As reported on Drugs, Eli Lilly has reported positive topline findings from two additional Phase 3 trials of retatrutide, its investigational triple hormone receptor agonist designed to target GIP, GLP-1, and glucagon pathways. The studies, known as TRIUMPH-2 and TRIUMPH-3, evaluated the therapy in adults living with obesity complicated by either type 2 diabetes or established cardiovascular disease. In both trials, the drug met its primary endpoint, producing substantial reductions in body weight over 80 weeks while also demonstrating benefits across several cardiometabolic measures.
Significant Weight Reduction in Patients With Type 2 Diabetes
TRIUMPH-2 enrolled 1,152 adults with obesity or overweight and type 2 diabetes, a population that often experiences greater difficulty achieving meaningful weight loss. Participants were randomized to receive retatrutide at doses of 4 mg, 9 mg, or 12 mg once weekly, or placebo.
At 80 weeks, average weight reductions reached:
- 12.7% with the 4 mg dose
- 19.1% with the 9 mg dose
- 20.8% with the 12 mg dose
- 4.0% with placebo
Patients receiving the highest dose lost an average of 49.6 pounds, compared with roughly 9 pounds in the placebo group.
The study also showed notable improvements in glycemic control. Participants began with an average HbA1c of 7.7%, and retatrutide lowered HbA1c by approximately 1.4% to 1.6%, while placebo produced only a modest 0.2% reduction.
Robust Results in Severe Obesity and Cardiovascular Disease
TRIUMPH-3 evaluated 1,949 adults with severe obesity and established cardiovascular disease, regardless of diabetes status. Participants received either 9 mg or 12 mg of retatrutide or placebo for 80 weeks.
Weight-loss outcomes were similarly impressive:
- 21.6% mean reduction with 9 mg
- 22.6% mean reduction with 12 mg
- 3.2% reduction with placebo
Those receiving the 12 mg dose lost an average of 55.8 pounds from baseline, highlighting the potential of retatrutide in patients at particularly high cardiometabolic risk.
Cardiovascular Risk Marker Improvements
Beyond weight loss, investigators observed meaningful improvements in several cardiovascular risk indicators among participants treated with retatrutide.
At the highest dose, average reductions included:
- 37.0% in triglycerides
- 16.5% in non-HDL cholesterol
- 9.3 mmHg in systolic blood pressure
- 7.5 inches (19 cm) in waist circumference
- 51.2% in high-sensitivity C-reactive protein (hsCRP)
These findings suggest the therapy may influence a broad range of metabolic and inflammatory pathways in addition to promoting weight reduction.
Cardiovascular Outcomes Data Remain Preliminary
The TRIUMPH-3 trial also tracked major adverse cardiovascular events (MACE). Event rates were lower than expected overall, limiting definitive conclusions.
For the composite MACE-5 endpoint, 44 events occurred among retatrutide-treated participants compared with 52 in the placebo group, corresponding to a hazard ratio of 0.82. For the narrower MACE-3 endpoint, investigators recorded 27 events in the treatment arm and 23 in the placebo arm, resulting in a hazard ratio of 1.12.
While these analyses provide early insight into cardiovascular outcomes, the confidence intervals crossed unity, meaning the results are not sufficient to establish cardiovascular benefit or risk reduction at this stage.
Safety Profile Consistent With Incretin-Based Therapies
The most frequently reported adverse events were gastrointestinal in nature and were generally characterized as mild to moderate. Common side effects included:
- Diarrhea
- Nausea
- Constipation
- Reduced appetite
- Vomiting
Investigators also reported higher rates of dysesthesia and urinary tract infections in retatrutide-treated participants compared with placebo. Most adverse events resolved during treatment.
Treatment discontinuation due to adverse events ranged from 3.8% to 11.6% in TRIUMPH-2 and from 9.8% to 13.5% in TRIUMPH-3, compared with approximately 5% in placebo groups.
Regulatory Plans and Future Development
According to Lilly, the latest results complete the clinical data package needed to support global regulatory submissions for obesity. The company indicated it plans to file a Biologics License Application with the U.S. Food and Drug Administration in the first quarter of 2027.
Retatrutide remains an investigational therapy and has not yet received regulatory approval. The drug is also being studied across multiple Phase 3 programs in conditions including obstructive sleep apnea, knee osteoarthritis pain, metabolic dysfunction-associated steatotic liver disease, chronic low back pain, and cardiovascular and renal outcomes.
With five positive Phase 3 studies now reported, retatrutide is emerging as one of the most closely watched next-generation obesity therapies, potentially expanding treatment options for patients with obesity and related cardiometabolic diseases.
