Retatrutide Delivers 20.8% Weight Loss in Adults With Type 2 Diabetes

Eli Lilly and Company announced detailed results from TRIUMPH-2 (NCT05929079), a phase 3 trial of retatrutide in adults with type 2 diabetes and obesity or overweight. At 80 weeks, all 3 doses tested (4 mg, 9 mg, and 12 mg) reduced weight and A_1C. The results 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.¹

Weight Loss Results Across 3 Doses

Retatrutide is an investigational, once weekly, first-in-class triple hormone receptor agonist. A single molecule activates the receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. Lilly reported topline results from TRIUMPH-2 in July.²

The trial randomized 1152 participants 1:1:1:1 to retatrutide 4 mg, 9 mg, or 12 mg, or to placebo. Participants started at 2 mg once weekly and stepped up every 4 weeks until they reached their target dose. Average baseline weight was 106.4 kg (234.6 lb), with a body mass index (BMI) of 38.2 kg/m².¹

Participants lost an average of 12.7% (29.8 lb) on 4 mg, 19.1% (45.4 lb) on 9 mg, and 20.8% (49.6 lb) on 12 mg, compared with 4.0% (9.3 lb) on placebo. Among those with a baseline BMI of 35 or higher, the 12-mg group lost an average of 60.8 lb (23.4%). By the end of the study, 59.5% of participants taking 12 mg no longer met the BMI criteria for obesity. A weight reduction of at least 20% was reached by 52.0% of the 12-mg group, versus 1.5% on placebo, and 34.9% reached at least 25%, versus 0.8%.¹

"The vast majority of people with type 2 diabetes are also living with obesity, and treating the two together has always been a challenge," Juan P. Frías, MD, medical director and principal investigator at the Los Angeles Institute for Metabolic Research, said in a news release.¹ He added that 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."

All figures in the release reflect the efficacy estimand. That measure estimates efficacy had every randomized participant stay on the study intervention (with possible dose interruptions and modifications) for 80 weeks without starting prohibited weight management treatments or glycemic rescue therapy for glycemic end points.¹

The average baseline A_1C was 7.7%. It dropped by 1.4% with 4 mg, 1.6% with 9 mg, and 1.5% with 12 mg, compared with 0.2% with placebo. An A_1C of 6.5% or lower was reached by 73.1%, 79.2%, and 79.0% of participants across the 3 doses, versus 26.3% with placebo. An A_1C below 5.7% was reached by 28.4%, 40.0%, and 39.3%, versus 4.4%. Lilly noted that the below 5.7% end point was not controlled for family-wise type 1 error.¹

At the highest dose, average reductions were 39.5% in triglycerides, 19.6% in non–high-density lipoprotein cholesterol, 10.8 mm Hg in systolic blood pressure, 6.7 in (16.9 cm) in waist circumference, and 58.3% in high-sensitivity C-reactive protein.¹

Safety and Tolerability

The most common adverse events with retatrutide 4 mg, 9 mg, and 12 mg versus placebo were diarrhea (27.4%, 33.5%, and 33.6% versus 13.2%), nausea (13.7%, 20.8%, and 28.0% versus 8.0%), and constipation (14.0%, 16.2%, and 16.8% versus 9.4%). Decreased appetite occurred in 5.8%, 12.3%, and 17.1% versus 4.5%, respectively, and vomiting in 5.5%, 10.2%, and 15.7% versus 4.2%, respectively.¹

Dysesthesia, a distortion of the sense of touch, occurred in 4.5%, 5.6%, and 7.3% of participants versus 0.7% with placebo. Lilly said the adverse events were generally mild to moderate and that the majority resolved during treatment. Discontinuations because of adverse events were 3.8% with 4 mg, 11.6% with 9 mg, and 7.7% with 12 mg, compared with 4.9% with placebo.^1,2

Regulatory Timeline and Pharmacy Implications

Lilly plans to submit a biologics license application to the FDA in the first quarter of 2027. Additional results from the obstructive sleep apnea trial within TRIUMPH-2 will be presented at a future medical meeting. The TRIUMPH program began in 2023 and has enrolled more than 5800 participants, with more results expected over the next year.¹

"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," Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in the news release.¹

For pharmacists, the type 2 diabetes population is a notable one. Patients with the condition have historically had more difficulty achieving large weight reductions than those without it.² Retatrutide remains unapproved, and Lilly states that it "cannot be legally sold or marketed for human use."¹

Even so, Hailey Choi, PharmD, BCACP, CDCES, associate professor of pharmacy practice at the Massachusetts College of Pharmacy and Health Sciences, named the growing online market for investigational products, including retatrutide, as something pharmacists should watch.³

"These products are already being marketed to consumers despite not being FDA-approved, which creates another important patient-safety concern," Choi said in an interview. She added pharmacists will continue to help patients judge whether a product is legitimate and being used safely.³

Earlier coverage of retatrutide trials noted that pharmacists are tasked with managing the most common adverse events, which were primarily gastrointestinal in TRIUMPH-1.⁴

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. Gallagher A. Retatrutide delivers weight loss, A1C improvements in additional trials. Drug Topics. July 25, 2026. Accessed September 30, 2026. https://www.drugtopics.com/view/retatrutide-delivers-weight-loss-a1c-improvements-in-additional-trials

3. Nowosielski B, Choi H, Murry J, Casella S. Pharmacists' look at the future of GLP-1 compounding. Drug Topics. August 20, 2026. Accessed September 30, 2026. https://www.drugtopics.com/view/pharmacists-look-at-the-future-of-glp-1-compounding

4. Nowosielski B. Retatrutide exhibits meaningful weight loss in phase 3 trial. Drug Topics. May 21, 2026. Accessed September 30, 2026. https://www.drugtopics.com/view/retatrutide-exhibits-meaningful-weight-loss-in-phase-3-trial