ACHIEVE-4
the oral GLP-1 agonist orforglipron is cardiovascularly non-inferior to insulin glargine in high-risk type 2 diabetes, with an unproven mortality signal and a third of the hypoglycaemia
Presented at EASD 2026 in Milan by Klara Klein and published simultaneously in The Lancet. ACHIEVE-4, an event-driven, open-label phase 3 trial at 317 sites in 16 countries, randomised 2,749 adults with type 2 diabetes (HbA1c 8.2 percent, BMI 33, mean age 63; 86 percent with established cardiovascular disease, 38 percent with CKD) to oral orforglipron at maximum tolerated dose or titrated insulin glargine. Over a median two years, MACE-4 occurred in 4.2 versus 5.0 percent (HR 0.84, 95% CI 0.59 to 1.20; non-inferiority met, superiority not). MACE-3 HR 0.77 (0.52 to 1.13). Deaths 19 versus 43 (all-cause HR 0.43, 0.25 to 0.75; cardiovascular death HR 0.47), prespecified but not multiplicity-controlled. At 52 weeks HbA1c -1.6 versus -1.0 points, weight -8.8 versus +1.7 percent, systolic BP -4.4 mmHg, hsCRP -38.9 percent; less eGFR decline and more albuminuria reduction. Gastrointestinal events 62.1 versus 14.2 percent, discontinuation 10.6 percent; clinically significant hypoglycaemia 6.8 versus 19.2 percent. Cardiovascular safety shown; benefit awaits ATTAIN-OUTCOMES.
