Understanding Tirzepatide Peptide

The injection of Tirzepatide is utilized in the treatment of type 2 diabetes. It is taken in conjunction with a healthy diet and regular exercise to assist in maintaining control of your blood sugar levels. Insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist are both characteristics of the peptide Tirzepatide, which is glucose-dependent. 

Tirzepatide injection is also used to assist patients who are obese as a result of certain conditions in losing weight and maintaining the weight loss that they have managed to achieve. Additionally, it is utilized in the treatment of patients who are obese and suffer from moderate to severe obstructive sleep apnea (OSA).

As far as its structure is concerned, it is a linear peptide consisting of 39 amino acids that are linked to a C20 fatty diacid moiety by a linker that is coupled to the lysine20 residue. When compared to the use of a GLP-1 agonist (Semaglutide) by itself, the dual agonist strategy results in a synergistic effect on the interactions between insulin and glucagonostatic responses.

Mechanism of Action of Tirzepatide Peptide

In a glucose-dependent way, it acts to boost insulin production during the first and second phases, and it also works to lower glucagon levels throughout the body.  Tirzepatide was also demonstrated to delay the emptying of the stomach, lower the concentration of glucose in the blood during fasting and after meals, limit the amount of food consumed, and bring about a reduction in body weight in individuals who had type 2 diabetes. 

Glucagon-like peptide-1 (GLP-1) receptors, also known as GLP-1R, are molecules that are expressed in several parts of the body, including the pancreatic beta-cells and the gastrointestinal tract.  Due to the fact that GLP-1R signalling is involved in glucose control, they have been linked to the pathophysiology of type II diabetes mellitus. This is because GLP-1R signalling is responsible for increasing glucose-stimulated insulin secretion, delaying gastric transit, lowering plasma glucagon levels, and reducing body weight by activating anorexigenic pathways in the brain.  GLP-1 and hyperglycemia-dependent insulinotropic polypeptide (GIP) are both examples of peptide hormones that play a role in maintaining glucose homeostasis. These hormones encourage the pancreatic beta cells to secrete insulin in response to having glucose.  Nevertheless, GIP is the primary incretin hormone that is responsible for the insulinotropic effects that are triggered by the consumption of food.

In spite of the fact that the precise mechanism of action of Tirzepatide has not been completely defined, it is possible that dual agonism at GIP and GLP-1R may be responsible for the glycaemic and weight control effects of the therapeutic agent.  When compared to the administration of either hormone on its own, studies have shown that the combination of GIP with a GLP-1R agonist results in a much greater rise in insulin responsiveness and a suppression of glucagon secretion.  Tirzepatide has a strong affinity for both GIP and GLP-1R, to which it binds.  Tirzepatide has a GIP receptor binding affinity that is comparable to that of native GIP, but it has a GLP-1R affinity that is five times lower than that of natural GLP-1.3 through in vitro testing.  Through action at either the GIP receptor (GIPR) or the GLP-1R, Tirzepatide causes a powerful activation of the GLP-1R signalling pathway, which in turn stimulates glucose-dependent insulin release into the bloodstream.  It is necessary to do additional research in order to determine the role that GIPR agonism plays in the mechanism of action of the medicine. This is because the evidence of GIPR agonism on glycemic control and weight control in preclinical and clinical studies disagrees with one another.

Research Evidence

Tirzepatide, a new injectable weight-loss drug with the trade name Zepbound, was found to reduce the risk of diabetes in people with type 2 diabetes and prediabetes by more than 90 percent over a period of three years, in comparison with placebo, according to the findings of a new study that was led by researchers from Weill Cornell Medicine, NewYork-Presbyterian, Yale School of Medicine, and other institutions.

Tirzepatide is a member of a broad new class of medications that mimic nutrient-stimulated hormones. These medications assist patients in losing a large amount of weight and improving their ability to control their blood sugar levels.  The medications work, at least in part, by activating one or several receptors throughout the body. These receptors include glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors on cells in the brain, pancreas, and other parts of the body.  Tirzepatide is able to activate both GLP-1 and GIP, which results in a higher reduction in body weight and fewer adverse effects compared to previous drugs that only stimulate GLP-1.  Overall, the medicine has the effect of promoting a feeling of fullness, often known as "satiety," which in turn lessens the urge for food. Additionally, the drug increases insulin production, which in turn lowers the amount of glucose that is present in the blood.

