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Daily treatment with oral glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron (Emgality; Eli Lilly) results in substantial weight loss in people living with obesity who did not have type 2 diabetes mellitus, according to results from a phase III, multinational, randomised double-blind trial of the once-daily pill.
The drug is currently being appraised by the National Institute for Health and Care Excellence, with a decision expected next year about NHS use in England and Wales.
The study of more than 3,100 adults with a BMI of at least 30 or a BMI between 27 and 30 and to have at least one obesity-related complication, as well as a history of at least one patient-reported unsuccessful dietary effort to lose body weight, was funded by Eli Lilly and published on 16 September 2025 in the New England Journal of Medicine. The results were presented at the Annual Meeting of the European Association for the Study of Diabetes in Vienna on the same day.
“In adults with obesity, 72-week treatment with orforglipron led to significantly greater reductions in body weight than placebo,” the research paper concluded.
The results showed that patients who were randomised to receive 6mg of orforglipron as an adjunct to healthy diet and physical activity lost an average of 7.5% of their body weight over 72 weeks.
Average weight loss increased with higher doses: 8.4% loss with 12mg of orforglipron, and 11.2% loss with 36mg of orforglipron, as compared with 2.1% loss with placebo.
Participants taking orforglipron also recorded reductions in waist circumference, blood pressure and cholesterol.
The study authors noted that while other GLP-1 receptor agonists, such as semaglutide, are reported to result in mean weight reductions of 15–20% and beyond, most are administered as a subcutaneous injection, which may limit treatment initiation and adherence.
The results showed that 5.3–10.3% of patients taking orforglipron were affected by adverse effects that led to treatment discontinuation, compared with 2.7% of those in the placebo group. Adverse effects were mostly mild-to-moderate gastrointestinal symptoms, including nausea, constipation, diarrhea, vomiting, and dyspepsia.
During the 72-week trial period, three deaths were reported: one each in the orforglipron 6mg and 12mg groups and one in the placebo group.
Five cases of adjudication-confirmed mild pancreatitis occurred in the orforglipron groups, with no complications reported.
Hannah Beba, clinical lead for obesity at the West Yorkshire Health and Care Partnership, commented: “Orforglipron is an exciting development in the portfolio of medications we have to treat obesity. It has had impressive impact on weight reduction and cardiovascular risk factors, solving some of the early teething problems that first generation GLP-1s (for the treatment of diabetes) have had in terms of administration.
“Ongoing trials will be looking also at how we use this medication as a ‘step down’ from more potent incretin therapies, aiming to help people maintain their weight loss. There is a real sense now of a rapid expansion in the area of novel medications in the area of obesity.”
Claire Davies, diabetes and endocrinology specialist pharmacist at Gateshead Health NHS Foundation Trust, said: “This is an exciting new piece of research and shows the ongoing rapid advancement of GLP-1 and other therapies for diabetes and obesity. As remarked by the study the potential option of another oral medication creates potentially greater access to medication for those who are not keen to use an injectable agent and may be more appropriate for some individuals. Any medication or treatment choice should be individualised and holistic.
“It will be very interesting to see any future data comparing orforglipron with other currently available products in order to fully review and analyse the potential benefits and scope for use in future.”
Olivier Picard, chair of the National Pharmacy Association, commented: “The introduction of a new GLP1-RA in a daily tablet formulation has the potential to make weight management treatment more accessible and convenient for some patients. Some will prefer the routine of a daily tablet, while others may value the less frequent dosing of injections.
“It is important that any patient who is prescribed weight-loss medicines should receive it as part of a comprehensive treatment programme, that also supports lasting lifestyle changes in diet and physical activity.”
However, he added: “Any new medicines require regulatory approval and vigorous safety and efficacy checks before being rolled out to patients.”
“While affordability and NHS resource considerations inevitably play a role, the priority must be safe, effective, and sustainable patient care. Any rollout should focus on the right support for patients around medication use, rather than reducing the debate to price alone,” he said.
“We will await any decision made by UK regulatory bodies.”
