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

Abstract

The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, and is referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known as a ‘twincretin’, is a ‘first-in-class’ and the only dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels and improve insulin sensitivity, as well as reducing body weight by more than 20% and improving lipid metabolism. This novel anti-diabetic drug is a synthetic peptide analog of the human GIP hormone with a C20 fatty-diacid portion attached which, via acylation technology, can bind to albumin in order to provide a dose of the drug, by means of subcutaneous injection, once a week, which is appropriate to its a half-life of about five days. Tirzepatide, developed by Eli Lilly, was approved, under the brand name Mounjaro, by the United States Food and Drug Administration in May 2022. This started the ‘twincretin’ era of enormously important and appealing dual therapeutic options for diabetes and obesity, as well as advanced management of closely related cardiometabolic settings, which constitute the leading cause of morbidity, disability, and mortality worldwide. Herein, we present the key characteristics of tirzepatide in terms of synthesis, structure, and activity, bearing in mind its advantages and shortcomings. Furthermore, we briefly trace the evolution of this kind of medical agent and discuss the development of clinical studies.

In silico structure-based designers of therapeutic targets for diabetes mellitus or obesity: A protocol for systematic review

“…Synthetic peptides are examples of the application of bioinformatics techniques, where the elaboration of the same can be done, aiming at the optimization of the interaction of the substances with the chosen targets. Among the most promising synthetic peptides is the recently approved Tirzepatide (LY3298176) for treating DM, whose anti-obesity and anti-diabetes properties have been studied through clinical trials [ 32 ].…”

Peptide-Drug Conjugates: A New Hope for Cancer Management

“…Peptide-drug conjugates (PDCs) are composed of different components, which include a homing peptide or device, cytotoxic payload, and a linker that works synergistically to deliver cytotoxins to the targeted receptor on cancer cells ( Figure 1 ) [ 37 ]. Each component’s role and mechanisms of action are important considerations when assembling PDCs [ 38 ].…”

“…For the treatment of cancer, several cancer-specific receptors or markers are targeted by PDCs such as the integrin (αvβ3) receptor for ovarian cancer, EGFR receptor and MUC1 (CD227) for lung, breast, bladder, and ovarian cancer, NPY(Hy1R) receptor for breast cancer and Ewing sarcoma, and MC1R receptor for melanoma (REFS) [ 154 , 155 , 156 ]. By the targeted drug delivery approach, side-effects can be reduced, and the efficacy of the drug can be increased [ 38 ]. Trafficking of extracellular macromolecules into cells (endocytosis) and across cells (transcytosis) is facilitated by receptor-mediated transport mechanisms.…”

Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity

“…The exact mechanisms explaining these findings are not completely understood, but there is some evidence that agonist-induced internalization of the two receptors for GLP-1 and GIP differs markedly. Structural alterations of the ligand peptides as in GIP/ GLP-1 dual-receptor agonists may alter these cellular processes strongly and may explain that an antagonist may activate while an agonist may block receptor signaling (46)(47)(48)(49). The most important known patterns for the therapeutic effects of GIP agonism as well as antagonism in preventing obesity and in reducing body weight are summarized in Table 1 (49).…”