Patients with obesity who took Tirzepatide for a period of 72 weeks saw a significant average reduction in their levels of glycated hemoglobin, also known as A1c levels, which is a standard measure of blood sugar control. Additionally, the SURMOUNT-1 trial discovered that patients lost between 15% and 22.5% of their initial weight, on average, depending on the dose.  Prediabetes is a disorder that is considered to be a precursor to diabetes. It is characterized by A1c levels that are higher than normal but lower than the threshold for diabetes. The current study focused on 1,032 of these patients who initially had obesity and prediabetes.

 According to the findings of the study, after 176 weeks, just ten individuals who were treated with Tirzepatide developed diabetes. This represents a reduction in risk of almost 93% when compared to the group that received a placebo.  At 176 weeks, patients who were treated with Tirzepatide had normal A1c levels, but patients who were treated with a placebo had normal A1c levels just 59% of the time.

 The experiment did not reveal any new safety concerns; the most common gastrointestinal side effects, such as nausea and vomiting, decreased as the trial progressed, which suggests that Tirzepatide is rather safe to use for an extended period of time.  Following the cessation of medication for 17 weeks, a follow-up analysis revealed that some patients had experienced slight increases in their weight and A1c values. This resulted in some patients falling back into the ranges of prediabetes and diabetes, highlighting the likely requirement for ongoing treatment.

 According to Dr. Aronne, who is also an internist who specializes in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Centre, the findings indicate that there is a possibility that the medicine could one day become the first treatment for prediabetes that is approved by the FDA.

Clinical Research Applications

Both the glucagon-like peptide-1 receptor agonist (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP) receptors are activated by the hormone Tirzepatide, making it a dual agonist.  In patients with type 2 diabetes, the medicine leads to a significant improvement in glycemic control and weight reduction, maximizing advantages that are comparable to those of GLP-1 treatments such as Tirzepatide versus Semaglutide with regard to weight loss.

The use of Tirzepatide may have a beneficial effect on cardiovascular disease through a variety of different ways.  The first benefit is that it enhances glycemic management by lowering HbA1c levels, which in turn mitigates the damage to the blood vessels that is caused by hyperglycemia.  High blood glucose levels or changes in glucose levels can cause vascular endothelial dysfunction and atherosclerosis through a number of different processes. These mechanisms include increased oxidative stress, the production of advanced glycation end products (AGEs), and the activation of protein kinase C (PKC).  Furthermore, the effect of Tirzepatide has the potential to assist in the reduction of cardiovascular burden and blood pressure through direct effects, such as the enhancement of vascular endothelial function, as well as indirect benefits, which result from the management of weight.  In addition to their benefits in decreasing glucose levels and promoting weight loss, there is evidence from a few trials that suggests that GLP-1 receptor agonists' efficacy and safety may also have direct cardiovascular preventive effects.  Liraglutide and Semaglutide, for instance, have demonstrated anti-atherosclerotic benefits in animal models. These effects include the reduction of vascular inflammation, the improvement of endothelial function, and the stabilization of plaques.  Nevertheless, despite the fact that the research on Tirzepatide is still in the basic stage, there is some evidence to suggest the potential benefits that it may have in protecting the cardiovascular system.  It was also shown that Liraglutide inhibited atherosclerosis by a mechanism that was independent of AMPK in a hyperglycemic ApoE gene deletion mice model. This finding suggests that GLP-1 receptor agonists may exert cardiovascular protective benefits through different mechanisms.  It is possible that these effects are partially mediated by mechanisms that are driven by the GLP-1 receptor, which is anti-inflammatory and antioxidant in nature.

Future Research Perspectives

Tirzepatide, a novel medication for type 2 diabetes, has been shown to have considerable impacts on glycemic control and weight management. These effects are achieved by the combined activation of GLP-1 and GIP receptors.  According to the results of the SURMOUNT and SURPASS studies, its effects on weight loss were significant.  To validate Tirzepatide's promise as a safe and effective treatment option for diabetes and heart disease, however, future research needs to conduct long-term follow-up and large sample studies. This will allow for a more comprehensive evaluation of the impact that Tirzepatide has on the cardiovascular system.  Further, it is imperative that research be conducted on specific groups, such as individuals who are elderly or those who have renal impairment.

References

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2. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A: LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 Oct 3

3. Eli Lilly and Company Investors News Release: FDA approves Lilly's Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes.

4. Frias JP: Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. 2020 Nov;15(6):379-394. doi: 10.1080/17446651.2020.1830759. Epub 2020 Oct 8. [Article]

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6. FDA Approved Drug Products: MOUNJARO (tirzepatide) Injection, for subcutaneous use.