ACHIEVE-4 topline report finds orforglipron noninferior to insulin glargine for MACE-4

What happened

Lilly announced topline ACHIEVE-4 results on April 16, 2026. The phase 3 trial randomly assigned 2,749 adults across 15 countries to once-daily oral orforglipron or insulin glargine. Participants had type 2 diabetes, a BMI of at least 25, and increased cardiovascular risk. The comparison was open label, so participants and investigators knew which treatment was assigned.

The primary cardiovascular endpoint was MACE-4, a composite of cardiovascular death, heart attack, stroke, or hospitalization for unstable angina. Lilly reported a hazard ratio of 0.84 for orforglipron versus insulin glargine, with a 95% confidence interval from 0.59 to 1.20. The result met the prespecified noninferiority criterion.

For MACE-3, which excluded unstable-angina hospitalization from the composite, the hazard ratio was 0.77 and the confidence interval ran from 0.52 to 1.13. Both cardiovascular intervals included 1, so the announcement did not establish statistical superiority for either MACE composite.

A preplanned analysis reported a hazard ratio of 0.43 for death from any cause, with a 95% confidence interval from 0.25 to 0.75. Lilly described the associated p value as nominal. That result should be separated from the trial's primary noninferiority conclusion and checked in a full publication when available.

At week 52, average HbA1c declined 1.6 percentage points with orforglipron and 1.0 point with insulin glargine. Average body weight fell 8.8% with orforglipron and rose 1.7% with insulin. Lilly said the glycemic and weight differences continued through 104 weeks.

Nausea, vomiting, diarrhea, reduced appetite, and constipation were the most frequently reported adverse events with orforglipron. During the minimum 52-week treatment period, 10.6% of participants assigned orforglipron discontinued treatment because of adverse events.

What it means

ACHIEVE-4 directly compared an oral GLP-1 medicine with basal insulin in adults who had diabetes and elevated cardiovascular risk. Meeting the noninferiority margin supports the trial's cardiovascular safety objective relative to insulin glargine. The separate HbA1c and weight findings describe additional differences between the assigned strategies.

The event-driven design and roughly two-year study period give the comparison more cardiovascular information than a short glucose-lowering trial. The trial registry confirms the randomized, parallel, open-label design and identifies Lilly as the sponsor.

What it does not mean

A hazard ratio of 0.84 does not prove that orforglipron reduces MACE-4 by 16% for every patient. Noninferiority asks whether the result stays within a prespecified margin; it is not the same as demonstrating superiority. The confidence interval allowed possibilities ranging from a meaningful reduction to a higher hazard.

The mortality result is potentially important, but it came from a preplanned analysis reported with nominal significance. The company announcement did not provide the full event tables, subgroup analyses, missing-data details, or every safety outcome expected in a peer-reviewed report.

Insulin glargine remains an established diabetes treatment, and the trial does not rank orforglipron against every GLP-1 medicine or determine the right therapy for an individual. Treatment choice can depend on glucose pattern, other health conditions, adverse effects, cost, access, and patient preference.