Triple agonists of GIP, GLP-1, and glucagon - the future of obesity treatment: a review of the latest findings

Background: The epidemic of obesity and type 2 diabetes poses a growing challenge to global public health, necessitating effective intervention strategies. Currently conducted research on novel pharmacotherapeutic approaches to obesity treatment is yielding promising results. Among them are the triple agonists of GIP/GLP/GCG (glucose-dependent insulinotropic peptide/ glucagon-like peptide/ glucagon) receptors, representing the latest discovery. Preclinical studies and phase I and II trials demonstrate significant clinical prospects for GIP/GLP/GCG receptor agonists. Aim of the study: This paper aims to summarize and analyze the current knowledge on triple agonists of GIP/GLP-1/GCG and their impact on body weight based on clinical studies conducted in recent years and currently ongoing. Material and methods: The search was conducted using the PubMed, Google Scholar, and NIH databases. Articles published between 1971 and 2022 were analyzed. The keywords used were "triple agonists," "obesity," "GIP," "GLP-1," and "glucagon." Results: According to our best knowledge, there are currently clinical trials underway for four GIP/GLP-1/ glucose-dependent insulinotropic peptideagon triagonists, including NN9423NC9204-1706, efpegtrutide, SAR441255, and retatrutide. Studies on retatrutide have shown promising results, with observed weight reduction of up to 17 kg. Additionally, another triagonist, efocipegtrutyd, besides its effects on weight loss, demonstrates the ability to prevent liver fibrosis and has neuroprotective effects. Conclusion: The action of GIP/GLP-1/GCG triple agonists is multifaceted, and preliminary research results are encouraging further exploration of their potential. Despite promising outcomes, continued research is necessary to gain a deeper understanding of their mechanism of action and to assess their long-term effects. Such studies will be crucial in providing information to support the development of personalized therapeutic strategies and optimizing their clinical utility in diverse patient populations.