Incretin-based dual and triple agonists like tirzepatide and retatrutide deliver unprecedented efficacy for metabolic disorders

The management of type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD) has been revolutionized by incretin-based therapies. While early treatments like DPP-4 inhibitors offered modest glycemic control, the field has rapidly advanced to more potent GLP-1 receptor agonists (GLP-1RAs). A critical gap remains in achieving comprehensive multi-system benefits beyond glycemic control, particularly for significant weight reduction and improvement in associated cardiometabolic risks. This review addresses how next-generation dual and triple incretin agonists are filling this gap, offering a more holistic approach to these complex metabolic conditions.

This comprehensive review synthesized literature from PubMed, Scopus, and Google Scholar, covering publications up to July 2025. The authors focused on the evolving role of incretin pharmacology, emphasizing pivotal clinical trials and real-world evidence. The review systematically explored the efficacy and safety profiles of various incretin-based therapies, ranging from DPP-4 inhibitors and GLP-1RAs like liraglutide and semaglutide, to advanced dual agonists such as tirzepatide and triple agonists like retatrutide, as well as agents like cotadutide and efinopegdutide targeting specific conditions like MASLD and MASH.

Incretin-based therapies have shown a progressive increase in efficacy. While DPP-4 inhibitors provide modest glycemic benefits, GLP-1RAs such as liraglutide and semaglutide have demonstrated significant weight loss and substantial cardiometabolic protection. The review highlights that dual GIP/GLP-1 agonist tirzepatide and the triple GIP/GLP-1/Glucagon agonist retatrutide have achieved unprecedented efficacy. These multi-agonists led to up to 24% body weight reduction in clinical trials. This significant weight loss was accompanied by marked improvements in hepatic and inflammatory markers, indicating broad metabolic benefits. > Triple and dual incretin agonists like retatrutide and tirzepatide achieved up to 24% body weight reduction, alongside improvements in hepatic and inflammatory markers. Furthermore, agents like cotadutide and efinopegdutide are expanding therapeutic indications to include MASLD and metabolic dysfunction-associated steatohepatitis (MASH), demonstrating their potential beyond traditional glycemic control and weight management.