Eli Lilly Reports Topline Results From TRIUMPH-2 And TRIUMPH-3 Phase 3 Trials Evaluating Retatrutide; Treatment Met Primary Endpoint, With Substantial Weight Loss In Adults With Obesity

Eli Lilly and Company (NYSE:LLY), the maker of Zepbound (tirzepatide) and Foundayo (orforglipron), today announced positive topline results from TRIUMPH-2 and TRIUMPH-3, two pivotal Phase 3 trials evaluating retatrutide, an investigational, first-in-class GIP, GLP-1, and glucagon triple hormone receptor agonist. In both studies, retatrutide met the primary endpoint, delivering substantial weight loss in adults with obesity and some of its most serious complications: type 2 diabetes and established cardiovascular disease.

"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," said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. "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. We look forward to working with regulators as they evaluate this first-of-its-kind medicine."

In TRIUMPH-2, all three studied doses of retatrutide (4 mg, 9 mg, and 12 mg) delivered substantial weight loss and improved glycemic control at 80 weeks in adults with type 2 diabetes and obesity or overweight. Participants taking retatrutide 4 mg, 9 mg, and 12 mg lost an average of 29.8 lbs (12.7%), 45.4 lbs (19.1%), and 49.6 lbs (20.8%), respectively, alongside A1C reductions of up to an average of 1.6%.

TRIUMPH-2 Efficacy Estimand Results in Participants with Obesity and Type 2 Diabetes1
Primary Endpoint at 80 Weeks
	Retatrutide 4 mg	Retatrutide 9 mg	Retatrutide 12 mg	Placebo
Percent change in body weight from avg. baseline of 106.4 kg (234.6 lbs; BMI of 38.2 kg/m²)i	-12.7% (-13.5 kg; -29.8 lbs)	-19.1% (-20.6 kg; -45.4 lbs)	-20.8% (-22.5 kg; -49.6 lbs)	-4.0% (-4.2 kg; -9.3 lbs)
Key Secondary Endpoint at 80 Weeks
Change in A1C from a baseline of 7.7%	-1.4‌%	-1.6‌%	-1.5‌%	-0.2‌%
iPercent body weight reduction with retatrutide 4 mg was a key secondary endpoint.

In TRIUMPH-3, both studied doses of retatrutide (9 mg and 12 mg) delivered substantial weight loss in adults with severe obesity and established cardiovascular disease, with or without type 2 diabetes. Participants lost up to an average of 55.8 lbs (22.6%) at 80 weeks.

In the study, major adverse cardiovascular events (MACE) occurred less frequently than anticipated in both retatrutide and placebo arms. In pre-specified analyses for time to first occurrence of MACE, there were 44 MACE-5 (all-cause death, heart attack, stroke, heart failure event, or coronary revascularization) events observed in participants randomized to retatrutide (pooled 9 mg and 12 mg) and 52 events observed in those randomized to placebo, resulting in a hazard ratio of 0.82 (95.0% CI: 0.55 to 1.22). There were 27 MACE-3 (cardiovascular death, heart attack, or stroke) events in participants randomized to retatrutide and 23 in those randomized to placebo, resulting in a hazard ratio of 1.12 (95.0% CI: 0.64 to 1.96).

In TRIUMPH-3, retatrutide meaningfully reduced certain cardiovascular risk factors, with the highest dose delivering average reductions of 37.0% in triglycerides, 16.5% in non-HDL cholesterol, 9.3 mmHg in systolic blood pressure, 7.5 in (19.0 cm) in waist circumference, and 51.2% in high-sensitivity C-reactive protein (hsCRP).

TRIUMPH-3 Efficacy Estimand Results in Participants with Severe Obesity and Established Cardiovascular Disease1
Primary Endpoint at 80 Weeks
	Retatrutide 9 mg	Retatrutide 12 mg		Placebo
Percent change in body weight from avg. baseline of 111.4 kg (245.6 lbs; BMI of 40.4 kg/m²)	-21.6% (-23.9 kg; -52.7 lbs)	-22.6% (-25.3 kg; -55.8 lbs)		-3.2% (-3.5 kg; -7.7 lbs)
Additional Analysesi
	In-Study		On-Treatment
Time to first occurrence of MACE-5	Hazard ratio = 0.82 95.0% CI: 0.55 to 1.22		Hazard ratio = 0.73 95.0% CI: 0.47 to 1.12
Time to first occurrence of MACE-3	Hazard ratio = 1.12 95.0% CI: 0.64 to 1.96		Hazard ratio = 0.92 95.0% CI: 0.51 to 1.65
iHazard ratio was estimated from Cox proportional hazards model comparing retatrutide (pooled 9 mg and 12 mg) vs. placebo; in-study analysis (pre-specified) includes events which occurred during the study treatment period regardless of adherence to retatrutide or placebo, while on-treatment analysis (not pre-specified) excludes events which occurred more than 35 days after discontinuing retatrutide or placebo.

In TRIUMPH-2, the most common adverse events with retatrutide (4 mg, 9 mg, 12 mg vs. placebo, respectively) were diarrhea (27.4%, 33.5%, 33.6% vs. 13.2%), nausea (13.7%, 20.8%, 28.0% vs. 8.0%), constipation (14.0%, 16.2%, 16.8% vs. 9.4%), decreased appetite (5.8%, 12.3%, 17.1% vs. 4.5%), and vomiting (5.5%, 10.2%, 15.7% vs. 4.2%). In TRIUMPH-3, the most common adverse events with retatrutide (9 mg, 12 mg vs. placebo, respectively) were diarrhea (30.1%, 24.4% vs. 8.7%), nausea (21.7%, 22.4% vs. 5.8%), constipation (18.0%, 15.7% vs. 7.1%), decreased appetite (13.5%, 14.5% vs. 3.0%), and hyperglycemia (3.9%, 3.1% vs. 13.4%). In TRIUMPH-2, the incidence of dysesthesia and urinary tract infections were 4.5%, 5.6%, 7.3% vs. 0.7% and 3.8%, 6.3%, 8.0% vs. 6.6% with retatrutide 4 mg, 9 mg, 12 mg vs. placebo, respectively. In TRIUMPH-3, the incidence of dysesthesia and urinary tract infections were 6.4%, 6.4% vs. 1.3% and 6.1%, 7.0% vs. 5.3% with retatrutide 9 mg, 12 mg vs. placebo, respectively. These events were generally mild to moderate, and the majority resolved during treatment. Discontinuation rates due to adverse events in TRIUMPH-2 were 3.8% (4 mg), 11.6% (9 mg), and 7.7% (12 mg) with retatrutide, compared with 4.9% for placebo. Discontinuation rates due to adverse events in TRIUMPH-3 were 9.8% (9 mg) and 13.5% (12 mg) with retatrutide, compared with 4.8% for placebo.

Detailed results from TRIUMPH-2 and TRIUMPH-3 will be presented at future medical meetings and published in peer-reviewed journals. Lilly is completing the comprehensive Chemistry, Manufacturing, and Controls (CMC) data package required for a Biologics License Application (BLA) and plans to subsequently submit retatrutide in Q1 2027 for U.S. approval.