Lilly says oral GLP-1 pill orforglipron succeeded in first Phase 3 diabetes trial

Eli Lilly said on April 17, 2025 that its experimental once-daily pill orforglipron lowered blood sugar and body weight in adults with type 2 diabetes, the first Phase 3 success for an oral small-molecule GLP-1 drug ^[1][4]. Orforglipron is not approved for any use.

In the ACHIEVE-1 trial, 559 adults with type 2 diabetes and inadequate blood sugar control from diet and exercise alone were randomly assigned to 3 mg, 12 mg or 36 mg of orforglipron or to placebo for 40 weeks, at sites in the United States, China, India, Japan and Mexico ^[1]. Everyone in the treatment groups started at 1 mg and stepped up the dose every four weeks ^[1].

What the trial found

A1C, a measure of average blood sugar, fell by an average of 1.3% at 3 mg, 1.6% at 12 mg and 1.5% at 36 mg, from a baseline of 8.0%, compared with 0.1% on placebo ^[1]. More than 65% of people taking the 36 mg dose reached an A1C of 6.5% or lower, which is below the American Diabetes Association's threshold for diabetes ^[1].

Weight fell by an average of 9.7 pounds at 3 mg, 12.2 pounds at 12 mg and 16.0 pounds, or 7.9%, at 36 mg, from a baseline of about 199 pounds, compared with 2.9 pounds on placebo ^[1]. Lilly said participants had not reached a weight plateau when the study ended, so the full weight effect may not have been captured in 40 weeks ^[1].

Reuters reported that the results compared favorably with the injected drug Ozempic (semaglutide), where diabetes patients on the highest dose lost roughly 6% of body weight in its own trial ^[4]. That is a comparison across separate trials, not a head-to-head study; Ozempic lowered A1C by 2.1% in its trial, and the two drugs have not been tested against each other directly in the data released so far ^[4].

The most common side effects were gastrointestinal and generally mild to moderate, Lilly said. Diarrhea was reported by 19% to 26% of orforglipron participants versus 9% on placebo; nausea by 13% to 18% versus 2%; indigestion by 10% to 20% versus 7%; constipation by 8% to 17% versus 4%; and vomiting by 5% to 14% versus 1% ^[1]. Discontinuation because of side effects was 6% at 3 mg, 4% at 12 mg and 8% at 36 mg, versus 1% on placebo ^[1][4]. No liver-related safety signal was seen ^[1][4], a point of interest because Pfizer had halted development of its own weight-loss pill, danuglipron, days earlier after a trial participant had a possible drug-induced liver injury that resolved when the drug was stopped ^[4]. One secondary report lists placebo rates for vomiting at 4%, rather than the 1% in Lilly's release ^[2].

Why it matters for patients

All GLP-1 medicines currently sold in the U.S. are injections except Rybelsus, an oral form of semaglutide ^[2]. Rybelsus must be taken with restrictions on food and the amount of water, while orforglipron was designed to be taken any time of day without food or water restrictions ^[1][2]. Orforglipron is also a small molecule rather than a peptide, which Lilly says makes it simpler to manufacture; the company said it is confident it could launch the drug worldwide without supply constraints if approved ^[1][4]. Reuters reported that Lilly recorded $550 million related to the drug's inventory in February ^[4].

Several questions remain. Orforglipron's price, insurance coverage and long-term safety have not been disclosed, and no data have been reported on whether it reduces heart attacks, strokes or other complications. The ACHIEVE-1 results have not yet been published in full or presented publicly, so the numbers above are topline figures from the company and news reports ^[1][2][4]. Whether the weight loss seen at 40 weeks reaches the levels reported for tirzepatide (Mounjaro, Zepbound), which showed 22% weight loss over 72 weeks in a different trial, is not known ^[4].

What happens next

Lilly said the full ACHIEVE-1 results will be presented at the American Diabetes Association's 85th Scientific Sessions in June 2025 and published in a peer-reviewed journal ^[1][2]. More results from the ACHIEVE program, plus findings from the ATTAIN program testing orforglipron for weight management, are expected later in 2025 ^[1]. Lilly said it expects to submit orforglipron for weight management to global regulators by the end of 2025, with a submission for type 2 diabetes anticipated in 2026 ^[1][4]. The ACHIEVE program has enrolled more than 6,000 people with type 2 diabetes across five late-stage trials ^[1].