Eli Lilly’s retatrutide delivered up to 28.3% weight loss in Phase 3 trials, with significant improvements in type 2 diabetes, knee osteoarthritis pain, and obstructive sleep apnea, reinforcing its broad cardiometabolic potential.
Written By: Shaik Yasmeen, PharmD
Reviewed By: Pharmacally Editorial Team
Eli Lilly has unveiled new Phase 3 data for retatrutide, its investigational once-weekly triple hormone receptor agonist, at the American Diabetes Association’s 86th Scientific Sessions. Findings from the TRIUMPH-1 (NCT05929066) and TRANSCEND-T2D-1 studies (NCT06354660) showed substantial weight loss alongside meaningful improvements in knee osteoarthritis pain, obstructive sleep apnea, and glycemic control. Results from TRANSCEND-T2D-1 were simultaneously published in The Lancet, underscoring the therapy’s scientific impact.
First-in-Class Triple Agonist
Retatrutide activates glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. By targeting multiple metabolic pathways, the therapy addresses obesity and associated conditions such as type 2 diabetes, osteoarthritis, and obstructive sleep apnea. Obesity contributes to more than 200 associated diseases globally, making multi-pathway interventions an important area of therapeutic development.
TRIUMPH-1: Weight Loss, Osteoarthritis and Sleep Apnea Benefits
The Phase 3 TRIUMPH-1 study enrolled 2,339 adults with obesity, including dedicated cohorts with knee osteoarthritis pain and moderate-to-severe obstructive sleep apnea. At 80 weeks, retatrutide met primary endpoints across all study populations.
Participants receiving 9 mg and 12 mg achieved average weight reductions of 25.9% and 28.3%, respectively, while the 4 mg dose produced 19.0% weight loss. Among participants receiving 12 mg, 65.3% achieved a BMI below 30 and 33.3% reached a BMI below 25. In a pre-specified extension among participants with baseline BMI ≥35, continued treatment with 12 mg resulted in 30.3% weight loss through 104 weeks.
Retatrutide also improved obesity-related complications. WOMAC pain scores in participants with knee osteoarthritis declined by up to 73.1%, while the apnea-hypopnea index in moderate-to-severe obstructive sleep apnea decreased by up to 60.6%.
TRANSCEND-T2D-1: Significant HbA1c Reduction
The Phase 3 TRANSCEND-T2D-1 trial evaluated adults with type 2 diabetes inadequately controlled through diet and exercise alone. At 40 weeks, retatrutide met its primary endpoint and all key secondary endpoints.
Participants achieved HbA1c reductions of up to 2.0% from a baseline of 7.9%. Up to 90% reached HbA1c levels below 7.0%, 85% achieved HbA1c levels of 6.5% or lower, and 46% achieved normoglycemia, defined as HbA1c below 5.7%.
Participants receiving 12 mg lost an average of 16.8% of body weight, with weight loss continuing at week 40 without evidence of plateauing.
Cardiometabolic Benefits and Safety
Across both studies, retatrutide improved key cardiometabolic risk factors in addition to weight loss. In TRIUMPH-1, the therapy reduced triglycerides by up to 41.0%, lowered systolic blood pressure by up to 12.3 mmHg, and reduced waist circumference by up to 24.1 cm.
Safety findings were generally consistent with other incretin-based therapies. The most common adverse events included nausea, diarrhea, constipation, and vomiting, typically mild to moderate. Discontinuation rates due to adverse events reached 11.3% in the 12 mg group versus 4.9% with placebo, supporting tolerability across dose groups.
Background and Development Trajectory
Earlier Phase 2 studies of retatrutide demonstrated double-digit weight loss and improvements in glycemic control, laying the foundation for Phase 3 confirmation. The current results validate those findings in larger patient populations, positioning retatrutide among the most effective obesity therapies evaluated to date and supporting the therapeutic potential of its triple agonist mechanism.
Pipeline Expansion in Obesity and Metabolic Disease
Lilly continues to advance retatrutide across Phase 3 programs in obesity, type 2 diabetes, obstructive sleep apnea, knee osteoarthritis pain, cardiovascular outcomes, and metabolic dysfunction-associated steatotic liver disease. Additional results from Lilly’s ongoing obesity and diabetes programs are expected over the next year as the company advances retatrutide toward potential regulatory submissions.
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About the Writer
Shaik Yasmeen (LinkedIn) is a Pharm.D graduate with interests in clinical pharmacy, pharmacovigilance, and medical writing. She has gained experience through hospital clinical postings, patient case reviews, case presentations, and literature evaluation. Passionate about evidence-based healthcare, she is committed to creating accurate and engaging medical content while continuously expanding her professional knowledge.