Full ACHIEVE-1 results publish at the ADA meeting

Eli Lilly on June 21, 2025 released detailed Phase 3 results for orforglipron, an investigational once-daily GLP-1 pill, at the American Diabetes Association's 85th Scientific Sessions, with simultaneous publication in The New England Journal of Medicine ^[1]. In the ACHIEVE-1 trial, all three doses beat placebo on blood sugar control in adults with type 2 diabetes, and the two higher doses produced statistically significant weight loss ^[1].

Orforglipron is the first oral small molecule (non-peptide) GLP-1 receptor agonist to complete a Phase 3 trial, and it is taken without restrictions on food or water ^[1]. That sets it apart from injectable GLP-1 drugs like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), and from oral semaglutide (Rybelsus), which has dosing rules around food and water.

What the trial found

ACHIEVE-1 randomized 559 adults in the U.S., China, India, Japan and Mexico to orforglipron 3 mg, 12 mg, 36 mg, or placebo for 40 weeks ^[1]. Participants had type 2 diabetes managed with diet and exercise alone, an A1C between 7.0% and 9.5%, a BMI of at least 23, and had not taken diabetes medications for at least 90 days ^[1]. Everyone in the drug arms started at 1 mg and stepped up every four weeks to their assigned maintenance dose ^[1].

From a baseline A1C of 8.0%, orforglipron lowered A1C by 1.3% (3 mg), 1.6% (12 mg) and 1.5% (36 mg), versus 0.1% for placebo, using the efficacy estimand ^[1]. Up to 76.2% of participants on the drug reached the ADA target of A1C under 7%, compared with 28.0% on placebo, and up to 25.8% reached a normal A1C below 5.7% versus 3.8% on placebo ^[1]. Improvements showed up as early as four weeks ^[1].

Weight loss was a key secondary endpoint. From an average starting weight of 198.9 lbs, participants on the 36 mg dose lost 7.9%, or about 16.0 lbs, versus 1.6% (2.9 lbs) on placebo ^[1]. The 12 mg dose produced 6.1% (12.2 lbs) and the 3 mg dose 4.7% (9.7 lbs) ^[1]. Lilly noted that participants did not appear to hit a weight plateau by week 40, and said longer obesity trials will give a fuller picture ^[1].

Side effects were mostly digestive and mostly showed up during dose escalation ^[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%; dyspepsia in 11%, 20% and 15% versus 7%; constipation in 8%, 17% and 14% versus 4%; and vomiting in 5%, 7% and 14% versus 1% ^[1]. Discontinuations due to adverse events were 6%, 4% and 8% on orforglipron versus 1% on placebo ^[1]. Lilly said no hepatic (liver) safety signal was observed ^[1].

Why it matters for patients

The practical appeal of orforglipron is the format: a daily pill with no food or water timing rules, which Lilly frames as an option for people who prefer not to inject ^[1]. The A1C results in this trial were compared against placebo, not against an active drug, so ACHIEVE-1 does not answer how orforglipron stacks up against existing GLP-1 medicines ^[1]. Head-to-head data are coming: ACHIEVE-3 compares orforglipron with oral semaglutide, and ACHIEVE-2 compares it with dapagliflozin, both in adults on metformin ^[1].

The liver safety point drew attention because another experimental oral GLP-1 program was halted over liver concerns. The detail on that competing program is not covered in the sources available here, so this story does not describe it. What the published ACHIEVE-1 data show is that no hepatic safety signal was seen in this 40-week trial ^[1].

Orforglipron is not approved by the FDA, and the weight loss seen here — up to 7.9% at 40 weeks in people with type 2 diabetes — is a secondary finding in a diabetes trial, not an obesity trial result ^[1]. Pricing, insurance coverage and how supply would work are not yet known.

What happens next

Lilly said topline results from ATTAIN-1 and ATTAIN-2, the obesity trials, would be shared in the third quarter of 2025 ^[1]. ACHIEVE-2 and ACHIEVE-3 results were also expected later in 2025 ^[1]. The company said it remains on track to submit orforglipron to global regulators for weight management by the end of 2025 and for type 2 diabetes in 2026 ^[1]. The full ACHIEVE program has enrolled more than 6,000 people with type 2 diabetes across five registration trials, with results running into 2026 ^[1].