Retatrutide Achieved Up to 22.6% Weight Loss in 2 Phase 3 Obesity Trials

Eli Lilly announced positive topline results from 2 additional phase 3 trials of retatrutide, with the investigational triple hormone receptor agonist meeting the primary end point in adults with obesity and type 2 diabetes and in adults with severe obesity and established cardiovascular disease.

In TRIUMPH-2, adults with obesity or overweight and type 2 diabetes lost up to a mean 49.6 lb, or 20.8%, at 80 weeks with retatrutide. In TRIUMPH-3, adults with severe obesity and established cardiovascular disease, with or without type 2 diabetes, lost up to a mean 55.8 lb, or 22.6%, at 80 weeks.

Retatrutide is an investigational once-weekly glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist. Lilly stated that it plans to submit a Biologics License Application to the US Food and Drug Administration for retatrutide in the first quarter of 2027.

What did TRIUMPH-2 show in adults with obesity and type 2 diabetes?

TRIUMPH-2 was an 80-week, randomized, double-blind, placebo-controlled phase 3 trial that evaluated once-weekly retatrutide in adults with type 2 diabetes and obesity or overweight. The study randomized 1152 participants 1:1:1:1 to retatrutide 4 mg, 9 mg, 12 mg, or placebo.

At baseline, participants had a mean body weight of 234.6 lb and a mean BMI of 38.2 kg/m². At 80 weeks, mean body weight decreased by 12.7% with retatrutide 4 mg, 19.1% with retatrutide 9 mg, and 20.8% with retatrutide 12 mg, compared with 4.0% with placebo.

Participants receiving retatrutide also had greater reductions in A1C. From a baseline A1C of 7.7%, mean A1C decreased by 1.4% with retatrutide 4 mg, 1.6% with retatrutide 9 mg, and 1.5% with retatrutide 12 mg, compared with 0.2% with placebo.

What did TRIUMPH-3 show in adults with severe obesity and CVD?

TRIUMPH-3 was an 80-week, randomized, double-blind, placebo-controlled phase 3 trial that enrolled adults with severe obesity, defined as class 2 or class 3 obesity with BMI of at least 35 kg/m², and established cardiovascular disease. Participants could have type 2 diabetes. The study randomized 1949 participants 1:1:2 to retatrutide 9 mg, retatrutide 12 mg, or placebo.

At baseline, participants had a mean body weight of 245.6 lb and a mean BMI of 40.4 kg/m². At 80 weeks, mean body weight decreased by 21.6% with retatrutide 9 mg and 22.6% with retatrutide 12 mg, compared with 3.2% with placebo.

Lilly also reported reductions in several cardiovascular risk markers with the highest retatrutide dose, including mean reductions of 37.0% in triglycerides, 16.5% in non–high-density lipoprotein cholesterol, 9.3 mm Hg in systolic blood pressure, 7.5 in in waist circumference, and 51.2% in high-sensitivity C-reactive protein.

In prespecified analyses of time to first major adverse cardiovascular event, 44 MACE-5 events occurred among participants randomized to pooled retatrutide 9 mg and 12 mg vs 52 events among those randomized to placebo, for a hazard ratio of 0.82. MACE-5 included all-cause death, myocardial infarction, stroke, heart failure event, or coronary revascularization. For MACE-3, defined as cardiovascular death, myocardial infarction, or stroke, there were 27 events with retatrutide and 23 with placebo, for a hazard ratio of 1.12. The company noted that MACE occurred less frequently than anticipated in both treatment and placebo groups.

The most common adverse events with retatrutide in TRIUMPH-2 were gastrointestinal and appetite-related. Across the 4-mg, 9-mg, and 12-mg retatrutide groups vs placebo, diarrhea occurred in 27.4%, 33.5%, 33.6%, and 13.2%, respectively; nausea in 13.7%, 20.8%, 28.0%, and 8.0%; constipation in 14.0%, 16.2%, 16.8%, and 9.4%; decreased appetite in 5.8%, 12.3%, 17.1%, and 4.5%; and vomiting in 5.5%, 10.2%, 15.7%, and 4.2%.

In TRIUMPH-3, the most common adverse events with retatrutide 9 mg, retatrutide 12 mg, and placebo were diarrhea (30.1%, 24.4%, and 8.7%), nausea (21.7%, 22.4%, and 5.8%), constipation (18.0%, 15.7%, and 7.1%), decreased appetite (13.5%, 14.5%, and 3.0%), and hyperglycemia (3.9%, 3.1%, and 13.4%).

Discontinuation rates due to adverse events in TRIUMPH-2 were 3.8% with retatrutide 4 mg, 11.6% with retatrutide 9 mg, and 7.7% with retatrutide 12 mg, compared with 4.9% with placebo. In TRIUMPH-3, discontinuation rates due to adverse events were 9.8% with retatrutide 9 mg and 13.5% with retatrutide 12 mg, compared with 4.8% with placebo.

Why does this matter for primary care?

The findings are notable because both trials enrolled patients with obesity and high cardiometabolic risk—groups commonly managed in primary care. TRIUMPH-2 focused on adults with type 2 diabetes, a population in whom weight loss can be more difficult, while TRIUMPH-3 evaluated adults with severe obesity and established cardiovascular disease.

The topline data suggest retatrutide may offer substantial weight reduction and metabolic improvement if approved. However, the agent remains investigational, detailed results have not yet been presented at a medical meeting or published in a peer-reviewed journal, and cardiovascular outcomes remain under study.

Reference

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.