Retatrutide, Eli Lilly’s first-in-class triple hormone receptor agonist, delivered meaningful weight loss at 80 weeks in all doses in the TRIUMPH-1 phase 3 trial.

Retatrutide is an investigational, triple hormone receptor agonist that activates the body's receptors for GIP, GLP-1, and glucagon. It’s given as a once-weekly injection.

Meaningful Results at Three Doses 

Trial participants were adults with obesity or overweight and at least one weight-related health condition, but without diabetes. They were randomized to one of three retatrutide doses or placebo for 80 weeks. Those on the 12 mg dose lost an average of 28.3% of their body weight — or roughly 70 lbs — compared with 2.2% in the placebo group, while 45.3% of participants achieved ≥ 30% weight loss.

Participants on 9 mg lost an average of about 64 lbs, or nearly 26% of body weight. The 4 mg dose, reached with a single escalation step, produced 19% weight loss, or an average of 47 lbs.

Notably, two-thirds of participants (65.3%) on the highest dose for 80 weeks achieved a BMI less than 30, falling out of the obesity range, including more than a third of those who began the trial with severe obesity (BMI ≥ 40).

In a subset of participants with a baseline BMI ≥ 35 or higher who continued in a pre-specified extension study, those on the 12 mg dose who continued through 104 weeks lost an average of 85 lbs, or 30.3% of their body weight, over 2 years.

Retatrutide also led to significant improvements from baseline across certain cardiovascular risk factors, including waist circumference, non-high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and high-sensitivity C-reactive protein.

Side effects were consistent with other drugs in the incretin class — most commonly nausea, diarrhea, constipation, and vomiting — which tended to be more frequent at higher doses. 

Dysesthesia events and urinary tract infections were generally mild to moderate. The majority resolved during treatment, and most participants continued taking retatrutide.

Discontinuation rates due to adverse events were 4.1%, 6.9%, 11.3%, with retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 4.9% with placebo.

Lilly said additional TRIUMPH-1 results will be presented at the 86th annual American Diabetes Association Scientific Sessions in June along with other results from the company’s cardiometabolic pipeline. Additional detailed results will be presented at future medical meetings and published in peer-reviewed journals.

‘Encouraging, But Needs Confirmation’ 

Early commentary from experts suggests enthusiasm and some caution. Marie Spreckley, PhD, research programme manager at University of Cambridge, UK, said, “These topline findings are very encouraging… 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.”

“However,” she added, “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.”

Similarly, Simon Cork, PhD, senior lecturer in physiology, Anglia Ruskin University, Cambridge, UK, said: “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.”

Spreckley declared being a postdoctoral researcher at the MRC Epidemiology Unit, University of Cambridge, working in obesity, nutrition and behavioral 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. Cork declared no conflicts of interest. 

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDEdge, The Lancet (where she was a contributing editor), and Reuters Health.