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Published in final edited form as: Endocr Metab Immune Disord Drug Targets. 2023;23(8):1046–1050. doi: 10.2174/1871530322666221004151212

Tirzepatide: A New Generation Therapeutic for Diabetes Type 2

Rami A Al-Horani 1,*, Milad Chedid 1
PMCID: PMC10473544  NIHMSID: NIHMS1925816  PMID: 36200219

Abstract

Tirzepatide (mounjaro®) is a derivative of the human glucose-dependent insulinotropic polypeptide (GIP) hormone with a position-20 being modified with 1,20-eicosanedioic acid via a chemical linker. It acts as a glucagon-like peptide-1 (GLP-1) receptor and GIP receptor agonist. It has recently been approved by FDA as an adjunct therapy to exercise and diet to improve glycemic control in patients with type II diabetes mellitus (T2DM). It represents a new transforming paradigm in the management of T2DM. This mini-review will shed light on its different pharmacokinetic and pharmacodynamic aspects.

Keywords: Tirzepatide, T2DM, GLP-1, GIP, Semaglutide, Dulaglutide

1. INTRODUCTION: TYPE 2 DIABETES MELLITUS (T2DM)

T2DM was formerly known as insulin-independent diabetes or adult-onset diabetes. In this type, the pancreas generally produces insulin, occasionally even at higher-than-normal levels. Nevertheless, the body develops resistance to insulin’s effects on various organs, including muscles, adipose tissue, and the liver. As T2DM progresses, the ability of the pancreas to produce insulin decreases. T2DM is generally characterized by late onset. The disease usually starts in people of 30 years and older. Approximately 26% of people older than 65 have T2DM. Nevertheless, T2DM is also becoming common in children and adolescents. People of certain ethnic and racial origins are at elevated risk of developing T2DM, including African Americans, Native Americans, Asian Americans, and Latin and Spanish Americans. T2DM is not an autoimmune disorder, yet there are strong genetic correlations to the susceptibility to this type of DM [1-4].

Obesity is the main risk factor for developing T2DM. < 80% of people with T2DM are obese or overweight. Certain diseases and drugs can contribute to the development of T2DM. Generally, patients with this type of DM may exhibit no symptoms for a number of years before they are diagnosed. When symptoms appear, they can be subtle. Thirst and frequent urination are mild at the beginning but progressively worsen over time. Patients may feel very fatigued and are more likely to have blurred vision. Patients with T2DM produce insulin; they are unlikely to develop ketoacidosis. The blood glucose concentrations rarely become very high at > 1,000 mg/dL, yet high concentrations can occur because of an infection or drug use. Under these conditions, patients may develop a hyperosmolar hyperglycemic state, in which they suffer from severe dehydration, mental confusion, drowsiness, and seizures. Although diet and exercise are fundamental in managing the disease, many oral and injectable antidiabetic drugs are available nowadays [1-4].

2. CURRENT STATE-OF-THE-ART

Several categories of antidiabetics are available for patients with T2DM, including 1) insulin secretagogues (sulfonylureas and meglitinides); 2) drugs that decrease the intestinal absorption of glucose (α-glucosidase inhibitors); 3) drugs that decrease glucose levels by their actions on muscle, liver, and adipose tissue (metformin and thiazolidinediones); 4) drugs that inhibit the renal reabsorption of glucose (sodium-glucose co-transporter inhibitors); 5) drugs that mimic or prolong the effect of incretin (dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists); 6) bromocriptine; 7) colesevelam, and 8) amylin agonist pramlintide [1-4].

2.1. GLP-1 receptor agonists

Exenatide (Bydureon BCise®) was approved by FDA on April 28, 2005, as an adjunct therapy to exercise and diet to improve glycemic control in pediatric patients ≥ 10 years of age and adults with T2DM [5]. Exenatide is an analog of GLP-1, which decreases food intake, slows gastric emptying, increases β-cell growth/replication, increases glucose-dependent insulin secretion, and decreases glucagon secretion. The drug possesses a 53% homology with endogenous GLP-1 and has a Gly residue substitution to decrease degradation by the proteolytic enzyme DPP-IV. It is subcutaneously administered within one hour before dinner and breakfast. It reaches a maximal concentration in about 2 hours with an active duration of up to 10 hours. Exenatide extended release is a once-weekly preparation. Exenatide monotherapy and combination therapy result in hemoglobin A1c reductions of 1.5-1.9% (extended-release) or 0.5-1% (immediate release). Weight loss of 2-3 kg may also occur, contributing to the improvement in glycemic control. Exenatide undergoes glomerular filtration, and the drug is not approved for use in patients with an estimated glomerular filtration rate (GFR) of < 30 mL/min per 1.73 m2. Antibodies against exenatide develop in ~ 6% of patients, which may attenuate glycemic response [6-15].

