Retatrutide meets primary endpoints in two phase III obesity trials, reporting up to 22.6% weight loss

Topline data from the TRIUMPH-2 and TRIUMPH-3 trials show substantial weight loss, improved glycemic control, and favorable changes in cardiometabolic risk markers with the investigational triple hormone receptor agonist in adults with obesity and type 2 diabetes or established cardiovascular disease.

Eli Lilly and Company (Indianapolis, IN) has reported positive topline results from two phase III trials of retatrutide, an investigational glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptor agonist, according to a company press release issued July 23, 2026.¹

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Obesity is a major contributor to cardiometabolic disease, and its coexistence with type 2 diabetes (T2D) or established cardiovascular disease increases clinical burden and complicates management. Therapies that produce clinically meaningful weight loss while also improving glycemic control and cardiovascular risk markers could therefore have particular relevance to endocrinology practice.

Retatrutide is administered by once-weekly subcutaneous injection and is a single molecule that activates the GIP, GLP-1, and glucagon receptors. The inclusion of glucagon receptor agonism distinguishes it from currently available single- and dual-receptor agonists, although neither of the two trials compared retatrutide directly with another obesity medicine.

TRIUMPH-2 (NCT05929079)was an 80-week, randomized, double-blind, placebo-controlled trial involving 1,152 adults with obesity or overweight and T2D. Participants were randomized equally to receive retatrutide 4 mg, 9 mg, or 12 mg, or placebo.²

Using the efficacy estimand, mean body weight decreased by 12.7%, 19.1%, and 20.8% with retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 4.0% with placebo at week 80. These reductions corresponded to average weight losses of 29.8 lbs, 45.4 lbs, and 49.6 lbs in the retatrutide groups, compared with 9.3 lbs in the placebo group. The efficacy estimand estimated outcomes had all randomized participants remained on their assigned intervention, with permitted dose interruptions or modifications, and without prohibited weight-management treatment.

From a mean baseline glycated hemoglobin (HbA1c) level of 7.7%, mean HbA1c decreased by 1.4, 1.6, and 1.5 percentage points with retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 0.2 percentage points with placebo.

TRIUMPH-3 (NCT05882045) enrolled 1,949 adults with a body mass index of at least 35 kg/m² and established cardiovascular disease, with or without T2D. Participants were randomized in a 1:1:2 ratio to retatrutide 9 mg, retatrutide 12 mg, or placebo.³

Using the efficacy estimand, participants receiving retatrutide 9 mg and 12 mg achieved mean weight reductions of 21.6% and 22.6%, respectively, at week 80, compared with 3.2% with placebo. This corresponded to average weight losses of 52.7 lbs and 55.8 lbs with retatrutide, compared with 7.7 lbs with placebo.

At the 12 mg dose, Lilly also reported 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.

Major adverse cardiovascular events occurred less frequently than anticipated across the treatment and placebo groups, limiting the precision of the cardiovascular analyses. In the prespecified in-study analysis, the hazard ratio for the five-component major adverse cardiovascular event endpoint was 0.82 (95% confidence interval [CI] 0.55–1.22) for pooled retatrutide doses versus placebo. For the three-component endpoint of cardiovascular death, myocardial infarction, or stroke, the hazard ratio was 1.12 (95% CI 0.64–1.96). These results do not establish a reduction in cardiovascular events with retatrutide.

The most commonly reported adverse events in both trials were primarily gastrointestinal and included diarrhea, nausea, constipation, decreased appetite, and, in TRIUMPH-2, vomiting. According to Lilly, these events were generally mild to moderate, and most resolved during treatment.

In TRIUMPH-2, discontinuation because of adverse events occurred in 3.8%, 11.6%, and 7.7% of participants receiving retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 4.9% receiving placebo. In TRIUMPH-3, the corresponding rates were 9.8% with retatrutide 9 mg, 13.5% with retatrutide 12 mg, and 4.8% with placebo. Dysesthesia was reported more frequently with retatrutide than with placebo in both studies.

Lilly stated that it plans to submit a Biologics License Application to the US Food and Drug Administration in the first quarter of 2027. Detailed results from TRIUMPH-2 and TRIUMPH-3 have not yet been presented at a medical meeting or published in a peer-reviewed journal.

The findings add to the Phase 3 evidence supporting retatrutide as a potential treatment for obesity, including in people with T2D or established cardiovascular disease. Fuller assessment will require publication of the complete efficacy and safety results, including further details of treatment discontinuations and the cardiovascular-event analyses.

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. Press release. July 23, 2026. Available at: https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-successful-two-additional (accessed July 24, 2026).