Eli Lilly and Company (NYSE: LLY) reported Phase III data from three ACHIEVE program trials showing that orforglipron (Foundayo), its once-daily oral GLP-1 receptor agonist, outperformed each active comparator and placebo across A1C reduction and weight loss in adults with type 2 diabetes — results that position Lilly to file for a diabetes indication by end of Q2 under a Commissioner's National Priority Review Voucher. Orforglipron, a non-peptide small molecule originally discovered by Japan-based Chugai Pharmaceutical and licensed by Lilly in 2018, is already US FDA-approved for chronic weight management.
In the landmark ACHIEVE-3 trial — a Phase III, 52-week, randomized, open-label study enrolling 1,698 adults with type 2 diabetes inadequately controlled on metformin — orforglipron 17.2 mg reduced A1C by a mean of 2.2 percentage points from a baseline of 8.3%, compared with 1.4 percentage points for Novo Nordisk's Ozempic oral formulation, semaglutide (Rybelsus, 14 mg), a 57.1% greater relative reduction (p < 0.001). Weight loss at the highest dose comparison was 19.7 lbs (9.2%) versus 11.0 lbs (5.3%), a 73.6% greater relative reduction. Some 76.8% of participants on orforglipron 17.2 mg achieved an A1C ≤ 6.5%, compared with 50.9% on oral semaglutide 14 mg.
In ACHIEVE-2 (Phase III, 40-week, 962 participants, active-controlled vs. dapagliflozin 10 mg added to metformin), orforglipron 17.2 mg reduced A1C by 1.7 percentage points from a baseline of 8.1%, versus 0.8 percentage points with AstraZeneca's Farxiga (dapagliflozin); 68.6% of participants reached A1C ≤ 6.5% versus 21.6%. In ACHIEVE-5 (Phase III, 40-week, 546 participants, placebo-controlled, insulin glargine background), orforglipron 9 mg reduced A1C by 2.1 percentage points from a baseline of 8.5%, compared with 0.8 percentage points for placebo, with 69.1% achieving A1C ≤ 6.5% versus 11.1%. Gastrointestinal adverse events were the most common side effects across all three trials, consistent with the class profile. Treatment discontinuation rates due to adverse events were modestly higher with orforglipron than comparators in ACHIEVE-2 and ACHIEVE-3, though the overall safety profile was described as consistent with prior studies.