According to research in the United States, Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist used in the context of type 2 diabetes research. As per research studies, Tirzepatide is a synthetic acylated peptide designed to stimulate the GIP and GLP-1 receptors, two of the most important mediators of insulin production in the brain areas responsible for controlling appetite.
Tirzepatide has been suggested in five clinical studies in test subjects with type 2 diabetes to reduce hemoglobin A1c and body weight significantly. Twenty-three percent to sixty-two percent of subjects appeared to have achieved an HbA1c of less than five point seven percent (the top limit of the normal range indicating normoglycaemia), and twenty-one point seven percent to sixty-eight point four percent seemed to have lost more than ten percent of their initial body weight.
Studies suggest that compared to the selective GLP-1 RA Semaglutide with titrated basal insulin, Tirzepatide appeared more efficacious in lowering HbA1c and body weight in research. Similar to what has been observed with selective GLP-1RA, Tirzepatide was associated with various gastrointestinal side effects, the frequency of which increased, as per clinical trials. Adjudications for cardiovascular events for the whole research program show a trend toward reducing MACE-4 (nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality, and hospital admission for angina) occurrences for up to 2 years, but with low numbers of events. A meta-analysis of the entire clinical trial program found no hazard ratios for any cardiovascular events analyzed (MACE-4 or its components) greater than 1.0 compared to pooled comparators.
As suggested by research, Tirzepatide was linked with lower prandial insulin and glucagon concentrations and a larger improvement in insulin sensitivity and secretory responses than Semaglutide. The appetite suppressant effects of both medicines were comparable, but Tirzepatide seemed to have led to more significant weight loss, as indicated by research. Despite Tirzepatide’s promising results, many uncertainties remain about the medication’s mechanism of action. Moreover, it is still unclear whether or not GIPR agonism may increase insulin secretion in type 2 diabetes test subjects who have shown no response to GIP in earlier investigations.
A renewed interest in the research capacity of GIP in type 2 diabetes, obesity, and associated co-morbidities is inevitable in light of the apparent superiority of the dual incretin agonist Tirzepatide versus GLP-1RA.
Dual GLP-1R/GIPR Co-agonist: Tirzepatide
After initial research on multi-receptor peptides, numerous single-molecule GIPR and GLP-1R agonists were produced, including Tizerapide. It is a linear peptide of 39 amino acids, the same length as the closely related hormones glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-1 (GIP). As suggested by research, GIP’s amino acid sequence was a starting point for developing Tirzepatide, which maintains 9 homologous GIP amino acids and 10 GIP/GLP-1 common amino acids.
GLP-1 and exendin-4 have a total of 14 amino acids in common, including 4 that are identical to their counterparts in GLP-1 and 10 that are located immediately next to each other at the amino terminus (a peptide from the saliva of a lizard called Heloderma suspectum, later becoming exenatide, the first GLP-1 RA.
Research indicates that Tirzepatide may have unique amino acid positions, including amino-iso-butyric acid residues at position 2 (a recognition site for dipeptidyl peptidase-4) and position 13. Important for a prolonged effect is the attachment of an (AEEA)2-gamma Glu-C20 diacid to the lysine residue at position 20. This diacid facilitates binding to albumin (like in Liraglutide and Semaglutide, as well as in long-acting insulin analogs degludec and codec).
Studies purport that when added to GIP and GLP-1, Tirzepatide may have a similar effect on cAMP production in pancreatic ß-cells [i]. Incretin receptors were expressed in embryonic kidney cells, and the response curve for cAMP production suggested exogenous GIP-activated GIPR receptors like that of native GIP.
In contrast, findings implied that GLP-1 appeared to have less effect on the GLP-1R than endogenous GLP-1. Binding to and stimulating GIP receptors are equivalent to natural GIP, as tracer displacement and cAMP production assays show. In contrast, binding to and actions at the GLP-1 receptor is less than native GLP-1 [i]. As per research findings, consistent with the observations in transfected cells, Tirzepatide may induce a concentration-dependent increase in cAMP generation in differentiated adipocytes. Overall, in isolated cell cultures with a high-grade expression of GIP and GLP-1 receptors, Tirzepatide appeared to activate GIP receptors over GLP-1 receptors preferentially.
Data for structural requirements explaining receptor bifunctionality and GIP’s preferential binding to and activation of GLP-1 receptors has been analyzed at length. Researchers speculate that Tirzepatide, GIP, and GLP-1 concentrations may have resulted in 50% tracer displacement (binding affinity) and 50% cAMP production. Insulin production driven by Tirzepatide was stopped by a GIPR antagonist in GLP-1 receptor-deficient mouse pancreatic islets [i], whereas GLP-1R antagonism had the same effect in islets from GIP receptor knock-out animals, as indicated by research. It has been hypothesized that Tirzepatide may have been more productive than Semaglutide, the most potent selective GLP-1 agent now available, in reducing food intake and body weight in rodents with diet-induced obesity.
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References
[i] Nauck, M.A., D‘Alessio, D.A. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol 21, 169 (2022). https://doi.org/10.1186/s12933-022-01604-7
