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A randomised controlled trial published in Nature Medicine looks at the use of Orforflipron for maintenance of body weight reduction.
Dr Marie Spreckley, Research Programme Manager, University of Cambridge, said:
“This is a very clinically relevant study because it addresses one of the biggest unanswered questions in obesity care: how weight reduction can best be maintained after significant weight loss achieved with injectable incretin therapies.
“The findings suggest that switching from injectable semaglutide or tirzepatide to oral orforglipron helped participants maintain a substantially greater proportion of the body weight reduction previously achieved over 52 weeks compared with placebo. This is important because weight regain after discontinuation of incretin-based therapies is well documented and remains one of the major challenges in long-term obesity management.
“One of the most valuable aspects of this study is that it reflects a highly realistic clinical scenario. Many people do not want to remain on injectable therapy indefinitely due to treatment burden, convenience, travel, storage requirements, cost, or personal preference. The possibility of transitioning to an oral therapy while maintaining a substantial proportion of the previously achieved weight reduction could therefore represent an important additional option within longer-term obesity care pathways.
“The study itself was well conducted, using a randomised, double-blind, placebo-controlled design, and the conclusions are generally supported by the data presented. The gastrointestinal side effects observed were also broadly consistent with what we already know about incretin-based therapies.
“However, there are important limitations to consider. The study duration was only one year, so we still do not know how durable these effects will be over longer periods of time. The population was predominantly white and based entirely in the United States, which may limit generalisability. Importantly, there was no comparison group that continued injectable therapy, so this study cannot determine whether switching to oral orforglipron is comparable to remaining on injectable treatment long term.
“Overall, this study reinforces the growing recognition that obesity is a chronic, relapsing disease that often requires ongoing treatment and support. It also highlights the potential future role of oral incretin therapies in creating more flexible and scalable long-term obesity treatment pathways.”
Comments from our friends at the Spanish SMC:
Cristóbal Morales, head of the Metabolic Health, Diabetes and Obesity Unit at Vithas Hospital in Seville and a member of the Spanish Society for the Study of Obesity (SEEDO), said:
“This study is very important because it focuses not so much on losing weight, but on maintaining the benefits, something we are currently concerned about. Previous studies showed that stopping medication could lead to a rebound effect if things weren’t done properly. That is why we are very keen to incorporate certain key concepts into obesity therapy that allow us to understand and treat it effectively, such as the fact that, as it is a chronic and complex condition, it requires long-term treatment and sustained support over time. That is why the maintenance phase is so important.
“In this trial on orforglipron it is demonstrated and published how strategies based on oral obesity therapy using a small molecule that acts on GLP-1 receptors maintain that benefit over time (52 weeks). It is true that longer studies are needed, but these will surely be reported in due course. This is very good news because what we want is to maintain that benefit. We currently have clinical trials with different alternatives for that maintenance phase”.
Francisco Jesús Gómez Delgado, coordinator of the Vascular Risk Unit and head of the Department of Internal Medicine at Jaén University Hospital, associate professor of Medicine at the University of Jaén and member of the Diabetes, Obesity and Nutrition Group of the Spanish Society of Internal Medicine, said:
Is this a high-quality study?
“The fact that it is a clinical trial specifically designed for a particular objective ensures the highest possible rigour. Specifically, it is a phase 3b, randomised, double-blind, placebo-controlled trial, with two well-defined cohorts from previous incretin-based treatments, where sample size has been calculated to analyse and demonstrate the primary and secondary endpoints defined for this study”.
What are its limitations?
“The main limitation is that it conducts a head-to-head comparison and does not compare orforglipron with continued treatment with semaglutide or tirzepatide, as was done in the SURMOUNT-5 clinical trial from which these patients were drawn. Furthermore, the study lasts only 52 weeks, which limits our full understanding of its long-term efficacy and safety.”
What are its implications and how does it fit with existing evidence?
“This study reinforces the idea that obesity is a chronic condition requiring a long-term therapeutic approach using the various tools available, including maintenance therapies with orally administered incretins, which are potentially more scalable and acceptable to many patients.”
