Tirzepatide — a dual GIP/GLP-1 receptor agonist — a new antidiabetic drug with potential metabolic activity in the treatment of type 2 diabetes

Abstract

intensively studied in clinical trials, showing not only hypoglycaemic effects but also influencing the comorbid metabolic components of the disease. These include the following: 1 -activin type II receptor modulators (bimagrumab), 2 -amylin or dual amylin-calcitonin receptor agonists (Pramlintide-amylin agonist), 3 -activator of adenosine monophosphate-activated protein kinase (AMPK) (A-769,662, thienopyridone), 4 -analogues of fibroblast growth factor 21 (pegbelfermin), 5 -fructose-1,6-bisphosphatase inhibitors (VK0612; MB07803), 6 -new GLP-1 receptor agonists (albiglutide, dulaglutide, exenatide, liraglutide, lyxisenatide, semaglutide, efpeglenatide, glutazumab, ITCA-650), 7 -drugs affecting the activity of the sodium-glucose cotransporter (SGLT 1 and 2) (SGLT 1 -licogliflozin, sotagliflozin and LX2761; SGLT 2 -kanagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin and tofogliflozin), or 8 -imeglimin belonging to a new group of drugs, so-called glimin [1,2].

A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

“…However, many of these drugs are poorly tolerated and are associated with significant adverse events. For example, once weekly dosing of tirzepatide (a dual GIPR and GLP-1R co-agonist) has superior efficacy for weight reduction compared to the GLP-1R agonist, semaglutide; at least 50% of patients receiving 10 or 15 mg of tirzepatide per week achieved a weight loss of 20% and more (Willard, Douros et al 2020, Min and Bain 2021, Rosenstock, Wysham et al 2021, Jastreboff, Aronne et al 2022, Nowak et al 2022.Tirzepatide was also superior to semaglutide at reducing levels of glycated hemoglobin (Frias, Davies et al 2021). However, tirzepatide treatment resulted in mild to moderate gastrointestinal symptoms, including nausea (12-24%), diarrhea (15-17%) and vomiting (6-10%).…”

“…While receptor levels, animal diet, dosing, and the presence of a GLP-1RA have a profound impact on insulin secretion and associated endocrine outcomes, the effects of dual or triple agonism of Y1-R and Y2-R, in the presence of a GLP-1RA remain unclear. Several groups have designed monomeric dual and triple agonists based on the interactions of GLP-1 with glucagon (Day, Gelfanov et al 2012, Sanchez-Garrido, Brandt et al 2017, Ambery, Parker et al 2018) and/or GIP (Finan, Yang et al 2015, Nowak, Nowak et al 2022, Tan, Akindehin et al 2022). This is a novel and promising approach to the development of drugs for the treatment of human obesity.…”

A peptide triple agonist of GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors promotes glycemic control and weight loss

“…While receptor levels, animal diet, dosing, and the presence of a GLP-1RA have a profound impact on insulin secretion and associated endocrine outcomes, the effects of dual or triple agonism of Y1-R and Y2-R, in the presence of a GLP-1RA remain unclear. Several groups have designed monomeric dual and triple agonists based on the interactions of GLP-1 with glucagon 54 – 56 and/or GIP 57 – 59 . This is a novel and promising approach to the development of drugs for the treatment of human obesity.…”

“…However, many of these drugs are poorly tolerated and are associated with significant adverse events. For example, once weekly dosing of tirzepatide (a dual GIPR and GLP-1R co-agonist) has superior efficacy for weight reduction compared to the GLP-1R agonist, semaglutide; at least 50% of patients receiving 10 or 15 mg of tirzepatide per week achieved a weight loss of 20% and more 6 , 59 – 62 .Tirzepatide was also superior to semaglutide at reducing levels of glycated hemoglobin 63 . However, tirzepatide treatment resulted in mild to moderate gastrointestinal symptoms, including nausea (12–24%), diarrhea (15–17%) and vomiting (6–10%).…”

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

“…45. Tirzepatide is the first agent that functions as a dual agonist for the two main human GLP-1 and GIP incretins, a promising drug against both T2D and obesity [34][35][36][37]. It has impressive glycemic efficacy.…”