Retatrutide Phase 2 (Obesity)

Background

Triple GIP/GLP-1/glucagon receptor agonism was hypothesised to combine incretin-mediated glucose-dependent insulin secretion and central appetite modulation with glucagon-mediated increases in energy expenditure. The Retatrutide Phase 2 obesity trial provided the first randomised Phase 2 evidence in the class in adults with obesity. ^[1]

Study design

Randomised, double-blind, placebo-controlled, dose-ranging Phase 2 trial. Participants were randomised across multiple Retatrutide dose arms (1, 4, 8 and 12 mg maintenance) and matching placebo, each administered subcutaneously once weekly for 48 weeks alongside lifestyle intervention.

Population

338 adults with a body-mass index of at least 30, or at least 27 with a weight-related coexisting condition, without type 2 diabetes.

Intervention

Once-weekly subcutaneous Retatrutide titrated over several weeks to 1, 4, 8 or 12 mg maintenance dose.

Comparator

Matching placebo administered subcutaneously once weekly.

Primary endpoints

Percent change in body weight from baseline to week 24 and week 48.

Secondary endpoints

Proportions achieving ≥5%, ≥10%, ≥15% and ≥20% weight reduction; change in waist circumference, systolic blood pressure, HbA1c, fasting glucose, lipid parameters and patient-reported outcomes.

Key findings

• Mean change in body weight at week 48 was approximately −8.7% (1 mg), −17.1% (4 mg), −22.8% (8 mg) and −24.2% (12 mg) with Retatrutide versus approximately −2.1% with placebo.
• Substantial proportions of participants at higher doses achieved ≥20% and ≥25% weight reduction.
• Improvements were reported in waist circumference, blood pressure and cardiometabolic parameters.
• Gastrointestinal adverse events were the dominant tolerability finding and were dose-dependent.

Mechanistic significance

• Consistent with the triple-agonist hypothesis that adding glucagon receptor agonism to dual GIP/GLP-1 co-agonism further modulates energy balance.
• The magnitude of weight reduction observed extends the incretin-agonist dose-response curve beyond Semaglutide (STEP) and Tirzepatide (SURMOUNT) references.

Limitations

Research context

The Retatrutide Phase 2 obesity trial is the reference Phase 2 dataset for the triple-agonist class in obesity and framed the ongoing Phase 3 TRIUMPH programme. It is routinely contextualised against STEP-1 (Semaglutide) and SURMOUNT-1 (Tirzepatide).