A new daily pill called orforglipron lowers blood sugar and body weight in people with type 2 diabetes more than the currently available semaglutide pill, which targets the same GLP-1 receptors.

The study, funded by Eli Lilly and published yesterday in The Lancet, included 1,500 people and found that those who tookthe new drug lost 6-8% of their weight, compared with 4-5% with oral semaglutide. However, 9-10% of participants in the orforglipron group stopped taking the pill due to side effects (especially gastrointestinal issues) — twice as many as those who took oral semaglutide.  

The All Ireland SMC asked local experts to comment.

Professor Raymond O’Connor, Adjunct Clinical Professor of General Practice, University of Limerick School of Medicine, comments: 

“Oral GLP-1 RA drugs are certainly a welcome addition to the list of drugs useful for the management of diabetes. They have the advantage of improving blood glucose control while helping the patient lose weight, thus further improving their insulin resistance. This will have a knock-on effect on improving diabetes control. Oral drugs also avoid the huge amount of waste generated by injecting devices which are necessary for most GLP-1 drugs.

“However there are a few issues with GLP-1 drugs in general:

  • What are the rates of complications with the oral GLP-1 drugs? In particular the rates and severity of gastrointestinal symptoms such as nausea, diarrhoea, malnutrition and dehydration? What about rarer complications such as pancreatitis, thyroid tumours and Non Arteritic Ischaemic Optic Neuropathy (NAION). How do the rates compare with the injectable drugs?”
  • These are surrogate end points i.e. lower glucose levels and reduced weight; we do not have “hard” outcomes such as rates of diabetic neuropathy or kidney disease or amputation which are the ones that matter to patients
  • What proportion of the weight lost is lean mass i.e. muscle and bone? With injectable GLP-1 drugs this can be as high as 30%. This can lead to sarcopaenia (muscle loss causing falls) and osteopaenia (bone thinning ) that may lead to fracture
  • While the rate of cessation of the new drug seems low at 10%, this rate is always higher outside of the controlled environment of a drug trial. For GLP-1 injectable drugs the 1 year cessation can be as high as 50%.”

Declaration of interest: no conflicts to declare

Our friends at the UK Science Media Centre also gathered comments 


 Dr Marie Spreckley, Prevention of Diabetes and Related Metabolic Disorders in High Risk Groups, MRC Epidemiology Unit, University of Cambridge, said:

“This is a large phase 3 randomised trial comparing oral orforglipron with oral semaglutide in adults with type 2 diabetes, making it a clinically important and policy-relevant comparison. The press release broadly reflects the main findings, including greater reductions in HbA1c and body weight with orforglipron over 52 weeks.

“Importantly, orforglipron is a non-peptide small-molecule GLP-1 receptor agonist, whereas oral semaglutide is a peptide-based GLP-1 receptor agonist, meaning these are pharmacologically distinct agents acting on the same receptor. The primary outcomes are objective clinical measures, which support confidence in the efficacy findings.

“However, 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. The trial duration was one year and focused on glycaemic and weight outcomes, so longer-term safety, cardiovascular outcomes, and sustained effectiveness remain important unanswered questions.

“Overall, this study provides important comparative evidence within the emerging field of oral incretin therapies. Its real-world impact will depend not only on efficacy, but also on tolerability, adherence, access, and the level of clinical and behavioural support provided alongside pharmacotherapy.”

Declaration of interest: “Dr Marie Spreckley is a postdoctoral researcher and Registered Nutritionist (Public Health) at the MRC Epidemiology Unit, University of Cambridge, specialising in obesity, nutrition, behavioural science, and incretin-based therapies. She conducts independent academic research on incretin-based treatments and patient experiences and declares no industry funding, advisory roles, or financial relationships with manufacturers of orforglipron or semaglutide.”

Prof Naveed Sattar, Professor of Cardiometabolic Medicine/Honorary Consultant, 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. Excess weight is the major driver of type 2 diabetes, and it also contributes to higher blood pressure and abnormal lipid levels.

“In this study, both orforglipron and oral semaglutide improved blood pressure and blood lipids, with slightly greater reductions observed with orforglipron – likely reflecting its stronger weight‑loss effect. It is worth noting, however, that the dose of oral semaglutide used here was relatively modest. Higher doses are now approved for weight management and are expected to be tested in people with diabetes as well.

“Currently, oral semaglutide has the advantage of proven cardiovascular benefit, whereas similar evidence for orforglipron is not yet available. Ongoing trials should provide clarity soon.

“Overall, the field is moving toward treatments that meaningfully improve weight, blood sugar, and cardiovascular risk at the same time. These more holistic approaches, which also benefit patient well-being, are likely to offer the greatest benefits for people living with type 2 diabetes. Indeed, we have suggested recently that incretin‑based therapies associated with considerable 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.”

Declaration of interest: “NS has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gan & Lee, GlaxoSmithKline, Hanmi Pharmaceuticals, Janssen, Kailera, Mass Medicines, Menarini-Ricerche, Merck Sharp & Dohme, Metsera, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche, Sanofi, UCB Pharma and Verdiva Bio; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche.  No shares in any medical areas.”