among 1,127 participants with prediabetes at baseline in ATTAIN-1, up to 91% achieved near-normal blood sugar levels by week 72, compared to 42% in the placebo group.
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