Drug pipeline
ACHIEVE‑4: Oral orforglipron meets CV safety endpoint in high‑risk T2DM
As regulators and clinicians increasingly prioritize cardiovascular outcomes in type 2 diabetes, oral alternatives to injectable GLP‑1 receptor agonists face heightened scrutiny. The event‑driven ACHIEVE‑4 trial—the largest and longest phase 3 study of orforglipron (Foundayo) in diabetes to date—directly compared once‑daily oral orforglipron with insulin glargine in 2,749 adults with type 2 diabetes and overweight or obesity at elevated CV risk, positioning cardiovascular safety as the primary test while also assessing long‑term glycemic and weight outcomes through 104 weeks.
The study met its primary endpoint: orforglipron was non‑inferior to insulin glargine for time to first major adverse cardiovascular event (MACE‑4), with a hazard ratio (HR) of 0.84 (95% confidence interval [CI], 0.59–1.20), representing a 16% numerically lower risk. A key secondary endpoint showed a 23% lower risk of MACE‑3 (HR, 0.77; 95% CI, 0.52–1.13), though superiority was not formally tested.
Metabolic outcomes favored orforglipron. At 52 weeks, mean A1C decreased by 1.6% with orforglipron vs. 1.0% with insulin glargine (treatment difference, –0.66%; P<0.001). Mean body weight fell by 8.8% in the orforglipron arm, compared with a 1.7% increase in the insulin glargine group; both glycemic and weight benefits were maintained through 104 weeks.
In a pre‑planned analysis not adjusted for multiplicity, all‑cause mortality was 57% lower with orforglipron vs. insulin glargine (HR, 0.43). The safety profile was consistent with the GLP‑1 class, with gastrointestinal adverse events (including nausea, vomiting, and diarrhea) most commonly reported.
“ACHIEVE‑4 adds a critical layer of evidence—cardiovascular safety alongside sustained glucose and weight reduction—in a population where treatment trade‑offs matter,” said Thomas Seck, MD, senior vice president of product development, Lilly Cardiometabolic Health. “For patients at elevated CV risk, having these data with a once‑daily oral option could meaningfully influence therapeutic decisions.”
Lilly announced plans to submit orforglipron to FDA for a type 2 diabetes indication by the end of the second quarter of 2026.
Source: Eli Lilly and Company News release. (2026, April 16). ACHIEVE‑4, the longest Phase 3 study of Lilly’s Foundayo (orforglipron) to date, reaffirmed its cardiovascular and overall safety profile as well as consistent improvements across key measures of cardiometabolic health