Retatrutide lowers weight and A1C in Phase 3 TRIUMPH-2 trial

Why it matters

TRIUMPH-2 tested retatrutide, an investigational, once-weekly triple hormone receptor agonist that activates the receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon, in adults with type 2 diabetes who have obesity or overweight. At 80 weeks, all three dose groups showed weight loss and A1C reductions, with the highest dose group losing an average of 20.8% of body weight against 4.0% for placebo.

"The vast majority of people with type 2 diabetes are also living with obesity, and treating the two together has always been a challenge," said Juan P. Frías, M.D., Medical Director and Principal Investigator, Los Angeles Institute for Metabolic Research. In the same statement, Frías said: "Results such as these may change what we set out to achieve with a single therapy for adults living with type 2 diabetes and obesity."

"TRIUMPH-2 shows what the next generation of cardiometabolic medicine could deliver: substantial weight loss, A1C reduction and improvements across other critical cardiovascular risk factors," said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. Custer added: "With efficacy this powerful and consistent across our Phase 3 program, we believe retatrutide could become an important option for people living with type 2 diabetes and obesity."

The details

• Body weight at 80 weeks, from an average baseline of 106.4 kg: a reduction of 12.7% in the lowest dose group, 19.1% in the middle dose group and 20.8% in the highest dose group, compared with 4.0% for placebo. Percent body weight reduction in the lowest dose group was a key secondary endpoint.
• Participants with a baseline BMI of 35 or higher: the highest dose group lost an average of 23.4% of body weight. The release gives no placebo value for this subgroup.
• Obesity criteria: by the end of the study, 59.5% of participants in the highest dose group no longer met the BMI criteria for obesity. No placebo value is given for this measure.
• A1C change at 80 weeks, from an average baseline of 7.7%: a reduction of 1.4% in the lowest dose group, 1.6% in the middle dose group and 1.5% in the highest dose group, versus 0.2% for placebo.
• A1C of 6.5% or below: 73.1% of the lowest dose group, 79.2% of the middle dose group and 79.0% of the highest dose group, versus 26.3% for placebo.
• A1C below 5.7%, described as a normal blood sugar level: 28.4% of the lowest dose group, 40.0% of the middle dose group (the highest share reported) and 39.3% of the highest dose group, versus 4.4% for placebo. This endpoint was not controlled for family-wise type 1 error.
• Weight loss thresholds: 15% or more was reached by 36.6% of the lowest dose group, 62.2% of the middle dose group and 67.0% of the highest dose group, versus 6.4% for placebo; 20% or more by 24.0%, 45.3% and 52.0% respectively, versus 1.5% for placebo; 25% or more by 10.8%, 30.6% and 34.9% respectively, versus 0.8% for placebo.
• Cardiovascular risk factors: the highest dose delivered average reductions of 39.5% in triglycerides, 19.6% in non-HDL cholesterol, 10.8 mmHg in systolic blood pressure, 16.9 cm in waist circumference and 58.3% in high-sensitivity C-reactive protein. The release gives no placebo values for these measures.
• Most common adverse events (lowest, middle and highest dose groups versus placebo): diarrhea 27.4%, 33.5%, 33.6% versus 13.2%; nausea 13.7%, 20.8%, 28.0% versus 8.0%; constipation 14.0%, 16.2%, 16.8% versus 9.4%; decreased appetite 5.8%, 12.3%, 17.1% versus 4.5%; vomiting 5.5%, 10.2%, 15.7% versus 4.2%.
• Other events: dysesthesia in 4.5%, 5.6% and 7.3% of the lowest, middle and highest dose groups versus 0.7% for placebo; urinary tract infections in 3.8%, 6.3% and 8.0% versus 6.6% for placebo. These events were generally mild to moderate and the majority resolved during treatment.
• Discontinuation due to adverse events: 3.8% in the lowest dose group, 11.6% in the middle dose group and 7.7% in the highest dose group, compared with 4.9% for placebo.
• Design: TRIUMPH-2 (NCT05929079) is a Phase 3, 80-week, randomized, double-blind, placebo-controlled trial under a basket design, with a master trial for obesity and type 2 diabetes and a basket trial for moderate-to-severe obstructive sleep apnea. It randomized 1,152 participants in a 1:1:1:1 ratio and included a post-treatment follow-up period of 4 weeks.
• Who took part: the registry record lists inclusion criteria of a BMI of at least 27.0, type 2 diabetes and stable treatment for type 2 diabetes for at least 90 days, with the study planned to last about 89 weeks and include up to 24 visits.

What it does not change

This is a trial read-out, not an approval. Retatrutide is an investigational molecule that cannot be legally sold or marketed for human use, and Lilly plans to submit a Biologics License Application to the U.S. Food and Drug Administration in Q1 2027. All data in the release represent the efficacy estimand, which represents efficacy had all randomized participants remained on study intervention for 80 weeks without initiating prohibited weight management treatments (and glycemic rescue therapy for glycemic endpoints only), so the figures are not a measure of what every randomized participant experienced. The share of participants reaching an A1C below 5.7% was not controlled for family-wise type 1 error, and percent body weight reduction in the lowest dose group was a key secondary endpoint rather than the primary one. Results from the obstructive sleep apnea trial within TRIUMPH-2 have not been presented.

What's next

Lilly plans to submit a Biologics License Application in Q1 2027 to the U.S. Food and Drug Administration. Additional results from the obstructive sleep apnea trial within TRIUMPH-2 will be presented at a future medical meeting and published in a peer-reviewed journal. The initial TRIUMPH Phase 3 program covers obesity or overweight, type 2 diabetes, moderate-to-severe obstructive sleep apnea with obesity, and knee osteoarthritis pain across four global registrational trials; it began in 2023, has enrolled more than 5,800 participants, and additional results are anticipated over the next year. Lilly is also studying retatrutide in Phase 3 trials in chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease.

What we don't know yet

The comparator in TRIUMPH-2 was placebo, and the release reports no head-to-head comparison with another medicine. It gives no placebo values for the cardiovascular risk factor changes, for the subgroup with a baseline BMI of 35 or higher, or for the share of participants who no longer met the BMI criteria for obesity. TRIUMPH-2 included a post-treatment follow-up period of 4 weeks, and the release does not report what happens to weight or A1C beyond the 80-week measurements. Outcomes for obstructive sleep apnea, knee osteoarthritis pain, chronic low back pain, cardiovascular and renal outcomes and metabolic dysfunction-associated steatotic liver disease are still under study in Phase 3. Because the Biologics License Application is only planned for Q1 2027, the release reports no regulatory review or decision.