New oral GLP-1RA orforglipron comparable to semaglutide for weight loss

Results from the ACHIEVE-1 trial show that treatment with orforglipron was associated with weight loss ranging from 4.7 – 7.9% (4.4 – 7.3 Kg) of body weight in obese, diabetic patients. Orforglipron is the first oral, small molecule (non-peptide), glucagon-like peptide-1 receptor agonist (GLP-1RA). The trial was designed to evaluate the safety and efficacy of orforglipron compared with placebo in adults with type 2 diabetes and inadequate glycaemic control with diet and exercise alone.

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).