José Pablo Miramontes González, a consultant in internal medicine at the Department of Internal Medicine at Río Hortega Hospital (Valladolid), said:
“The ATTAIN-MAINTAIN study is a trial of high methodological quality: a phase 3b, randomised, double-blind, placebo-controlled trial in patients who had previously lost weight with tirzepatide or semaglutide within the SURMOUNT-5 trial.
Its main value is that it answers a very clinical question: what happens if, following significant weight loss with an injectable treatment, patients switch to an oral option such as orforglipron to maintain the benefit. The results are consistent and clinically relevant: orforglipron enabled a higher proportion of weight loss to be maintained than placebo, following both tirzepatide and semaglutide, with a safety profile dominated by gastrointestinal effects, generally mild or moderate. However, there are significant limitations: it was not compared against continuing semaglutide or tirzepatide; the population was drawn solely from the United States; it was a selected cohort—patients who had already tolerated and responded to incretins; it did not include patients with diabetes; and the follow-up period was only one year. Furthermore, the use of orforglipron as rescue therapy in the placebo group partially limits a pure long-term comparison. Overall, the study fits very well with previous evidence showing that obesity is a chronic and relapsing condition, and that discontinuing treatment often leads to weight regain. Its most practical implication is that a sequential strategy—potent injectable treatment to induce weight loss followed by maintenance with an oral GLP-1 receptor agonist—could be a realistic alternative to improve adherence, acceptability and scalability, although it does not yet demonstrate that it is superior to continuing the injectable treatment.
Dr Simon Cork, Senior Lecturer in Physiology, Anglia Ruskin University (ARU), said:
“This is a really important study that addresses a key limitation with injectable, GLP-1 based weight loss medications – that patients experience significant weight rebound after stopping the drugs.
“There are some important points to note here: injectable GLP-1 medications (semaglutide (Wegovy) and tirzepatide (Mounjaro)) produce superior weight loss compared to other weight loss medications but are expensive. This limits their long-term applicability both for private purchasers and the NHS.
“Newer, oral medications (orforglipron (Foundayo)) are significantly cheaper to manufacture, but do not tend to produce the same level of weight loss seen with injectable medications.
“This paper demonstrates an important next step in the treatment regimen for obesity. Significant weight loss achieved through injectable GLP-1 medications, which is then sustained through cheaper, oral GLP-1 based medications.
“What is also important to note is that the decrease in blood pressure, lipids and blood glucose were also maintained in those patients taking oral medications. These parameters have all been shown to increase following cessation of the drugs and reverse the reduction in risk for cardiovascular complications seen on patients taking these medications.
“Whilst the study design is robust, with patients taking oral GLP-1 medications for a year to demonstrate long-term weight stability, a larger cohort is needed to robustly demonstrate these effects to the general population. The study is limited by the relatively small number of people in the active treatment arms (125 who switch from tirzepatide to orforglipron and 105 who switch from semaglutide to orforglipron).
“The results of this study points to a potential future for how patients with obesity are treated, and how the success of weight loss can be maintained in both a clinically meaningful and economically practical way.”
‘Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial’ by Louis J. Aronne et al. was published in Nature Medicine at 23:00 UK time on Tuesday 12th of May 2026.
DOI: https://doi.org/10.1038/s41591-026-04386-7
Declared interests
Dr Marie Spreckley: “Dr Marie Spreckley is a postdoctoral researcher in obesity, nutrition, and behavioural weight management. She has conducted research on incretin-based therapies and nutrition support in obesity care. No relevant competing financial interests to declare.”
Cristóbal Morales: “I am a researcher working on orforglipron and with pharmaceutical companies conducting clinical trials in diabetes and obesity, such as Lilly, Novo Nordisk, Amgen, Boehringer and Pfizer”.
Francisco Jesús Gómez Delgado:
José Pablo Miramontes González: He has not responded regarding any conflicts of interest.
Dr Simon Cork: “No CoI to declare.”