ACHIEVE-1: the first Phase 3 win for an oral small-molecule GLP-1

Eli Lilly said on April 17, 2025 that its experimental once-daily pill orforglipron met the main goal of ACHIEVE-1, a 40-week Phase 3 trial in adults with type 2 diabetes ^[1]. It is the first oral small-molecule GLP-1 receptor agonist to successfully complete a Phase 3 trial anywhere ^[1][2].

ACHIEVE-1 randomized 559 adults across the U.S., China, India, Japan and Mexico to orforglipron 3 mg, 12 mg or 36 mg once daily, or to placebo ^[1]. Participants had an A1C between 7.0% and 9.5%, a BMI of at least 23, had not taken diabetes medication for at least 90 days, and had never used insulin ^[1]. Everyone started at 1 mg and stepped up every four weeks to their assigned maintenance dose; flexible dosing was not allowed ^[1].

What the numbers showed

From a starting A1C of 8.0%, orforglipron lowered A1C by an average of 1.3% at 3 mg, 1.6% at 12 mg and 1.5% at 36 mg, compared with 0.1% for placebo, using what Lilly calls the efficacy estimand — the estimate of what would happen if people stayed on treatment and did not add other diabetes drugs ^[1]. More than 65% of people on the 36 mg dose reached an A1C of 6.5% or lower, which is below the American Diabetes Association's threshold for diabetes ^[1][2].

Weight loss was a secondary endpoint. From an average starting weight of 198.9 pounds, participants lost 4.7% (9.7 lbs) at 3 mg, 6.1% (12.2 lbs) at 12 mg and 7.9% (16.0 lbs) at 36 mg, versus 1.6% (2.9 lbs) on placebo ^[1]. Lilly noted that average weight had not plateaued by week 40, so the full effect may not have been reached ^[1][2]. Using the more conservative treatment-regimen estimand, which counts everyone regardless of whether they stopped or added drugs, A1C fell 1.2% to 1.5% and weight fell 4.5% to 7.6% ^[1].

Side effects were mostly digestive and generally mild to moderate ^[1]. Across the 3 mg, 12 mg and 36 mg doses, diarrhea occurred in 19%, 21% and 26% of participants versus 9% on placebo; nausea in 13%, 18% and 16% versus 2%; indigestion in 10%, 20% and 15% versus 7%; constipation in 8%, 17% and 14% versus 4%; and vomiting in 5%, 7% and 14% ^[1]. Lilly reported 1% vomiting on placebo, while a table published by TCTMD lists 4% — the sources disagree on that one figure ^[1][2]. Discontinuation because of side effects was 6%, 4% and 8% across doses versus 1% on placebo ^[1]. No liver safety signal was seen ^[1], which drew attention because Pfizer had discontinued its oral GLP-1 danuglipron on April 14 after a trial participant had a possible drug-induced liver injury that resolved after stopping the drug ^[4].

Why it matters for patients

Every GLP-1 approved for weight loss in the U.S. today is an injection, and the one oral option, semaglutide (Rybelsus), must be taken with limited water and on an empty stomach. Orforglipron is designed to be taken any time of day without food or water restrictions ^[1][2]. Because it is a synthetic small molecule rather than a peptide, it is simpler to manufacture; Lilly said it is confident it could launch worldwide without supply constraints if approved ^[1][4].

Reuters compared the 8% weight loss with roughly 6% for diabetes patients on high-dose Ozempic, and the 1.3% A1C drop with 2.1% for Ozempic — but these are cross-trial comparisons, not head-to-head results ^[4]. Tirzepatide (Mounjaro/Zepbound) has shown 22% weight loss over 72 weeks in obesity trials ^[4]. Orforglipron is not approved anywhere, and price and coverage are not yet known.

What happens next

Full ACHIEVE-1 results were slated for the ADA's 85th Scientific Sessions in June 2025 and peer-reviewed publication ^[1][2]. Lilly said it expects to file for weight management approval with global regulators by the end of 2025 and for type 2 diabetes in 2026 ^[1]. The broader ACHIEVE program has enrolled more than 6,000 people with type 2 diabetes across five registrational trials, with results into 2026 ^[1].