Lilly's Foundayo Meets Cardiovascular Safety Goal in Phase 3 ACHIEVE-4 Trial

Eli Lilly said on April 16 that its once-daily oral GLP-1 drug Foundayo (orforglipron) met the primary endpoint of the Phase 3 ACHIEVE-4 trial, showing a non-inferior risk of major cardiovascular events compared with insulin glargine in adults with type 2 diabetes and obesity or overweight at increased cardiovascular risk. The company's announcement was distributed by PR Newswire, read via Placera.

The figures are company-reported topline results and have not been presented at a medical meeting or published in a journal.

Cardiovascular and mortality results

ACHIEVE-4 (NCT05803421) is an event-driven, randomized, open-label trial that enrolled 2,749 participants across 15 countries, according to Lilly. Participants had an A1C between 7.0% and 10.5%, a body mass index of at least 25 and were taking one to three oral diabetes drugs. They received escalating doses of Foundayo or insulin glargine. Lilly called it the largest and longest study of the drug in type 2 diabetes to date.

The primary endpoint was time to a first MACE-4 event: cardiovascular death, heart attack, stroke or hospitalization for unstable chest pain. The hazard ratio was 0.84 (95% CI, 0.59 to 1.20), which met the prespecified non-inferiority margin of an upper confidence limit below 1.8, the company said. The hazard ratio for MACE-3, a key secondary endpoint, was 0.77 (95% CI, 0.52 to 1.13; p = 0.181).

In a pre-planned analysis, the risk of death from any cause was 57% lower with Foundayo (hazard ratio 0.43; 95% CI, 0.25 to 0.75; nominal p = 0.002). Lilly said that analysis was not controlled for multiplicity. BioPharm International described the mortality signal as hypothesis-generating pending adjudicated follow-up and noted the study was not powered for superiority on MACE-3.

"ACHIEVE-4 adds a new dimension to that evidence — cardiovascular safety and a lower observed risk of all-cause death in patients who carry elevated cardiovascular risk," said Thomas Seck, senior vice president of product development at Lilly Cardiometabolic Health.

Blood sugar, weight and safety

At 52 weeks, A1C fell 1.6 percentage points from a mean baseline of 8.22% with Foundayo and 1.0 point with insulin glargine (estimated treatment difference -0.66; p < 0.001). Body weight fell 8.8% with Foundayo and rose 1.7% with insulin glargine. Lilly said the improvements persisted through 104 weeks and that Foundayo also improved non-HDL cholesterol, systolic blood pressure, triglycerides and hsCRP.

The most common adverse events were nausea, vomiting, diarrhea, decreased appetite and constipation. During the 52-week minimum treatment period, 10.6% of patients taking Foundayo stopped treatment because of adverse events. The company said a detailed analysis of potential drug-induced liver injury found no hepatic safety signal.

Foundayo is FDA-approved for chronic weight management in adults with obesity, or overweight with weight-related medical problems. Lilly said it will submit the drug for type 2 diabetes to the FDA by the end of the second quarter under the Commissioner's National Priority Review Voucher program.