Retatrutide Delivers Weight Loss, A1C Improvements in Additional Trials

Eli Lilly and Company announced positive topline results from TRIUMPH-2 (NCT05929079) and TRIUMPH-3 (NCT05882045), 2 pivotal phase 3 trials evaluating retatrutide, an investigational, first-in-class glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon triple hormone receptor agonist. Both trials met their primary end points, delivering substantial weight loss in adults with obesity alongside 2 of its most serious complications: type 2 diabetes and established cardiovascular disease.¹

"Across 5 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," Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a news release.¹ "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."

TRIUMPH-2: Weight Loss and Glycemic Control in Type 2 Diabetes

TRIUMPH-2 randomized 1152 participants with type 2 diabetes and obesity or overweight to retatrutide 4 mg, 9 mg, 12 mg, or placebo in an 80-week trial. All 3 doses delivered substantial weight loss and improved glycemic control. Participants taking the 4 mg, 9 mg, and 12 mg doses lost an average of 29.8 lbs (12.7%), 45.4 lbs (19.1%), and 49.6 lbs (20.8%), respectively, from an average baseline weight of 234.6 lbs. A_1C reductions reached up to an average of 1.6% from a baseline of 7.7%.¹

This population is notable for pharmacists because patients with type 2 diabetes have historically had more difficulty achieving substantial weight loss than those without the condition, as previously explored in retatrutide's earlier TRANSCEND-T2D-1 trial. That 40-week study similarly found that weight loss had not plateaued by the study's end, suggesting continued therapy could yield further reductions.²

TRIUMPH-3: Outcomes in Severe Obesity With Cardiovascular Disease

TRIUMPH-3 enrolled 1949 participants with severe obesity (body mass index [BMI] ≥35 kg/m²) and established cardiovascular disease, with or without type 2 diabetes, randomizing them to retatrutide 9 mg, 12 mg, or placebo. At 80 weeks, participants lost up to an average of 55.8 lbs (22.6%) from an average baseline weight of 245.6 lbs.¹

Beyond weight loss, the highest dose delivered average reductions of 37.0% in triglycerides, 16.5% in nonhigh-density lipoprotein (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.¹

In a pre-specified analysis, major adverse cardiovascular events (MACE) occurred less frequently than anticipated in both treatment arms: 44 MACE-5 events (all-cause death, heart attack, stroke, heart failure event, or coronary revascularization) occurred with retatrutide compared with 52 with placebo, for a hazard ratio of 0.82 (95.0% CI, 0.55-1.22). For MACE-3 (cardiovascular death, heart attack, or stroke), there were 27 events with retatrutide versus 23 with placebo, for a hazard ratio of 1.12 (95.0% CI, 0.64-1.96).¹

Safety and Tolerability

The safety profile in both trials was consistent with other incretin-based therapies, with gastrointestinal events predominating. In TRIUMPH-2, the most common adverse events with retatrutide (4 mg, 9 mg, 12 mg versus placebo) included diarrhea (27.4%, 33.5%, 33.6% versus 13.2%, respectively), nausea (13.7%, 20.8%, 28.0% versus 8.0%, respectively), and constipation (14.0%, 16.2%, 16.8% versus 9.4%, respectively). In TRIUMPH-3, adverse events with retatrutide (9 mg, 12 mg versus placebo) included diarrhea (30.1%, 24.4% versus 8.7%, respectively), nausea (21.7%, 22.4% versus 5.8%), and constipation (18.0%, 15.7% versus 7.1%, respectively).¹

Dysesthesia, a distortion of the sense of touch that pharmacists have been tracking as a distinguishing feature of retatrutide's pharmacology since earlier trials in the program, occurred at rates of 4.5% to 7.3% across doses in TRIUMPH-2 and 6.4% in TRIUMPH-3, generally mild and resolving during treatment. Discontinuation rates due to adverse events ranged from 3.8% to 11.6% across doses in TRIUMPH-2 and 9.8% to 13.5% in TRIUMPH-3, compared with approximately 4.8% to 4.9% for placebo.¹

The Broader TRIUMPH Program

TRIUMPH-2 and TRIUMPH-3 build on TRIUMPH-1, the first obesity-only trial in the program, in which participants with obesity or overweight and at least 1 weight-related comorbidity lost an average of 70.3 lbs (28.3%) at 80 weeks on the 12 mg dose, with more than 45% of participants achieving at least 30% weight loss.³

In an extension of that trial among participants with a baseline BMI of 35 or higher, those who reached 104 weeks of treatment achieved a mean weight reduction of 30.3%, or approximately 85 lbs, suggesting weight loss had not yet plateaued. Ania Jastreboff, MD, PhD, professor of medicine and pediatrics at the Yale School of Medicine and lead investigator on TRIUMPH-1, said in a news release that every dose of retatrutide produced clinically meaningful weight reduction for nearly all participants.³

What This Means for Pharmacists

With 5 positive phase 3 trials now completed across the TRIUMPH program, retatrutide's clinical data package spans obesity, type 2 diabetes, and cardiovascular comorbidities, positioning pharmacists to prepare for a potential new entrant in the crowded incretin therapy space alongside semaglutide and tirzepatide. As these advanced incretin-based therapies move toward the clinic, pharmacists are increasingly central to person-centered, shared decision-making standards of care for obesity medications, including patient eligibility assessment, administration counseling, and dosing optimization.³

Pharmacists should also be prepared to navigate coverage barriers since Medicare is currently prohibited from covering pharmacotherapy used specifically for obesity management and to continue steering patients away from nonFDA-approved compounded versions of these therapies now that federal enforcement discretion for compounding has ended. Perioperative safety is another area of pharmacist involvement, as these agents carry a risk of pulmonary aspiration under anesthesia or deep sedation, requiring careful medication-withholding guidance ahead of procedures.³

Detailed results from TRIUMPH-2 and TRIUMPH-3 will be presented at future medical meetings and published in peer-reviewed journals, and Lilly is completing the Chemistry, Manufacturing, and Controls data package required for a BLA, which the company plans to submit for US approval in the first quarter of 2027.¹

REFERENCES

1. Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C. News release. Eli Lilly and Company. July 23, 2026. Accessed July 24, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-successful-two-additional

2. Gallagher A. Retatrutide shows reductions in glycated hemoglobin and body weight in phase 3 trial. Drug Topics. March 23, 2026. Accessed July 24, 2026. https://www.drugtopics.com/view/retatrutide-shows-reductions-in-glycated-hemoglobin-and-body-weight-in-phase-3-trial

3. Nowosielski B. Retatrutide exhibits meaningful weight loss in phase 3 trial. Drug Topics. May 21, 2026. Accessed July 24, 2026. https://www.drugtopics.com/view/retatrutide-exhibits-meaningful-weight-loss-in-phase-3-trial