TRIUMPH-1 - retatrutide in the treatment of obesity in patients without diabetes

Retatrutide is a single-molecule triple-receptor agonist targeting glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors (1):

• simultaneous activation of GIP, GLP-1, and glucagon receptors provides synergistic metabolic control
• GLP-1 and GIP receptor agonism enhances glucose-dependent insulin secretion, delays gastric emptying, and reduces central appetite
• is a once-weekly subcutaneous injection for chronic weight management and associated cardiometabolic comorbidities in adults with obesity
• glucagon receptor agonism increases resting energy expenditure and promotes hepatic lipid metabolism while mitigating GLP-1/GIP-driven nausea

TRIUMPH-1 study (1)

• study design: phase 3, randomized, double-blind, placebo-controlled trial evaluating once-weekly retatrutide (4 mg, 9 mg, or 12 mg) over 80 weeks
• study population: 2,339 adults with obesity without type 2 diabetes, including pre-specified subgroups with knee osteoarthritis (n = 574) and obstructive sleep apnoea (n = 243)
• weight loss (primary endpoint):
  • 4-mg dose: −17.6% mean weight change vs −3.9% placebo (difference −19.8 percentage points; P < 0.001)
  • 9-mg dose: −23.7% mean weight change vs −3.9% placebo (difference −21.0 percentage points; P < 0.001)
  • 12-mg dose: −25.0% mean weight change vs −3.9% placebo (difference −21.0 percentage points; P < 0.001)
• knee osteoarthritis pain (co-primary endpoint in subgroup):
  • WOMAC pain score reduction (1–10 scale) using hybrid estimand: −3.2 (4 mg), −3.5 (9 mg), and −3.6 (12 mg) vs −1.9 with placebo (differences −1.6 and −1.8 points for 9 mg and 12 mg vs placebo; P < 0.001 for both)
  • WOMAC pain score reduction using ITT estimand: −3.4 (4 mg), −3.9 (9 mg), and −4.1 (12 mg) vs −2.5 with placebo (differences −1.4 and −1.6 points for 9 mg and 12 mg vs placebo; P < 0.001 for both)
• obstructive sleep apnea (co-primary endpoint in subgroup):
  • apnea–hypopnoea index (AHI) event reduction (events/hour) using hybrid estimand: −22.9 (4 mg), −34.3 (9 mg), and −31.7 (12 mg) vs −9.9 with placebo (differences −24.4 and −21.9 for 9 mg and 12 mg vs placebo; P < 0.001 for both)
  • AHI event reduction using ITT estimand: −22.8 (4 mg), −34.3 (9 mg), and −32.1 (12 mg) vs −9.6 with placebo (differences −24.7 and −22.5 for 9 mg and 12 mg vs placebo; P < 0.001 for both)

Adverse Effects and Safety Profile

• most common adverse events: gastrointestinal effects (including nausea, diarrhea, constipation, and vomiting), predominantly mild-to-moderate in severity during dose escalation

The study authors concluded:

“In adults with obesity, retatrutide resulted in significant weight reduction, reduced pain in participants with knee osteoarthritis, and reduced apnea–hypopnea events in participants with obstructive sleep apnea.”

Reference:

1. Jastreboff AM, Kaplan LM, Davies MJ, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity. N Engl J Med. Published online September 29, 2026.