Drug pipeline
Retatrutide nears bariatric surgery–level weight loss in phase 3 trial
Clinical Takeaway: Retatrutide produced some of the largest weight-loss effects yet reported with pharmacotherapy for obesity, approaching results historically associated with bariatric surgery. The investigational triple agonist also improved multiple cardiometabolic risk markers, though gastrointestinal adverse effects and treatment discontinuation increased at higher doses.
New phase 3 data suggest the investigational triple hormone receptor agonist retatrutide may substantially expand the upper range of achievable weight loss with medical therapy. Adults with obesity or overweight and at least one weight-related comorbidity experienced weight reductions approaching those traditionally associated with bariatric surgery in the TRIUMPH-1 trial.
Retatrutide is a once-weekly investigational agonist targeting glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. The phase 3 TRIUMPH-1 trial randomized 2,339 adults without diabetes to retatrutide 4 mg, 9 mg, 12 mg, or placebo for 80 weeks.
At 80 weeks, participants receiving retatrutide 12 mg lost an average of 28.3% of body weight, equivalent to 70.3 lb, compared with 2.2% with placebo. Among patients receiving the 12 mg dose, 45.3% achieved at least 30% weight loss and 27.2% achieved at least 35% weight loss. At the 4 mg dose, participants lost an average of 19.0% of body weight with only a single dose-escalation step.
A pre-specified extension in participants with baseline body mass index ≥35 showed continued weight reduction through 104 weeks. Patients continuing retatrutide 12 mg achieved mean weight loss of 30.3%, corresponding to approximately 85 lb.
Retatrutide also improved several cardiometabolic measures, including waist circumference, triglycerides, non-HDL cholesterol, systolic blood pressure, and high-sensitivity C-reactive protein.
The most common adverse effects were gastrointestinal and generally consistent with other incretin-based therapies. Nausea, diarrhea, constipation, and vomiting increased with higher doses. Discontinuation due to adverse events occurred in 4.1%, 6.9%, and 11.3% of participants receiving retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 4.9% with placebo.
Lilly said additional results from the TRIUMPH phase 3 program are expected later this year, including studies evaluating retatrutide in obesity with type 2 diabetes, obstructive sleep apnea, cardiovascular disease, osteoarthritis pain, chronic low back pain, metabolic dysfunction-associated steatotic liver disease, and cardiovascular and renal outcomes. The company has not yet announced a regulatory submission timeline.
“It was impressive to see that every dose of retatrutide resulted in clinically meaningful weight reduction for nearly all participants, and people with severe obesity on the highest dose lost on average 30% of their body weight over two years,” said Ania Jastreboff, MD, PhD, professor of medicine and pediatrics at Yale School of Medicine and lead investigator of the trial. “Importantly, treatment with retatrutide not only resulted in robust weight reduction, but also in clear improvements in assessed cardiometabolic health measures.”
Source: Eli Lilly and Company. (2026, May 21). Press release. Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal phase 3 obesity trial