Phase 3 ACHIEVE-4: daily oral orforglipron met cardiovascular non-inferiority against insulin glargine in type 2 diabetes at increased risk
In the 2,749-participant phase 3 ACHIEVE-4 trial published in The Lancet, once-daily oral orforglipron was non-inferior to injected insulin glargine for four-component major adverse cardiovascular events over a median two years in adults with type 2 diabetes at increased cardiovascular risk (hazard ratio 0.84, 95% CI 0.59-1.20), with more gastrointestinal side effects but less hypoglycaemia.
The Lancet published ACHIEVE-4, the first cardiovascular outcomes trial of a non-peptide GLP-1 receptor agonist. Orforglipron is Eli Lilly's once-daily, oral small-molecule GLP-1 agonist; while several injectable peptide GLP-1 agonists have established cardiovascular benefit, the cardiovascular safety of the non-peptide class had not been studied in a dedicated outcomes trial.
The event-driven, phase 3, multicentre, randomised, open-label, active-comparator study ran at 317 sites across 16 countries and territories. Adults with type 2 diabetes at increased cardiovascular risk - glycated haemoglobin 7.0% to 10.5%, BMI of 25 kg/m2 or more, treated with up to three glucose-lowering medications (metformin, a sulfonylurea, and/or an SGLT2 inhibitor), and with established cardiovascular or chronic kidney disease - were randomly assigned 1:1 to oral orforglipron at the maximum tolerated dose (up to 36 mg capsule, equivalent to 17.2 mg tablet) or once-daily injected titrated insulin glargine.
Between May 1, 2023 and September 5, 2024, 2,749 participants were randomly assigned (1,371 to orforglipron, 1,378 to glargine); 38% were female, 85.9% had established cardiovascular disease and 37.6% had chronic kidney disease, with mean baseline age 63.1 years, HbA1c 8.2% and BMI 33 kg/m2. The primary outcome was time to four-component major adverse cardiovascular events (MACE-4): cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina. Non-inferiority required the upper limit of the 95% confidence interval for the hazard ratio to stay below 1.8.
Over a median follow-up of two years, the primary outcome occurred in 4.2% of orforglipron participants and 5.0% of glargine participants (hazard ratio 0.84; 95% CI 0.59-1.20; p<0.0001 for non-inferiority), confirming cardiovascular non-inferiority. Gastrointestinal adverse events were far more frequent with orforglipron (62.1% vs 14.2%) and were the most common reason for discontinuation, while clinically significant or severe hypoglycaemia was less common with orforglipron (6.8% vs 19.2%).
Sixty-two deaths occurred during the study - 19 (1.4%) on orforglipron and 43 (3.2%) on glargine; investigators deemed all but one (in the glargine group) unrelated to treatment. The authors conclude the findings support orforglipron as a potential once-daily oral treatment option with established cardiovascular safety in this population.
Limits: the trial was open-label, funded by Eli Lilly, and designed to establish safety non-inferiority rather than superiority, so the point estimate favouring orforglipron should not be read as proof of cardiovascular benefit; orforglipron remains an investigational medicine and is not FDA-approved. This brief is not a treatment recommendation.