Retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, provides robust HbA1c and body weight reductions to people with type 2 diabetes: a 36--week, phase 2 study

How efficacious is retratrutide (RETA) for HbA1c reduction in people with type 2 diabetes (T2D) compared to dulaglutide (DULA) and placebo?

Methods: In this 36-week, phase 2, randomized, double-blinded, parallel, placebo- and active comparator-controlled study, participants with T2D treated with diet and exercise alone or with a stable dose of metformin, an HbA1c (glycated hemoglobin) ≥53 to ≤91 mmol/mol (≥7% to ≤10.5%), and body mass index (BMI) of 25 to 50 kg/m2 were eligible to participate. Participants were randomized to PBO, DULA 1.5 mg, or maintenance doses of RETA 0.5 mg, 4 mg, 8 mg, or 12 mg. Gradual dose escalation was employed to improve tolerability; two starting doses (2 mg vs 4 mg) were explored for doses greater than 0.5 mg. Treatments were administered once weekly via subcutaneous injection. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and body weight at 36 weeks, and several additional measures relevant for cardiovascular risk.

Results: At 24 weeks, RETA decreased HbA1c in a dose-dependent manner, ranging from -4.7 to -22.1 mmol/mol (-0.4 to -2.0%) vs -0.1 mmol/mol (<0.1%) with PBO and -15.4 mmol/mol (-1.4%) with DULA. Findings were consistent for HbA1c at 36 weeks The proportion of participants achieving HbA1c<7.0%, ≤6.5%, or<5.7% at 36 weeks was higher in the RETA-treated participants vs PBO. Body weight decreased dose-dependently with RETA at 36 weeks, with 16.9% reduction with RETA 12 mg. Fasting glucose, waist circumference, non-HDL cholesterol, triglycerides, and systolic blood pressure also decreased to a greater extent with RETA vs PBO. Mild-to-moderate gastrointestinal-related adverse events, including nausea, diarrhea, vomiting, and constipation, were reported in 13-50% of RETA-treated participants, 13% with PBO, and 35% with DULA; these events occurred primarily during dose-escalation, and were mitigated by a lower starting dose (2 mg vs 4 mg). There were no reports of clinical meaningful or severe hypoglycemia. Dose-dependent increases in pulse rate of up to 3.9 bpm were observed with RETA at 36 weeks, vs -3.2 bpm for PBO (p<0.05) and 1.8 bpm for DULA.

Conclusion: In people with T2D, RETA demonstrated clinically meaningful improvements in glycemic control and robust clinically meaningful body weight loss, with a safety profile consistent with GLP-1 receptor agonist and GIP/GLP-1 receptor agonist classes.

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Artikel online veröffentlicht:
18. April 2024