Retatrutide Yields Up to 20.8% Weight Loss in Obesity With T2D

Once-weekly retatrutide reduced body weight by an average of 20.8% at the highest dose and lowered hemoglobin A_1C (HbA_1C) by up to 1.6% over 80 weeks in adults with type 2 diabetes and obesity or overweight, according to detailed phase 3 TRIUMPH-2 (NCT05929079) results announced by Eli Lilly and Company.¹

The findings were presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes in Milan, Italy, and simultaneously published in The Lancet. Retatrutide is an investigational, first-in-class agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors.

"The vast majority of people with type 2 diabetes are also living with obesity, and treating the 2 together has always been a challenge," said Juan P. Frías, MD, medical director and principal investigator, Los Angeles Institute for Metabolic Research, in a statement. "In TRIUMPH-2, retatrutide reduced both weight and blood sugar substantially, with more than half of participants no longer qualifying as having obesity and up to 40% reaching an [Hb]A_1C in the normal range. 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 randomly assigned 1152 participants 1:1:1:1 to retatrutide 4 mg, 9 mg, or 12 mg or to placebo. Participants started at 2 mg weekly and stepped up every 4 weeks to their target dose. At baseline, participants had an average weight of 234.6 lbs, a body mass index (BMI) of 38.2, and an HbA_1C of 7.7%. All reported data reflect the efficacy estimand, which assumes participants remained on treatment, with possible dose interruptions and modifications, for 80 weeks without starting prohibited weight management or glycemic rescue therapy.

Weight Loss Reached 23.4% in Participants With a BMI of 35 or Higher in Highest Dose

Participants lost an average of 12.7% (29.8 lbs), 19.1% (45.4 lbs), and 20.8% (49.6 lbs) of their body weight with the 4-mg, 9-mg, and 12-mg doses, respectively, compared with 4.0% (9.3 kg) with placebo. Among participants with a baseline BMI of 35 or higher, the 12-mg dose produced an average loss of 23.4%.

More than half (52.0%) of participants taking 12 mg lost at least 20% of their body weight, compared with 1.5% of those taking placebo. By the end of the study, 59.5% of the 12-mg group no longer met the BMI criteria for obesity.

The highest dose also lowered triglycerides by 39.5%, non-high-density lipoprotein cholesterol by 19.6%, systolic blood pressure by 10.8 mm Hg, waist circumference by 16.9 cm, and high-sensitivity C-reactive protein by 58.3%.

TRIUMPH-2 follows TRIUMPH-1 (NCT05929066), a phase 3 trial of 2339 adults with obesity or overweight and at least 1 weight-related comorbidity but without diabetes. In that trial, the 12-mg dose produced a mean weight loss of 28.3% at 80 weeks, and 532 participants with a baseline BMI of 35 or higher who tolerated treatment and continued to 104 weeks, those in the 12-mg arm lost an average of 30.3%.²

Up to 40% of Participants Reached a Normal HbA_1C

HbA_1C fell by an average of 1.4%, 1.6%, and 1.5% with the 4-mg, 9-mg, and 12-mg doses, respectively, vs 0.2% with placebo. An HbA_1C of 6.5% or lower was reached by 73.1%, 79.2%, and 79.0% of participants across the retatrutide arms, compared with 26.3% of the placebo group. In an analysis not adjusted for multiple comparisons, 40.0% of the 9-mg group and 39.3% of the 12-mg group reached an HbA_1C below 5.7%, vs 4.4% with placebo.

The results build on the phase 3 TRANSCEND-T2D-1 (NCT06354660) trial, in which retatrutide lowered HbA_1C by up to 2.0% vs 0.8% with placebo at 40 weeks among 537 adults with type 2 diabetes inadequately controlled with diet and exercise alone. In that trial, the 12-mg group lost 16.8% of body weight.³

Gastrointestinal Events Were the Most Common Adverse Effects

The most common adverse events were gastrointestinal. Diarrhea occurred in 27.4% to 33.6% of participants receiving retatrutide vs 13.2% with placebo, nausea in 13.7% to 28.0% vs 8.0%, and vomiting in 5.5% to 15.7% vs 4.2%. Dysesthesia, an abnormal skin sensation, was reported in 4.5% to 7.3% of retatrutide-treated participants vs 0.7% with placebo.¹ Most events were mild to moderate.

Discontinuation due to adverse events was 3.8%, 11.6%, and 7.7% with the 4-mg, 9-mg, and 12-mg doses, respectively, compared with 4.9% with placebo.

Eli Lilly plans to submit a Biologics License Application to the FDA in the first quarter of 2027. Results from the trial's obstructive sleep apnea basket trial will be published in the future.

"TRIUMPH-2 shows what the next generation of cardiometabolic medicine could deliver: substantial weight loss, [Hb]A_1C reduction and improvements across other critical cardiovascular risk factors," Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health, said in a statement. "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."

References

1. Lilly's triple agonist, retatrutide, delivered substantial weight loss and A1C reduction, underscoring its potential promise for people with obesity and type 2 diabetes. News release. Eli Lilly and Company. September 29, 2026. Accessed September 30, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-substantial-weight
2. Grossi G. Retatrutide achieves up to 30.3% average weight loss in phase 3 TRIUMPH-1 trial. AJMC^®. May 21, 2026. Accessed September 30, 2026. https://www.ajmc.com/view/retatrutide-achieves-up-to-30-3-average-weight-loss-in-phase-3-triumph-1-trial
3. Halpern L. Retatrutide delivers significant hemoglobin A1C reduction, weight loss in phase 3 type 2 diabetes trial. Pharmacy Times^®. April 3, 2026. Accessed September 30, 2026. https://www.pharmacytimes.com/view/retatrutide-delivers-significant-a1c-reduction-weight-loss-in-phase-3-type-2-diabetes-trial