Retatrutide Meets Phase 3 Weight-Loss Endpoints in 2 Obesity Trials

Eli Lilly announced positive topline results from 2 phase 3 trials of retatrutide in adults with obesity and major cardiometabolic comorbidities on July 23, 2026. The investigational once-weekly agent met the primary weight-loss endpoint at 80 weeks in TRIUMPH-2 and TRIUMPH-3, according to the company.1

“Across five positive Phase 3 studies, retatrutide has shown powerful efficacy, and we believe it could be an important future tool in the management of cardiometabolic health,” Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a statement. “With the positive results from TRIUMPH-2 and TRIUMPH-3, we now have the clinical data package to support global submissions for retatrutide as a potential treatment for obesity, knee osteoarthritis pain, and obstructive sleep apnea.”1

What the TRIUMPH-2 and TRIUMPH-3 Trials Showed

TRIUMPH-2 enrolled 1152 adults with type 2 diabetes (T2D) and obesity or overweight. Participants were randomly assigned 1:1:1:1 to retatrutide 4 mg, 9 mg, or 12 mg or placebo. Mean baseline body weight was 106.4 kg, mean body mass index was 38.2, and mean glycated hemoglobin (HbA1c) was 7.7%. Treatment began at 2 mg once weekly, followed by dose escalation every 4 weeks.1,2

At week 80, mean weight changes under the efficacy estimand were -12.7%, -19.1%, and -20.8% with the 4 mg, 9 mg, and 12 mg doses, respectively, compared with -4.0% with placebo. Mean HbA1c changes were -1.4, -1.6, and -1.5 percentage points, respectively, versus -0.2 points with placebo.1

TRIUMPH-3 randomly assigned 1949 adults with a body mass index of at least 35 and established cardiovascular disease to retatrutide 9 mg, retatrutide 12 mg, or placebo in a 1:1:2 ratio. T2D was permitted. At week 80, mean weight decreased by 21.6% and 22.6% with retatrutide 9 mg and 12 mg, respectively, compared with 3.2% with placebo.1,3

Cardiovascular Analyses and Safety Findings With Retatrutide

In the prespecified in-study analysis of TRIUMPH-3, 44 MACE-5 events occurred in the pooled retatrutide groups and 52 occurred with placebo, yielding a hazard ratio of 0.82 (95% CI, 0.55-1.22). MACE-5 included all-cause death, myocardial infarction, stroke, heart failure events, or coronary revascularization.1

For MACE-3, encompassing cardiovascular death, myocardial infarction, or stroke, 27 events occurred with retatrutide and 23 with placebo. The hazard ratio was 1.12 (95% CI, 0.64-1.96). Both confidence intervals crossed 1, leaving cardiovascular effects unresolved. Lilly also reported reductions in triglycerides, non–high-density lipoprotein cholesterol, systolic blood pressure, waist circumference, and high-sensitivity C-reactive protein with the 12-mg dose.1

Gastrointestinal events predominated in both trials. Diarrhea, nausea, constipation, decreased appetite, and vomiting were common in TRIUMPH-2. In TRIUMPH-3, diarrhea occurred in 30.1%, 24.4%, and 8.7% of participants receiving 9 mg, 12 mg, and placebo, respectively. Adverse-event discontinuation reached 13.5% with 12 mg in TRIUMPH-3 versus 4.8% with placebo.1

Retatrutide Mechanism and Planned FDA Submission

Retatrutide is a single-molecule agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors. Lilly is studying the agent across obesity-related conditions, including obstructive sleep apnea, knee osteoarthritis pain, cardiovascular and renal outcomes, and metabolic dysfunction–associated steatotic liver disease.1

The company plans to submit a Biologics License Application (BLA) to the US Food and Drug Administration (FDA) in the first quarter of 2027 after completing its chemistry, manufacturing, and controls package.1

References

1. Eli Lilly and Company. Lilly’s triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C. Published July 23, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-successful-two-additional

2. Eli Lilly and Company. A Study of Retatrutide (LY3437943) in Participants With Type 2 Diabetes Mellitus Who Have Obesity or Overweight (TRIUMPH-2). ClinicalTrials.gov Identifier: NCT05929079. Updated April 13, 2026. Accessed July 23, 2026. https://clinicaltrials.gov/study/NCT05929079

3. Eli Lilly and Company. A Study of Retatrutide (LY3437943) in Participants With Obesity and Cardiovascular Disease (TRIUMPH-3). ClinicalTrials.gov Identifier: NCT05882045. Updated May 22, 2026. Accessed July 23, 2026. https://clinicaltrials.gov/study/NCT05882045