Systematic review and network meta-analysis of the safety and efficacy of the triple incretin receptor agonist, retatrutide compared to the dual incretin receptor agonist, tirzepatide, for treatment of type 2 diabetes mellitus
Anastasia Tereshchenko, Belén Garay Gálvez, Javier Ananda TelloBackground
Type 2 diabetes mellitus (T2DM) is a common metabolic disorder marked by persistent hyperglycaemia that requires effective treatment to prevent complications. As current therapies do not achieve adequate glycaemic control in all patients, the triple receptor agonist retatrutide was developed to target incretin and glucagon receptors and improve glycaemic control.
Objective
This review evaluated the safety and efficacy of retatrutide and the dual incretin receptor agonist tirzepatide in adults with type 2 diabetes, using the single incretin mimetic dulaglutide and placebo as reference comparators.
Design
Systematic review and network meta-analysis.
Methods
Medline, Embase, PubMed, Web of Science and Scopus databases were searched for randomised controlled trials and post hoc analyses investigating retatrutide and tirzepatide in T2DM. Studies were selected according to PICOS criteria, appraised using the Critical Appraisal Skills Programme (CASP) checklist and synthesized using a network meta-analysis using RStudio.
Results
Fifteen studies including 2958 participants were eligible for review, and 10 studies contributed to the quantitative analysis. Compared with placebo and dulaglutide, both tirzepatide and retatrutide improved HbA1c, fasting plasma glucose, fasting insulin, body weight, and waist circumference, although the magnitude of benefit varied by outcome and dose. Relative to dulaglutide, tirzepatide 15 mg produced the greatest reduction in HbA1c (-1.30%), whereas retatrutide 8 mg with slow escalation produced the largest reductions in body weight (-13.03 kg) and waist circumference (-8.63 cm). Retatrutide 12 mg also reduced HbA1c by 0.78%, while tirzepatide 15 mg reduced body weight by 8.60 kg. All retatrutide doses produced large fasting insulin reductions relative to dulaglutide, ranking above all tirzepatide doses. Overall, both agents showed similar tolerability and safety profiles relative to dulaglutide.
Conclusion
Newer incretin receptor agonists are therapeutically superior to the single incretin receptor agonist and placebo for T2DM, with retatrutide showing greater weight-related potential.
Registration
PROSPERO (registration number: CRD420251014217).