Lilly’s retatrutide delivers powerful weight loss in pivotal Phase 3 obesity trial

Eli Lilly releases their new  positive topline results from TRIUMPH-1, a Phase 3 clinical trial assessing the efficacy and safety of retatrutide, an investigational, first in class GIP, GLP-1, and glucagon triple hormone receptor agonist, in adults living with obesity or overweight and at least one weight related comorbidity but without diabetes. At 80 weeks, every dose of retatrutide (4 mg, 9 mg, and 12 mg) achieved the primary and key secondary endpoints for obesity, producing clinically meaningful weight loss.

“Obesity is a chronic disease, and people living with obesity deserve treatment options that match the complex biology of their neurometabolic disease,” said Ania Jastreboff, M.D., Ph.D., Professor of Medicine & Pediatrics (Endocrinology) at the Yale School of Medicine, Director of the Yale Obesity Research Center (Y-Weight), and lead investigator. “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. Importantly, treatment with retatrutide not only resulted in robust weight reduction, but also in clear improvements in assessed cardiometabolic health measures. For patients I see in clinic, retatrutide may potentially be a highly impactful future tool to treat their obesity and transform their health trajectory.”

For the primary endpoint, participants on retatrutide 9 mg and 12 mg lost an average of 64.4 lbs (25.9%) and 70.3 lbs (28.3%) respectively. Those receiving the 4 mg dose, after just a single dose escalation step, lost an average of 47.2 lbs (19.0%). Notably, 65.3% of participants on retatrutide 12 mg achieved a BMI below 30, falling under the threshold for obesity at 80 weeks, including 37.5% of those who began the trial with class 3 obesity (BMI of 40 or higher). In a pre specified blinded extension for participants with a BMI of 35 or higher, those who continued on retatrutide 12 mg through to 104 weeks lost an average of 85.0 lbs (30.3%). Retatrutide also produced significant improvements from baseline across several cardiovascular risk factors, including waist circumference, non HDL cholesterol, triglycerides, systolic blood pressure and high sensitivity C reactive protein (hsCRP).

TRIUMPH-1 efficacy estimand results

Primary endpoint at 80 weeks (percent change in body weight from an average baseline of 112.7 kg / 248.5 lbs; BMI of 40.0 kg/m²): retatrutide 4 mg reduced body weight by 19.0% (21.4 kg / 47.2 lbs), retatrutide 9 mg by 25.9% (29.2 kg / 64.4 lbs), and retatrutide 12 mg by 28.3% (31.9 kg / 70.3 lbs), compared with 2.2% (2.5 kg / 5.5 lbs) on placebo. The percent body weight reduction with retatrutide 4 mg was a key secondary endpoint.

Key secondary endpoints at 80 weeks: change in waist circumference from a baseline of 118.3 cm (46.6 in) was 16.3 cm (6.4 in) for retatrutide 4 mg, 21.8 cm (8.6 in) for 9 mg, 24.1 cm (9.5 in) for 12 mg, and 3.6 cm (1.4 in) for placebo. The percentage of participants reaching a body weight reduction of at least 25% was 27.8% (4 mg), 52.9% (9 mg), 62.5% (12 mg) and 2.2% (placebo). Reductions of at least 30% were reached by 15.3%, 37.9%, 45.3% and 0.5% respectively, while reductions of at least 35% were reached by 5.9%, 20.8%, 27.2% and 0.3% respectively.

Pre specified extension at 104 weeks: the extension period enrolled 532 participants with a BMI of 35 or higher at baseline who had completed the main 80 week study and tolerated their assigned dose. Participants received retatrutide at a maximum tolerated dose of 9 mg or 12 mg. From an average baseline of 121.7 kg (268.3 lbs; BMI of 42.8 kg/m²), participants on retatrutide 4 mg titrated to maximum tolerated dose saw a body weight reduction of 27.9% (33.2 kg / 73.3 lbs), those on 9 mg to maximum tolerated dose saw 29.5% (36.6 kg / 80.7 lbs), those on 12 mg to maximum tolerated dose saw 30.3% (38.5 kg / 85.0 lbs), and those who moved from placebo to retatrutide at maximum tolerated dose saw 19.2% (22.6 kg / 49.9 lbs).

“TRIUMPH-1 highlights the importance of options and the potential for retatrutide to help people across various stages of their obesity journey,” said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. “From the 4 mg dose, reaching nearly 20% weight loss with one escalation step, to the 12 mg dose that delivered a level of weight loss long associated with bariatric surgery, retatrutide offers the potential for a patient-centric approach to obesity.”

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