Eli Lilly and Company reported additional results from pivotal Phase 3 trials of retatrutide, an investigational triple agonist of GIP, GLP‑1 and glucagon receptors, showing substantial weight loss along with improvements in obesity‑related conditions including knee osteoarthritis pain, moderate‑to‑severe obstructive sleep apnea and type 2 diabetes. The TRIUMPH‑1 and TRANSCEND‑T2D‑1 data were presented at the American Diabetes Association’s 86th Scientific Sessions, with TRANSCEND‑T2D‑1 results also published in The Lancet.
In TRIUMPH‑1, which included an overall obesity trial plus nested basket trials in knee osteoarthritis pain and obstructive sleep apnea, retatrutide met primary endpoints at 80 weeks. Participants on 9 mg and 12 mg doses lost an average of 64.4 lbs (25.9%) and 70.3 lbs (28.3%), respectively, while those on 4 mg lost 47.2 lbs (19.0%). Among participants on 12 mg, 65.3% achieved a BMI below 30 and 33.3% reached a BMI below 25; in an extension among those with baseline BMI ≥35, continued 12 mg treatment through 104 weeks led to an average loss of 85.0 lbs (30.3%). Retatrutide also reduced Western Ontario and McMaster Universities Osteoarthritis Index pain scores by up to 4.3 points (73.1%) from a baseline of 6.0 in participants with knee osteoarthritis and lowered apnea‑hypopnea index by up to 36.1 events per hour (60.6%) from a baseline of 58.6 events per hour in those with moderate‑to‑severe obstructive sleep apnea.
In TRANSCEND‑T2D‑1, retatrutide met the primary and all key secondary endpoints at 40 weeks in adults with type 2 diabetes. Participants achieved average A1C reductions of up to 2.0 percentage points from a baseline of 7.9%. Up to 90% of participants on retatrutide reached an A1C below 7.0%, up to 85% reached 6.5% or below, and up to 46% achieved an A1C below 5.7%, the threshold for normoglycemia. Individuals taking 12 mg also lost an average of 36.6 lbs (16.8%), with weight loss not yet plateauing at week 40.
Across both trials, retatrutide was associated with improvements in several cardiovascular risk factors. In TRIUMPH‑1 at 80 weeks, reductions reached up to 41.0% for triglycerides, 24.2% for non‑HDL cholesterol, 12.3 mmHg for systolic blood pressure, and 9.5 inches (24.1 cm) for waist circumference. In TRANSCEND‑T2D‑1 at 40 weeks, reductions were up to 39.6% in triglycerides, 19.8% in non‑HDL cholesterol, 6.4 mmHg in systolic blood pressure and 4.9 inches (12.4 cm) in waist circumference.
The types of adverse events seen in both studies were generally similar to those reported with other incretin‑based therapies. In TRIUMPH‑1, the most common adverse events with retatrutide 4 mg, 9 mg and 12 mg versus placebo were nausea (28.6%, 38.4%, 42.4% vs 14.8%), diarrhea (25.2%, 34.1%, 32.0% vs 13.5%), constipation (23.8%, 25.9%, 26.1% vs 10.9%), vomiting (10.6%, 22.8%, 25.3% vs 4.8%) and upper respiratory tract infection (14.2%, 12.2%, 13.1% vs 11.6%). Dysesthesia (5.1%, 12.3%, 12.5% vs 0.9%) and urinary tract infections (7.5%, 8.8%, 8.4% vs 5.3%) were also observed; these events were generally mild to moderate, most resolved during treatment and most participants continued therapy. Discontinuation due to adverse events occurred in 4.1%, 6.9% and 11.3% of retatrutide groups versus 4.9% with placebo.
In TRANSCEND‑T2D‑1, the most common adverse events with retatrutide 4 mg, 9 mg and 12 mg versus placebo were nausea (16.4%, 19.5%, 26.5% vs 3.7%), diarrhea (18.7%, 26.3%, 22.8% vs 4.5%) and vomiting (15.7%, 15.0%, 17.6% vs 2.2%). Dysesthesia (4.5%, 2.3%, 4.4% vs 0.0%) and urinary tract infections (0.7%, 1.5%, 2.9% vs 0.0%) were also reported; these were generally mild to moderate, mostly resolved during treatment, and most participants remained on retatrutide. Discontinuation rates due to adverse events were 2.2%, 4.5% and 5.1% with retatrutide versus 0.0% with placebo.
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