Dual and Triple Incretin Receptor Agonists in Metabolic Disease: Mechanisms, Clinical Evidence, Safety, and Future Perspectives

Abstract

Background Double glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor stimulation by tirzepatide and the development of triple GIP/GLP-1/glucagon receptor modulation by retatrutide are the latest additions to the category of incretin-based therapies for type 2 diabetes (T2D), obesity and other cardiometabolic conditions. Objective: Here is the objective to critically understand the mechanisms of both hormones, their clinical usage, therapeutic benefits, possible side effects and the role of pharmacy practice from an Indian perspective. Methods: A descriptive account of a study; in Section 5 the authors have clearly explained their methodology, search strategy and its disadvantages. Findings: A major feature of tirzepatide is the fact that it brings about larger glycaemic and weight reductions in head-to-head trials compared to GLP-1 RA's semaglutide and dulaglutide. In T2D with advanced atherosclerotic disease, tirzepatide was no inferior to dulaglutide for major adverse cardiac events. Obesity-related heart failure, which is associated with preserved ejection fraction (HFpEF), and reduced apnoea severity were all improved by it. In a steatohepatitis (NASH) phase 2 trial, it also improved histology in the liver. Retatrutide achieved significant phase 2 and phase 3 weight reductions but is still not a FDA approved drug due partly to gastrointestinal adverse effects at the top doses and a high rate of discontinuation for this reason, and to the absence of outcome or safety data. Gastrointestinal side effects, the need for gradual increase of the dosage (dose-titration), the risk of drug-drug interactions, cost and availability are the prime constraints from a practical viewpoint. Conclusions: In the opinion of the authors, both medicines should be seen as a complement, or part of a wider, coordinated care programme lasting many, or a whole life time where a clinical pharmacist helps with choosing the patient, dose titration, giving patient education, making sure patient remains loyal to therapy, monitoring adverse effects, and designing affordable drug regimen. Comparing one drug with another only based on trial results, and claiming that one is superior to others should be avoided, unless there is direct evidence of better results in head-to-head comparisons. Long-lasting safety, outcome of treatment and actual use of the medications in India are what remain as major gaps in the existing data.

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Garvi Patel, Darpi Patel, Esha Patel, S P Srinivas Nayak. Dual and Triple Incretin Receptor Agonists in Metabolic Disease: Mechanisms, Clinical Evidence, Safety, and Future Perspectives. ClinSphere Journals. 2026;undefined(undefined). https://doi.org/0.5281/zenodo.23854944

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