Lilly’s Phase 3 TRIUMPH-2 and TRIUMPH-3 trials show investigational retatrutide achieved up to 22.6% weight loss, supporting a planned FDA BLA in Q1 2027.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
Eli Lilly and Company has announced positive topline results from two pivotal Phase 3 studies of retatrutide, its investigational once-weekly triple hormone receptor agonist that targets glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Retatrutide remains an investigational therapy and has not been approved by the U.S. Food and Drug Administration (FDA) for any indication. Both TRIUMPH-2 and TRIUMPH-3 met their primary endpoints, expanding the clinical evidence for retatrutide in two of obesity’s most significant comorbidities: type 2 diabetes and established cardiovascular disease. With these findings, Lilly has now reported positive results from five Phase 3 studies and says the program provides the clinical evidence needed to support global regulatory submissions for obesity, knee osteoarthritis pain, and obstructive sleep apnea.
Weight and Glycemic Control in Type 2 Diabetes
TRIUMPH-2 (NCT05929079) enrolled 1,152 adults with obesity or overweight and type 2 diabetes, a population that often experiences greater difficulty achieving substantial weight loss. Participants were randomized in a 1:1:1:1 ratio to receive once-weekly retatrutide at doses of 4 mg, 9 mg, 12 mg, or placebo for 80 weeks. Treatment began at 2 mg once weekly and was increased every four weeks until participants reached their assigned maintenance dose.
At the primary endpoint, participants receiving retatrutide achieved substantial reductions in body weight from a mean baseline weight of 234.6 lbs. Average weight loss reached 12.7% (29.8 lbs) with the 4 mg dose, 19.1% (45.4 lbs) with the 9 mg dose, and 20.8% (49.6 lbs) with the 12 mg dose, compared with 4.0% (9.3 lbs) among participants receiving placebo. Retatrutide also produced clinically meaningful improvements in glycemic control. From a baseline HbA1c of 7.7%, participants achieved reductions of up to 1.6 percentage points compared with a 0.2 percentage-point reduction in the placebo group.
Severe Obesity and Established Cardiovascular Disease
TRIUMPH-3 (NCT05882045) evaluated 1,949 adults with Class II or Class III obesity (body mass index of at least 35 kg/m²) and established cardiovascular disease, with or without type 2 diabetes. Participants were randomized in a 1:1:2 ratio to receive once-weekly retatrutide 9 mg, retatrutide 12 mg, or placebo for 80 weeks, with treatment initiated at 2 mg and gradually escalated every four weeks to the assigned maintenance dose.
Participants receiving retatrutide experienced substantial weight loss from a mean baseline weight of 245.6 lbs. Average weight reduction reached 21.6% (52.7 lbs) with the 9 mg dose and 22.6% (55.8 lbs) with the 12 mg dose, compared with 3.2% (7.7 lbs) in the placebo group.
Cardiovascular Outcomes Analysis
Major adverse cardiovascular events occurred less frequently than anticipated in both the retatrutide and placebo groups, resulting in relatively few events during the study. In the pre-specified in-study analysis based on pooled 9 mg and 12 mg retatrutide groups, 44 participants receiving retatrutide experienced a MACE-5 event, defined as all-cause death, myocardial infarction, stroke, heart failure event, or coronary revascularization, compared with 52 participants receiving placebo, corresponding to a hazard ratio of 0.82 (95% CI: 0.55-1.22). For the narrower MACE-3 composite of cardiovascular death, myocardial infarction, or stroke, 27 events occurred among participants receiving retatrutide compared with 23 in the placebo group, resulting in a hazard ratio of 1.12 (95% CI: 0.64-1.96). Because fewer cardiovascular events occurred than anticipated, these analyses were not designed to establish cardiovascular benefit and should be interpreted cautiously.
Beyond weight reduction, the highest retatrutide dose produced clinically meaningful improvements in several cardiometabolic risk markers, including average reductions of 37.0% in triglycerides, 16.5% in non-HDL cholesterol, 9.3 mmHg in systolic blood pressure, 19.0 cm in waist circumference, and 51.2% in high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation.
Safety and Tolerability
Across both studies, gastrointestinal events were the most frequently reported adverse events and included diarrhea, nausea, constipation, decreased appetite, and vomiting. These events were generally mild to moderate in severity, occurred primarily during dose escalation, and most resolved during treatment.
In TRIUMPH-2, discontinuation due to adverse events ranged from 3.8% to 11.6% across retatrutide dose groups compared with 4.9% for placebo. In TRIUMPH-3, discontinuation rates were 9.8% and 13.5% with the 9 mg and 12 mg doses, respectively, compared with 4.8% for placebo. Lilly also reported higher rates of dysesthesia and urinary tract infections among participants receiving retatrutide than placebo in both studies.
Regulatory Path
Lilly said complete analyses will be presented at upcoming scientific meetings and published in peer-reviewed journals. According to the company, the clinical data package supporting retatrutide is complete, and it is finalizing the Chemistry, Manufacturing, and Controls (CMC) package required for regulatory submission. Lilly plans to submit a Biologics License Application (BLA) to the FDA during the first quarter of 2027.
Retatrutide continues to be evaluated in additional Phase 3 studies across obesity and obesity-related conditions, including knee osteoarthritis pain, moderate-to-severe obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease (MASLD). The broader global TRIUMPH clinical development program began in 2023 and has enrolled more than 5,800 participants across four registrational Phase 3 trials.
What This Means for Patients
People living with obesity alongside type 2 diabetes or established cardiovascular disease often face greater challenges achieving meaningful and sustained weight loss while managing the health risks associated with these conditions. The topline findings from TRIUMPH-2 and TRIUMPH-3 suggest that retatrutide has the potential to deliver substantial weight reduction alongside improvements in glycemic control and several cardiometabolic risk markers in these higher-risk populations.
However, retatrutide remains an investigational therapy, and its long-term safety, efficacy, and place in clinical practice will depend on complete peer-reviewed data, results from ongoing Phase 3 studies, and regulatory review. If approved, retatrutide could become the first triple hormone receptor agonist available for chronic weight management and several obesity-related conditions.
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About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.