A once-weekly injection of retatrutide, a triple hormone agonist targeting GIP, GLP-1, and glucagon receptors, reduced body weight by up to 28.3% at 80 weeks in adults with obesity, according to Phase 3 data presented at the American Diabetes Association’s 86th Scientific Sessions by Ania M. Jastreboff, MD, PhD, professor at Yale University and lead author of the study.
Study Design
TRIUMPH-1 (NCT05929066) was a randomized, double-blind, placebo-controlled trial that tested weekly subcutaneous retatrutide at 4 mg, 9 mg, and 12 mg against placebo over 80 weeks. All participants received lifestyle counseling on healthy diet and physical activity; notably, the protocol did not include guidance on caloric restriction.
Within the main cohort of approximately 2,000 participants, two baskets were enrolled based on obesity-related comorbidities: 574 participants with knee osteoarthritis and 243 with obstructive sleep apnea (OSA). The primary endpoint was change in Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee pain score for the knee osteoarthritis basket and change in apnea-hypopnea index (AHI) for the OSA basket.
The extension included 532 participants among eligible completers who had a baseline BMI greater than 35 and were on-target dose at 80 weeks. Extension participants continued treatment for an additional 24 weeks (to 104 weeks total) and were transitioned to their maximally tolerated dose of 9 or 12 mg.
Effects of Retatrutide on Body Weight
Percent change in body weight at 80 weeks (primary endpoint) showed a dose response. Using the efficacy estimand, participants in the placebo group lost 2.2% of their body weight. Those on 4 mg retatrutide lost up to 19%, the 9 mg group lost 25.9%, and the 12 mg group lost 28.3%. In absolute terms, the 12 mg dose translated to an average loss of approximately 70 pounds (32 kg) at 80 weeks of treatment.
In the extension, weight loss continued through week 104. The 12 mg group achieved an average body weight reduction of 30.3%, or roughly 85 pounds (38.5 kg). The placebo arm, which was switched to active drug in the extension, lost up to 19.2% during those 24 weeks.
Looking at weight-loss thresholds at 80 weeks with 12 mg, nearly all participants lost at least 5% of body weight, and more than 85% lost at least 15%. Nearly half reached the 30% threshold, and more than one in four lost at least 35%.
Two-thirds of participants achieved a BMI below 30, and one-third reached a BMI below 25, starting from a mean baseline BMI of 40. Weight loss was greater in female participants (up to 30.8%) than male participants (23.2%) at 80 weeks, a sex difference consistent with Phase 2 findings according to Dr. Jastreboff.
Effects of Retatrutide on Comorbidities and Cardiometabolic Markers
In the knee osteoarthritis basket, retatrutide resulted in a WOMAC pain score reduction exceeding the four-point clinically significant threshold, translating to up to more than a 70% decrease in pain.
In the OSA basket, retatrutide resulted in an AHI reduction exceeding the clinically significant threshold of 15 events per hour; a greater than 60% AHI reduction was reported for the 9 mg dose group.
Systolic blood pressure improved by up to 12 mmHg. Triglycerides fell by up to 41%, and low-density lipoprotein by roughly 20%. High-sensitivity C-reactive protein levels decreased by 63.8%. Among the 36% of participants who had prediabetes at baseline, more than 95% reverted to normoglycemia with the 12 mg dose.
Safety
Treatment-emergent adverse events occurred in 87% to 89.2% of participants in the retatrutide groups and in 80.7% of those in the placebo group. Serious adverse events were reported in 7.7% to 10.5% with retatrutide, compared with 5.5% with placebo. Deaths occurred in two placebo participants, three in the 9 mg group, and one in the 12 mg group.
Treatment discontinuation due to adverse event occurred in 4% to 11% of retatrutide-treated participants compared with 5% on placebo. Reported hypotension was more common with retatrutide than with placebo, and fatigue and dizziness were reported more frequently in the higher-dose groups.
Urinary tract infections were also more common in the retatrutide groups (6.8% to 8.1%) than with placebo (4.8%). These events were largely mild to moderate, resolved with treatment, and did not lead to discontinuation. Ninety-two percent occurred in female participants.
Retatrutide is an investigational therapy and has not been approved by the FDA. TRIUMPH-1 was funded by Eli Lilly and Company.
Collage by Jennifer Bogartz, Diana Connolly
