TRIUMPH-2 - retatrutide in adults with obesity and type 2 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):

• evaluated as a once-weekly subcutaneous injection for body weight management and glycemic control in adults with obesity and type 2 diabetes
• phase 3 evidence demonstrates substantial dose-dependent weight reduction alongside improvements in glycemic parameters

Mechanism of Action

• 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 appetite
• glucagon receptor agonism increases resting energy expenditure and promotes hepatic lipid metabolism

Key Trial Findings (TRIUMPH-2 Study)

• study design: phase 3, double-blind, parallel-group, randomized, placebo-controlled trial across 92 centers in eight countries over 80 weeks
• study population: 1,152 adults with BMI >= 27 kg/m2 and type 2 diabetes (HbA1c 6.5–10.5%) on stable anti-hyperglycaemic treatment
• weight loss at week 80 (primary endpoint; treatment regimen estimand):
  • 4-mg dose: −11.9% mean weight change vs −5.1% placebo (difference −6.9 percentage points; P < 0.0001)
  • 9-mg dose: −16.8% mean weight change vs −5.1% placebo (difference −11.8 percentage points; P < 0.0001)
  • 12-mg dose: −18.8% mean weight change vs −5.1% placebo (difference −13.8 percentage points; P < 0.0001)
• glycaemic control: associated with substantial overall improvements in glycaemic parameters across all dose cohorts

Adverse Effects and Safety Profile

• most common adverse events: gastrointestinal effects, predominantly dose-dependent diarrhea (27% to 34% vs 13% placebo) and nausea (14% to 28% vs 8% placebo)
• additional reported adverse events: increased incidence of hypotension (1% to 6% vs <1% placebo) and dysesthesia (4% to 7% vs 1% placebo
• treatment discontinuations due to adverse events or death: higher in the 9 mg (12%) and 12 mg (8%) groups compared with 4 mg (4%) and placebo (5%)
  • two participants died in the retatrutide 4 mg group, three in the 9 mg group, one in the 12 mg group, and one in the placebo group; all deaths were deemed to be unrelated to the study intervention by the investigator

Reference:

1. Bellido V, le Roux CW, Ekinci EI, et al. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. Lancet. Published online 2026.