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Scientists comment on topline results from a phase III clinical trial of the hormone receptor agonist Retatrutide.
Prof Graham Finlayson, Chair in Psychobiology, School of Psychology, University of Leeds, said:
“These topline results suggest that retatrutide may produce weight losses approaching the range historically associated with bariatric surgery, which is striking. Retatrutide is different from currently approved GLP-1-based obesity medicines because it activates three hormone receptors; GIP, GLP-1 and glucagon. In principle, that broader pharmacology could produce larger effects on body weight and metabolism, although the full peer-reviewed data will be needed to understand the balance between efficacy, tolerability and discontinuation.
“The headline efficacy results are impressive, particularly the proportion of participants reported to achieve very large weight losses. However, these are company-released topline findings rather than a full peer-reviewed scientific paper. That means important details are still pending, including the full statistical analysis, participant flow, handling of missing data, adverse event severity, and the trajectory of weight loss over time.
“It will also be important to understand not only how much weight people lose, but how treatment affects the lived experience of appetite and eating behaviour. Patient-reported outcomes on perceived control over eating, food cravings and food preferences are less consistently reported than weight and cardiometabolic endpoints, yet these constructs are increasingly relevant as patients and clinicians talk about reduced ‘food noise’ on incretin-based therapies. One clinically important question is whether patients feel less troubled by cravings and more able to maintain control over eating in their normal environment.
“Overall, these findings add to evidence that the next generation of obesity medicines will produce substantially greater weight loss than earlier pharmacological approaches. The main caveat is that we need to see the full peer-reviewed trial data before drawing firm conclusions about comparative effectiveness, safety, patient experience and long-term treatment value.”
Dr Marie Spreckley, Research Programme Manager, University of Cambridge, said:
“Retatrutide is an experimental once-weekly triple hormone receptor agonist that acts on GLP-1, GIP and glucagon receptors. This differs from semaglutide, which targets GLP-1 receptors alone, and tirzepatide, which targets both GLP-1 and GIP receptors. The addition of glucagon receptor activity is thought to contribute to increased energy expenditure alongside appetite suppression and glucose regulation.
“These topline findings are very encouraging. Lilly reports mean weight loss of 28.3% at 80 weeks with the 12 mg dose, with 45.3% of participants achieving at least 30% weight loss. If confirmed in the full peer-reviewed publication, this would represent one of the largest weight reductions reported for a pharmacological obesity treatment and begins to approach the magnitude of weight loss historically associated with bariatric surgery in some patients, although direct cross-trial comparisons should always be interpreted cautiously.
“The findings are broadly consistent with earlier retatrutide studies and with the wider trajectory of incretin-based obesity pharmacotherapy. The reported improvements in waist circumference, triglycerides, systolic blood pressure and inflammatory markers are also important, as obesity treatment should be evaluated not only by weight reduction but also by effects on broader metabolic and cardiovascular health.
“However, these are still company-reported topline results rather than a full peer-reviewed scientific publication. Without access to the complete dataset, it is not yet possible to fully assess issues such as adherence, missing data, subgroup effects, durability of response after discontinuation, and longer-term safety.
“The adverse event profile appears broadly consistent with incretin-based therapies, with gastrointestinal side effects remaining common and discontinuation rates increasing at higher doses. The dysesthesia signal will also require continued monitoring in future analyses, even if most reported events were mild to moderate.
“Overall, this appears to be a large, well-conducted Phase 3 randomised controlled trial with clinically meaningful findings that add to the growing evidence base supporting incretin-based therapies as potentially transformative tools in obesity treatment and chronic weight management.”
Dr Simon Cork, Senior Lecturer in Physiology, Anglia Ruskin University (ARU), said:
“These early results are incredibly promising in showing that we are now truly on the path to combating the obesity crisis. The results demonstrate Retatrutide’s superior weight loss effects over all currently available weight loss medications, with side effects similar to those seen with other GLP-1 based medications.
“Similar to Mounjaro, Retatrutide mimics the hormones GLP-1 and GIP, which work by suppressing appetite. Unlike Mounjaro, Retatrutide also targets glucagon, a hormone which actively burns fat to use as a fuel source. The addition of glucagon as a biological target is likely behind the superior weight loss effects seen compared to Mounjaro.
“Side effects are similar to those seen in other weight loss medications, notably gastrointestinal side effects. Dysesthesia (defined as abnormal skin sensations or increased sensitivity to touch) are reported in just over 12% of patients taking the highest dose, which has been reported with other weight loss medications. Notably, most patients who experienced this side effect remained on the medication.
“So far these are only headline results, with the full peer reviewed paper still awaited. Earlier results on Retatrutide from the same team have been methodologically sound and of high quality, so we can be confident the results described are robust, but analysis of the final paper will be needed to see the full scope of the effects.
“Obesity is a life-long, relapsing remitting disease that for many requires active medical treatment in order to control. The rapid advancement of effective and safe drugs for the treatment of obesity should be welcomed, but will take time for health services to adapt to be able to offer these treatments to all who could benefit.”
Declared interests
Prof Graham Finlayson: “Professor Finlayson has conducted academic and industry-collaborative research on appetite, food reward, eating behaviour and obesity. He has been involved in the development and validation of appetite and food reward assessment tools, including the Control of Eating Questionnaire and the Leeds Food Preference Questionnaire. He has previously received research funding and consultancy income from commercial organisations in the nutrition, appetite and obesity field.”
Dr Marie Spreckley: “Dr Marie Spreckley is a postdoctoral researcher at the MRC Epidemiology Unit, University of Cambridge, working in obesity, nutrition and behavioural science research. She has co-authored academic publications relating to GLP-1 receptor agonist therapies and nutrition support. She has no personal financial interests related to Eli Lilly or retatrutide.”
Dr Simon Cork: “No CoI to declare”