Lilly’s Retatrutide Achieves 30.3% Weight Loss in Phase 3 TRIUMPH-1 Trial

Eli Lilly and Company announced positive topline results from TRIUMPH‑1 (NCT05929066), a pivotal Phase 3 study evaluating retatrutide, its investigational once‑weekly triple agonist of GIP, GLP‑1, and glucagon receptors. The trial met all primary and key secondary endpoints, demonstrating substantial and sustained weight reduction in adults with obesity or overweight and at least one weight‑related comorbidity, but without diabetes.

Significant Weight Loss Across Dose Groups

At 80 weeks, participants receiving retatrutide 12 mg achieved an average 28.3% body weight reduction, equivalent to 70.3 pounds, while the 9 mg dose produced 25.9% (64.4 pounds) and the 4 mg dose delivered 19.0% (47.2 pounds). In a pre‑specified blinded extension through 104 weeks among patients with baseline BMI ≥35, those continuing on 12 mg reached 30.3% mean weight loss, or 85 pounds.

Responder analyses underscored the therapy’s impact: more than 62% of patients on 12 mg achieved at least 25% weight loss, while 45.3% achieved reductions of at least 30%. Notably, 65.3% of participants on 12 mg reduced BMI below 30, crossing out of the obesity range, and among those with class 3 obesity (BMI ≥40), 37.5% achieved BMI below 30.

Cardiometabolic Benefits Beyond Weight Reduction

Retatrutide produced broad cardiometabolic improvements. Waist circumference decreased by an average of 24.1 cm, accompanied by reductions in triglycerides, non‑HDL cholesterol, systolic blood pressure, and high‑sensitivity C‑reactive protein. These findings highlight the therapy’s potential to address multiple pathways involved in appetite regulation, metabolism, and energy expenditure.

Safety Profile Consistent with Incretin Therapies

The safety profile was consistent with incretin‑based therapies, with gastrointestinal adverse events such as nausea, diarrhea, constipation, and vomiting occurring more frequently at higher doses. Discontinuation rates due to adverse events were dose‑dependent, reaching 4.1% in the 4 mg arm, 6.9% in the 9 mg arm, and 11.3% in the 12 mg arm, compared with 4.9% for placebo.

Expert and Executive Perspectives

Lead investigator Ania Jastreboff emphasized that retatrutide delivered clinically meaningful weight reduction across all dose levels with accompanying cardiometabolic improvements. Lilly executive Kenneth Custer highlighted the therapy’s potential to support more individualized obesity treatment strategies.

Pipeline Context and Next Steps

Retatrutide is being advanced alongside Lilly’s approved Zepbound and investigational oral obesity therapy Foundayo as part of the company’s broader cardiometabolic pipeline. Lilly plans to present detailed TRIUMPH‑1 findings at the American Diabetes Association Scientific Sessions and release additional Phase 3 data later this year from TRIUMPH‑2, evaluating retatrutide in obesity with type 2 diabetes, and TRIUMPH‑3, assessing the therapy in obesity with cardiovascular disease.

More recently, TRANSCEND‑T2D‑1 demonstrated up to 2.0% A1C reduction and 16.8% weight loss in adults with type 2 diabetes, and TRIUMPH‑4 reported average 28.7% weight loss alongside significant reductions in knee osteoarthritis pain, underscoring the therapy’s potential across diverse patient populations.

Reference

Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial | Eli Lilly and Company

Study Details | NCT05929066 | A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight | ClinicalTrials.gov