Retatrutide Cuts Weight Up to 18.8% in Adults With T2D, Obesity

Retatrutide (Eli Lilly), an investigational once-weekly glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptor agonist, reduced body weight by up to 18.8% over 80 weeks in adults with obesity and type 2 diabetes (T2D), according to phase 3 TRIUMPH-2 (NCT05929079) results published in The Lancet and presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD). Because patients with T2D typically lose less weight on incretin therapies than those without diabetes, the data give pharmacists an early look at how a triple agonist performs in this population.^1-4

Trial Design and Weight Loss

TRIUMPH-2 enrolled 1152 adults at 92 sites across 8 countries with a body mass index (BMI) of 27 kg/m² or higher, glycated hemoglobin (HbA1c) of 6.5% to 10.5%, and stable T2D treatment. Participants were randomly assigned to placebo or retatrutide 4 mg, 9 mg, or 12 mg. At baseline, mean BMI was 38.2 kg/m², mean HbA1c was 7.71%, and 92% of participants were taking an oral glucose-lowering medication, including biguanides, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and sulfonylureas.¹

Under the treatment-regimen estimand, mean body weight change at week 80 was −11.9% with 4 mg, −16.8% with 9 mg, and −18.8% with 12 mg vs −5.1% with placebo (P < .0001 for all). Lilly's release reports efficacy-estimand results, which assume participants stayed on treatment: reductions of 12.7% (29.8 lbs), 19.1% (45.4 lbs), and 20.8% (49.6 lbs) versus 4.0% with placebo.^1,2

At the end of TRIUMPH-2, a significant portion—59.5%—of patients taking retatrutide 12 mg no longer met the BMI criteria for obesity, according to the news release. These results could “change what we set out to achieve with a single therapy for adults living with T2D and obesity,” Juan P. Frías, MD, medical director at the Los Angeles Institute for Metabolic Research and principal TRIUMPH-2 investigator, noted.²

Glycemic and Cardiometabolic Effects

According to the release, HbA1c fell by an average of 1.4%, 1.6%, and 1.5% with 4 mg, 9 mg, and 12 mg, respectively, vs 0.2% with placebo. The 12-mg dose also reduced triglycerides by 39.5%, non–high-density lipoprotein cholesterol by 19.6%, and systolic blood pressure by 10.8 mm Hg.²

In a previous interview with Pharmacy Times, Jennifer Goldman, PharmD, CDCES, BC-ADM, FCCP, professor of pharmacy practice at Massachusetts College of Pharmacy, pointed to the drug's third mechanism. "Retatrutide's glucagon receptor agonism provides an additional pathway: increased hepatic fatty acid oxidation and energy expenditure that is absent in the other agents," she said.³

Tolerability and Counseling

Gastrointestinal adverse events were most common. Diarrhea occurred in 27%, 34%, and 34% of participants on 4 mg, 9 mg, and 12 mg, respectively, vs 13% on placebo; nausea occurred in 14%, 21%, and 28% vs 8%. Hypotension (1%, 5%, and 6% vs <1%) and dysesthesia (4%, 6%, and 7% vs 1%) were also more frequent with retatrutide. Discontinuation due to adverse events or death was 4%, 12%, and 8%, respectively, vs 5% with placebo.¹

The hypotension signal, alongside the blood pressure reductions, may warrant attention in patients taking antihypertensive therapy.¹

Goldman has urged anticipatory counseling on dysesthesia, based on earlier retatrutide data. "Inform patients that altered or enhanced skin sensation, such as tingling or heightened sensitivity to touch, may occur, is typically mild and transient, and did not lead to discontinuation in trials," she said. "Preemptive education will eliminate unnecessary alarm and premature discontinuation." In TRIUMPH-2, participants started at 2 mg weekly and escalated every 4 weeks to their assigned dose.^2,3

Regulatory Outlook

Lilly plans to submit a biologics license application (BLA) to the FDA in the first quarter of 2027, and results from the obstructive sleep apnea basket trial within TRIUMPH-2 will be presented later. The data follow TRIUMPH-3, in which the 12-mg dose produced 22.6% weight loss at 80 weeks in adults with severe obesity and established cardiovascular disease.^2,4

Until then, retatrutide remains investigational and cannot be legally sold or marketed. If approved, Goldman has said it would likely serve as an escalation option within a stepwise intensification model, and she has cautioned that cardiovascular outcomes data are not yet available. For patients with T2D, labeling for tirzepatide (Zepbound; Eli Lilly) notes a higher risk of hypoglycemia when used with a sulfonylurea or insulin; whether similar guidance will apply to retatrutide is not yet known.^2,3

REFERENCES

1. Bellido V, le Roux CW, Ekinci EI, et al. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. Lancet. Published online September 29, 2026. doi:10.1016/S0140-6736(26)01861-1

2. 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

3. Goldman J, Halpern L. What pharmacists need to know about retatrutide's TRIUMPH-1 phase 3 results. Pharmacy Times. June 3, 2026. Accessed September 30, 2026. https://www.pharmacytimes.com/view/what-pharmacists-need-to-know-about-retatrutide-s-triumph-1-phase-3-results

4. Antrim A. Lilly prepares for retatrutide FDA filing following additional phase 3 data in diabetes, CVD. Pharmacy Times. July 24, 2026. Accessed September 30, 2026. https://www.pharmacytimes.com/view/lilly-prepares-for-retatrutide-fda-filing-following-additional-phase-3-data-in-diabetes-cvd