Lancet: oral orforglipron met cardiovascular non-inferiority versus insulin glargine in phase 3 ACHIEVE-4
ACHIEVE-4, a phase 3 outcomes trial in 2,749 adults with type 2 diabetes at increased cardiovascular risk, found the oral non-peptide GLP-1 drug orforglipron non-inferior to insulin glargine on four-component MACE (4.2% vs 5.0%; HR 0.84, 95% CI 0.59-1.20) over a median two years. Published September 30 in The Lancet and newly indexed this week.
The Lancet published ACHIEVE-4 on September 30, 2026, and the paper entered this week's PubMed listings: the first dedicated cardiovascular-outcomes trial of a non-peptide, oral GLP-1 receptor agonist. Some peptide GLP-1 drugs already have established cardiovascular benefit; this study asked whether the small-molecule agent orforglipron is cardiovascularly safe in people with type 2 diabetes at increased risk.
The trial randomized 2,749 adults between May 2023 and September 2024 at 317 sites in 16 countries and territories. Participants had type 2 diabetes, HbA1c between 7.0% and 10.5%, a BMI of 25 or more, and established cardiovascular or chronic kidney disease. They were assigned 1:1 to oral orforglipron (up to 36 mg capsule once daily) or injectable titrated insulin glargine, each added to existing glucose-lowering therapy. The trial was event-driven, open-label, and designed for non-inferiority; it is registered as NCT05803421 and is completed.
Over a median follow-up of two years, the primary four-component outcome (cardiovascular death, non-fatal heart attack, non-fatal stroke, or hospitalization for unstable angina) occurred in 4.2% of orforglipron participants versus 5.0% on insulin glargine, meeting the prespecified non-inferiority threshold (hazard ratio 0.84; 95% CI 0.59 to 1.20; p<0.0001 for non-inferiority). Non-inferiority means the drug was not worse than the comparator within the trial's agreed margin; it is not proof of cardiovascular benefit or superiority.
On tolerability, gastrointestinal adverse events were far more common with orforglipron (62.1%) than with insulin glargine (14.2%) and were the most common reason participants stopped orforglipron. Clinically significant or severe hypoglycemia was less frequent with orforglipron (6.8%) than with insulin glargine (19.2%). Sixty-two deaths occurred overall - 19 on orforglipron and 43 on insulin glargine - with all but one (in the glargine group) judged unrelated to treatment. Death counts in a non-inferiority safety trial are not, by themselves, evidence of a survival advantage.
Context for interpretation: orforglipron, sold as Foundayo, is FDA-approved for chronic weight management as of April 2026 but is not approved for type 2 diabetes. ACHIEVE-4 supplies cardiovascular-safety evidence relevant to that pending indication rather than a new approval, and its comparator was insulin glargine, not a peptide GLP-1 drug, so it does not rank orforglipron against semaglutide-class medicines on cardiovascular outcomes.
This is a summary of one peer-reviewed trial's reported findings, not treatment guidance. Medication decisions for type 2 diabetes or weight management belong with the treating clinician.