A new daily pill could be a more effective GLP-1 tablet for weight loss, according to a clinical trial that may pave the way for an improved non-injection alternative to Wegovy and Mounjaro.
The drug, called orforglipron and manufactured by Eli Lilly, is prescribed for type 2 diabetes and targets the same GLP-1 receptors as oral semaglutide. Like semaglutide, it lowers blood sugar levels, slows digestion and suppresses appetite. Unlike semaglutide tablets, it does not need to be taken on an empty stomach.
Orforglipron has not yet been approved by regulators in the UK, US or Europe, though the US Food and Drug Administration is reviewing it. At present, semaglutide is the only GLP-1 medication for type 2 diabetes available in pill form in the US.
The tablet form of semaglutide is available in the US under the name Rybelsus for treating diabetes, and the weight-loss pill version of Wegovy has also just been approved. However, oral semaglutide has been shown to be less effective for weight loss than semaglutide injections – such as Ozempic and Wegovy – or tirzepatide injections such as Mounjaro.
Experts believe tablet versions could prove transformative because they are easier to take and store, and may ultimately be cheaper.
Results of the first phase 3 trial comparing orforglipron with oral semaglutide found that patients with diabetes lost on average 6-8% of their body weight with orforglipron, compared with 4-5% on semaglutide.
The Achieve-3 trial, funded by Eli Lilly, studied more than 1,500 adults with type 2 diabetes from 131 medical research centres and hospitals in Argentina, China, Japan, Mexico and the US. Participants received either 12mg or 36mg of orforglipron, or 7mg or 14mg of oral semaglutide, over the course of a year.
In addition to greater weight loss, participants who took either dose of orforglipron recorded lower average blood sugar levels at the end of the trial than either dose of semaglutide.
However, discontinuation rates were higher in the orforglipron groups. About 9-10% of participants stopped treatment because of side-effects – mainly gastrointestinal issues – compared with 4-5% in the semaglutide groups.
Responding to the findings, Tam Fry, the chair of the National Obesity Forum, said: “Orforglipron [could prove] itself as the treatment of choice for the very obese diabetic. Its real bonus is in its straightforward use. When it is finally released, its availability must be more strictly controlled than semaglutide to avoid similar life-threatening usage.”
Dr Marie Spreckley, of the MRC epidemiology unit at the University of Cambridge, said: “Higher discontinuation due to adverse events, particularly gastrointestinal symptoms, is a key consideration and may have implications for tolerability and adherence in real-world settings.”
She added that because the trial lasted only one year, longer-term safety, cardiovascular outcomes and sustained effectiveness remained important unanswered questions.
Naveed Sattar, a professor of cardiometabolic medicine at the University of Glasgow, said: “These are important findings. The more effective oral medicines we have to help people with type 2 diabetes lose weight and keep it off, the better.”
He added that holistic approaches – targeting weight, blood sugar, and cardiovascular risk simultaneously – are likely to deliver the greatest benefits for people with type 2 diabetes. Incretin‑based therapies associated with substantial intentional weight loss “may well become first‑line treatments for type 2 diabetes within the next decade, potentially helping many people achieve remission for several years”, he said.
