Research Progress on the GIP/GLP-1 Receptor Coagonist Tirzepatide, a Rising Star in Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic progressive metabolic disease that has become a growing health problem worldwide, and the dangers of hyperglycemia and its chronic complications have long been considered a goal of diabetes treatment. In recent years, tirzepatide has become the first dual GIP/GLP-1R agonist approved for the treatment of diabetes mellitus in the United States as a new hypoglycemic medicine. Its hypoglycaemic and weight loss effects have been demonstrated in several large clinical trials, and there is also evidence that it has great potential for cardiovascular protection. In addition, the very concept of synthetic peptides opens up many unknown possibilities for tirzepatide. Ongoing trials (NCT04166773) and evidence suggest that it appears to be a promising drug in the areas of NAFLD, renal, and neuroprotection. Based on preclinical studies and clinical trials, the aim of this article is to discuss the latest clinical developments in tirzepatide, to focus on its differences with other incretin therapies, and to suggest future possibilities and mechanisms of tirzepatide therapy.

The Cardiac-Kidney-Liver (CKL) syndrome: the “real entity” of type 2 diabetes mellitus

“…This approach can enable the implementation of a ‘holistic person-centered’ interdisciplinary care for T2DM patients, according to the current guidelines [ 4 ]. In this context, certain antidiabetic drugs, namely sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 co-agonists represent ideal therapeutic agents that can target the whole spectrum of the CKL syndrome based on their beneficial cardiorenal effects and their benefits on MASLD [ 92 – 99 ].…”

Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD

“…Finally, cotadutide is gaining attention recently, as it seems to ameliorate lipid status and liver histology more than liraglutide, probably due to its dual action both as a GLP-1 and glucagon receptor agonist [ 131 ], which, according to in vivo studies in DIO mice, is probably due to an impairment in fat deposition through AMPK/mTOR signalling in the liver [ 132 ]. With this promising view, other dual agonists have been developed, such as ALT-801, which has just concluded a safety assessment in patients, after improving NAFLD characteristics in vivo more than semaglutide or elafibranor [ 133 ], or tirzepatide, a novel dual agonist for GIP and GLP-1, approved for T2D therapy in 2022, which is currently being tested for NAFL/NASH, since it seems to also have beneficial effects on the liver [ 134 ]. GLP-1 agonists with double actions, or the combination of drugs with different targets, like liraglutide and elafibranor [ 135 ], are therefore an interesting field to explore and exploit for NAFL/NASH treatment.…”

Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications

“…Some new therapeutic molecules are currently being investigated, such as GIP/GLP-1 Receptor Coagonist Tirzepatide, the first dual agonist approved for T2DM treatment, which has hypoglycemic weight loss effects and also presents great potential for cardiovascular protection [ 75 ].…”