ACHIEVE-4 reaffirms orforglipron's cardiovascular safety profile

Eli Lilly reported topline results on April 16, 2026 from ACHIEVE-4, the largest and longest Phase 3 trial of Foundayo (orforglipron) in type 2 diabetes. The study met its main goal of showing the once-daily pill was non-inferior to insulin glargine for major adverse cardiovascular events in adults with type 2 diabetes who were overweight or obese and at increased cardiovascular risk ^[3].

ACHIEVE-4 randomized 2,749 participants across 15 countries, including the U.S., in an event-driven, open-label design ^[3]. Participants had an A1C between 7.0% and 10.5% (7.5% to 10.5% if taking a sulfonylurea), a BMI of at least 25, and had been on one to three oral diabetes medicines for at least 90 days. Those assigned to Foundayo started at a 1 mg capsule (equal to the 0.8 mg tablet) and escalated every four weeks to a maximum tolerated dose, up to a 36 mg capsule (17.2 mg tablet) ^[3].

What the numbers showed

For the primary endpoint — MACE-4, meaning cardiovascular death, heart attack, stroke, or hospitalization for unstable or sudden chest pain — the hazard ratio was 0.84 (95% CI 0.59 to 1.20; p = 0.336) ^[3]. That is a 16% lower observed risk, but the p-value means superiority was not demonstrated; what the trial showed is that the upper limit of the confidence interval stayed below the prespecified non-inferiority threshold of 1.8 ^[3]. A narrower three-part measure, MACE-3, had a hazard ratio of 0.77 (95% CI 0.52 to 1.13; p = 0.181) ^[3].

The headline-grabbing figure is all-cause death: a hazard ratio of 0.43 (95% CI 0.25 to 0.75; nominal p = 0.002), or 57% lower risk versus insulin glargine ^[3]. Lilly labels this a pre-planned analysis that was not controlled for family-wise type 1 error, meaning it was not part of the formal statistical testing hierarchy and should be treated as exploratory rather than proof ^[3].

On glucose and weight, Foundayo outperformed insulin. At 52 weeks, A1C fell 1.6% with Foundayo versus 1.0% with insulin glargine from a mean baseline of 8.22% (treatment difference −0.66; p < 0.001) ^[3]. Body weight dropped 8.8% (8.1 kg, or 17.9 pounds) with Foundayo while rising 1.7% (1.4 kg, or 3.1 pounds) with insulin, from a mean baseline of 90.9 kg (200.4 pounds) — a difference of 10.42 percentage points ^[3]. Lilly says those advantages persisted through 104 weeks of therapy ^[3].

Side effects looked like the GLP-1 class: nausea, vomiting, diarrhea, decreased appetite and constipation were most common, and 10.6% of Foundayo patients stopped treatment because of adverse events during the 52-week minimum treatment period ^[3]. The trial also included what Lilly called a thorough analysis of potential drug-induced liver injury, which the company says found no hepatic safety signal, consistent with earlier ACHIEVE and ATTAIN studies ^[3]. The sources provided do not include any FDA statement about liver concerns, so the regulator's own position is not documented here.

Why it matters for patients

Foundayo was approved in the U.S. on April 1, 2026, but only for chronic weight management in adults with obesity, or overweight plus a weight-related condition ^[1][2]. It is not approved for type 2 diabetes. ACHIEVE-4 is the cardiovascular outcomes data regulators typically expect before a diabetes drug is broadly used, and it is the kind of evidence that insurers and guideline writers weigh.

For people with type 2 diabetes weighing a pill instead of injections, the trial adds two practical data points: Foundayo lowered A1C more than basal insulin and led to weight loss where insulin led to weight gain ^[3]. It also did not raise cardiovascular risk over a study that ran to 104 weeks ^[3]. What the trial does not establish is that Foundayo prevents heart attacks, strokes or deaths — the confidence intervals are wide, the MACE p-values were not significant, and the mortality finding was not statistically controlled ^[3].

What happens next

Lilly said it will submit Foundayo to the FDA for type 2 diabetes by the end of the second quarter of 2026, using the Commissioner's National Priority Review Voucher ^[3]. Full ACHIEVE-4 results beyond the topline have not been published in the sources here. Across seven Phase 3 studies, Lilly says more than 11,000 patients have taken Foundayo ^[3].