Retatrutide Achieves Up to 30.3% Average Weight Loss in Phase 3 TRIUMPH-1 Trial

Retatrutide, an investigational, first-in-class triple hormone receptor agonist (RA), demonstrated positive topline results in the phase 3 TRIUMPH-1 clinical trial (NCT05929066), according to an announcement made by Eli Lilly.¹ The 80-week trial evaluated the once-weekly medication in adults with obesity or overweight and at least 1 weight-related comorbidity, but without diabetes.

Retatrutide targets 3 metabolic pathways by activating receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. In the randomized, double‑blind, placebo‑controlled master trial of 2339 participants, all studied doses (4 mg, 9 mg, and 12 mg) met the primary and key secondary end points, demonstrating significant, clinically meaningful weight reduction alongside improvements in cardiometabolic risk factors.

How Much Weight Loss Did Retatrutide Demonstrate at 80 Weeks?

According to the primary efficacy end point, participants on the highest dose of retatrutide (12 mg) achieved an average weight loss of 70.3 lb (28.3%) from a baseline average of 248.5 lb (body mass index [BMI], 40.0 kg/m²). Notably, 45.3% of individuals in the 12-mg cohort achieved a body weight reduction of 30% or greater—a threshold historically associated with bariatric surgery. Furthermore, 65.3% of participants on the 12-mg dose reduced their weight below the threshold for obesity (BMI < 30 kg/m²) by week 80, including 37.5% of those entering the trial with class 3 obesity (BMI ≥ 40 kg/m²).

Intermediate dosing tiers also achieved substantial weight reduction. Participants receiving the 9-mg dose lost an average of 64.4 lb (25.9%). At the lowest dose of 4 mg, which requires only a single titration step from the 2-mg starting dose, patients experienced an average reduction of 47.2 lb (19.0%) at 80 weeks.

The treatment also led to distinct improvements in cardiovascular health measures. The 12-mg cohort experienced an average waist circumference reduction of 24.1 cm (9.5 inches) alongside documented improvements in non–high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and high-sensitivity C-reactive protein.

The efficacy observed in the phase 3 TRIUMPH-1 trial firmly validates a prior large-scale review published in Annals of Internal Medicine, which evaluated 12 GLP-1 RAs and coagonists across 26 randomized controlled trials involving 15,491 adults without diabetes.² In the previous analysis, retatrutide had already established itself as the top-performing investigational agent, leading the entire field with an anticipated 24.2% weight loss at a 12-mg weekly dose and outpacing the maximum evaluated doses of commercially available mainstays tirzepatide (17.8%) and subcutaneous semaglutide (13.9%). The new TRIUMPH-1 results solidify these earlier, smaller-scale observations by demonstrating that retatrutide’s therapeutic trajectory can actually surpass those benchmarks over extended timelines, reaching a surgical-level 28.3% average weight loss at 80 weeks and up to 30.3% at 104 weeks.¹

What Are the Long-Term Weight Loss Outcomes of Retatrutide at 104 Weeks?

To understand long-term outcomes in severe obesity, TRIUMPH-1 featured a prespecified, blinded extension to 104 weeks for 532 participants who had a baseline BMI of at least 35 kg/m² and tolerated their assigned treatment. In this extension, participants continued to lose weight, reaching a maximum tolerated dose of either 9 mg or 12 mg.

By week 104, individuals initially randomized to the 12-mg arm achieved an average total weight loss of 85.0 lb, representing a 30.3% reduction from an average baseline of 268.3 lb (BMI, 42.8 kg/m²).

What Are the Most Common Adverse Effects and Safety Concerns for Retatrutide?

The overall safety profile of retatrutide was consistent with other incretin-based therapies, driven primarily by gastrointestinal adverse events. The most common adverse effects reported across the 4-mg, 9-mg, and 12-mg retatrutide groups, compared with placebo, were:

• Nausea: reported by 28.6%, 38.4%, and 42.4% of retatrutide participants, respectively, compared with 14.8% for placebo
• Diarrhea: reported by 25.2%, 34.1%, and 32.0% of retatrutide participants compared with 13.5% for placebo
• Constipation: reported by 23.8%, 25.9%, and 26.1% of retatrutide participants compared with 10.9% for placebo
• Vomiting: reported by 10.6%, 22.8%, and 25.3% of retatrutide participants compared with 4.8% for placebo

Other observed adverse events included upper respiratory tract infections, urinary tract infections, and mild to moderate dysesthesia, although the majority of the urinary and neurological cases resolved during active treatment.

Discontinuation rates due to adverse events correlated directly with dosage escalation. The 4-mg arm demonstrated a 4.1% discontinuation rate—lower than the 4.9% rate observed in the placebo group. Discontinuation rates rose to 6.9% in the 9-mg group and 11.3% in the 12-mg group.

Lilly plans to present detailed data from the TRIUMPH-1 master trial at the 86th annual American Diabetes Association Scientific Sessions. Additional phase 3 results from the broader clinical program, including the TRIUMPH-2 trial in patients with type 2 diabetes and the TRIUMPH-3 trial in patients with established cardiovascular disease, are expected later this year.

References

1. Lilly's triple agonist, retatrutide, delivered powerful weight loss in pivotal phase 3 obesity trial. News release. Eli Lilly and Company. May 21, 2026. Accessed May 21, 2026. https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-delivered-powerful-weight-loss-in-pivotal-phase-3-obesity-trial-302778859.html
2. Shaw M. Top GLP-1 agonists balance weight loss efficacy, safety. AJMC^®. January 6, 2025. Accessed May 21, 2026. https://www.ajmc.com/view/top-glp-1-agonists-balance-weight-loss-efficacy-safety