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

Abstract

Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) are already established in the treatment of type 2 diabetes (T2D). The development of novel dual- or triple-receptor agonists that bind to the receptors not only for GLP-1 but also to the receptors for glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon is intended to address different metabolic pathways for carbohydrate, lipid, and protein metabolism simultaneously. Dual- and triple-receptor agonists acting via different receptors and postreceptor pathways seem attractive in view of potentially additive or synergistic effects in the treatment of T2D and obesity. Recently, the first approval for a dual-receptor agonist marks an important step in this development. The GIP/GLP-1-receptor agonist tirzepatide was approved for the treatment of T2D by the Food and Drug Administration (FDA) in the USA for once-weekly subcutaneous injections in May 2022 and has just received a positive opinion from the European Medicines Agency (EMA). Tirzepatide dose-dependently leads to clinically significant reductions in glycemic parameters and body weight and has been shown to have stronger effects in reducing these parameters than standard antidiabetic therapy. This article summarizes the current clinical study program and the respective outcomes and highlights further potential indications for tirzepatide in the treatment of obesity and potentially other comorbidities of T2D.

GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives

“…Due to the complex and heterogeneous pathophysiology of NASH, it has been hypothesized that the simultaneous action on different pathways could exert a synergistic effect, optimizing therapeutic results. In this perspective, the possibilities of double (GLP-1 and GIP or GLP1 and glucagon) or triple (GLP-1, GIP and glucagon) receptor agonism [ 147 , 148 ] are the issue of recent research. Glucose-dependent insulinotropic peptide (GIP) acts by increasing insulin secretion, hepatic glucose and triglyceride uptake in adipose tissue and liver as well as reducing gluconeogenesis and glucagon secretion [ 149 ].…”

A „másik” inkretin – a glükózdependens insulinotrop polipeptid terápiás újrafelfedezése

“…A GIP hosszú hatású agonistái ugyanakkor eredményesnek bizonyultak a testtömeg csökkentésében [27]. Minthogy a hosszú hatású GLP1-receptor-agonisták is étvágycsökkentő és attól független súlyleadást elősegítő természetűnek bizonyultak, a figyelem előterébe került a két receptor egyidejű stimulálásának, duális receptoragonista alkalmazásának gondolata [28].…”

Tirzepatide: A Systematic Update

“…The beneficial influence of Tirzepatide on cardiometabolic parameters suggests the availability, in the near future, of a new weapon effective against cardiovascular and metabolic disorders [ 88 , 91 , 92 , 93 ]. Different phase I, II, and III trials are now ongoing to test the effectiveness and safety of Tirzepatide for its potentials uses ( Table 8 ).…”