Researchers from the ATTAIN-2 trial reported their findings on Nov. 20, 2025 in The Lancet.

“We know it is harder for individuals with diabetes to lose weight. It is exciting to have an oral medication that provides double-digit weight loss, which on average was 23 lbs. Once FDA approved, orforglipron is scheduled to be available in 2026 at a significantly decreased cost compared to current injectables. This could position it to be the ‘metformin’ of obesity and become widely covered by insurance plans, opening the door to treatment for all,” said Deborah Horn, DO, MPH, professor and director of obesity medicine at McGovern Medical School at UTHealth Houston and principal author of the study.

Orforglipron stimulates insulin release, reduces glucagon secretion, lowers blood sugar and helps control appetite. No refrigeration is needed.

The investigators conducted the 72-week, phase 3, double-blind, placebo-controlled trial across 136 sites in ten countries.

The primary endpoint was the mean percent change in bodyweight from baseline to week 72.

The investigators enrolled 1613 subjects (757 female) and randomized them, after a dose escalation phase, to receive orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630), as an adjunct to lifestyle modification.

Of the total group, 1444 (89·5%) completed the 72-week study.

At endpoint, subjects treated with up to 6 mg of orforglipron averaged a weight loss of 5.5%, those who received 12 mg averaged 7.8%, and those who received 36 mg averaged 10.5%.

The placebo group averaged just 2.2% in weight loss.

Orforglipron treatment significantly improved blood sugar and caused only mild to moderate gastrointestinal side effects.

The authors reported, “All prespecified weight and cardiometabolic measures including HbA_1c statistically significantly improved with orforglipron. Treatment discontinuations due to adverse events (mainly gastrointestinal-related) were higher for orforglipron (6·1–9·9%) versus placebo (4·1%). The most common adverse events with orforglipron were mild-to-moderate gastrointestinal events, predominantly occurring during dose escalation.”

The authors concluded, “In adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists.”

Horn added, “The opportunity for an oral GLP-1 medication with highly effective weight loss that is simpler to take may provide increased access and opportunities for better health for our patients with obesity and diabetes.”

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Key points 

• The trial included 559 participants randomised in 1:1:1:1 ratio to receive 3 mg, 12 mg or 36 mg orforglipron or placebo.  All participants in the orforglipron treatment arms started the study at a dose of orforglipron 1 mg once-daily and then increased the dose in a step-wise approach at four-week intervals to their final randomised maintenance dose.
• The primary endpoint of the trial – a reduction of haemoglobin A1C – was achieved, with an average reduction of 1.3 – 1.6% from a baseline of 8%.
• Weight loss was a secondary endpoint. Participants in this 40-week trial had not reached a weight plateau by the end of the trial, leading researchers to suggest that further weight loss may be possible.
• The overall safety profile for orforglipron was comparable to other, established GLP-1RAs. The most common side effect was diarrhoea (affecting up to 26% of participants), followed by dyspepsia, constipation and vomiting. No hepatic safety signal was observed. (Note – April 14^th, 2025 Pfizer announced discontinuation of development of danuglipron because of drug-induced liver injury.)
• The full results of the ACHIEVE-1 trial will be presented at the forthcoming American Diabetic Association meeting in June 2025 and will be published in a peer-reviewed journal. (Note – The ATTAIN-1 trial is investigating the efficacy and safety of once daily oral orforglipron in adult participants with obesity or overweight with weight-related comorbidities.)

Orforglipron

Orforglipron is an orally bioavailable, non-peptide agonist of the GLP-1 receptor.

Unlike oral semaglutide (Rybelsus; Novo-Nordisk) It can be taken at any time of the day without restrictions on food or water intake. (Note – Rybelsus is approved for treatment of type 2 diabetes but not for weight management.)

In addition to studies for treatment of type 2 diabetes and weight management, orforglipron is also being studied as a potential treatment for obstructive sleep apnoea and hypertension in adults with obesity.

Lilly plans to seek approval for orforglipron for obesity later in 2025.

Interpretation

An oral GLP-1RA could fill an important gap in the market place – for many people a daily tablet is preferable to a weekly injection. Orforglipron might also find a place as a follow-on treatment for people who started their weight management with injectable semaglutide.

Two other major advantages of oforglipron are the relative ease of manufacturing a small molecule, compared to large molecular weight peptides, and easier storage and transport requirements (no refrigeration and less bulk).

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