Lixisenatide (Adlyxin®) was FDA approved on July 28, 2016, as an adjunct therapy to exercise and diet to improve glycemic control in adults with T2DM. Lixisenatide is a selective GLP-1 receptor agonist. Lixisenatide slows gastric emptying, decreases inappropriate glucagon secretion, and increases glucose-dependent insulin secretion. It is a synthetic analog of exendin-4 in which Pro residue was deleted and six Lys residues were added to the C-terminal region. It has a half-life of 3 hours. Its clinical effect is about the same as exenatide , with hemoglobin A1c lowering in the 0.4-0.6% range and the weight loss in the range of 1 to 3 kg. Antibodies to lixisenatide frequently occur (70%) and about 2.4% of patients with the highest antibody titers have reduced glycemic response [16].

Another GLP-1 analog is liraglutide (Saxenda® and Victoza®). It was approved by FDA on January 25, 2010 [17]. Victoza was approved as an adjunct therapy to exercise and diet to improve glycemic control in adults, adolescents, and children ≥ 10 years of age with T2DM. It also reduces the risk of major cardiovascular events of cardiovascular death, non-fatal stroke, and nonfatal myocardial infarction in adults with established cardiovascular disease and T2DM [17]. Saxenda was approved as an adjunct therapy to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index of or ≥ 27 kg/m2 (overweight) or ≥ 30 kg/m2 (obesity) in the presence of at least one weight-related comorbid condition such as dyslipidemia, hypertension, or T2DM, or as well as in pediatric patients ≥12 years of age with body weight > 60 kg [18].

Liraglutide is a long-acting GLP-1 analog. Lys residue in GLP-1 is replaced with Arg at position-34 and a C16-acyl chain is attached to Lys at position-26. As a result of binding to the GLP-1 receptor, liraglutide decreases food intake, slows gastric emptying, increases β-cell growth/replication, increases glucose-dependent insulin secretion, and decreases glucagon secretion. Liraglutide retains affinity for GLP-1 receptors, but the addition of the C16 acyl chain increases the noncovalent binding to albumin, contributing to its extended half-life of 12 hours and duration of action. In clinical trials, liraglutide led to a decrease in hemoglobin A1c of 0.8-1.5% and a weight loss of 0-3.2 kg. In a post-marketing analysis of 9,340 patients with T2DM with known cardiovascular disease, the addition of liraglutide led to a reduced primary composite outcome of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction. Patients taking liraglutide had lower hemoglobin A1c levels, lower systolic blood pressure, weight loss of more than 2 kg, and fewer episodes of severe hypoglycemia [19-29]

Dulaglutide (Trulicity®) was approved by FDA on September 18, 2014, as an adjunct therapy to exercise and diet to improve glycemic control in adults with T2DM and to reduce the risk of major cardiovascular events of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction in adults with T2DM who have multiple cardiovascular risk factors or established cardiovascular disease. It consists of two GLP-1 analog molecules that are covalently linked to an Fc fragment of human IgG4. The GLP-1 moiety has amino acid modifications that prevent degradation promoted by the action of DPP-IV. The half-life of dulaglutide is approximately 5 days. Dulaglutide is an agonist of the human GLP-1 receptor that slows gastric emptying and augments glucose-dependent insulin secretion [30].

Likewise, semaglutide (Ozempic®) was approved by FDA on December 05, 2017, as a subcutaneous adjunct therapy to exercise and diet to improve glycemic control in adults with T2DM and to reduce the risk of major cardiovascular events of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction in adults with T2DM who have multiple cardiovascular risk factors or established cardiovascular disease [31]. Semaglutide (Wegovy®) was approved as an adjunct therapy to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index of or ≥ 27 kg/m2 (overweight) or ≥ 30 kg/m2 (obesity) in the presence of at least one weight-related comorbid condition such as dyslipidemia, hypertension, or T2DM [32]. Simaglutide is a synthetic analog of GLP-1 with a half-life of about 1 week. It has an α-aminoisobutyric acid substitution at position-8, which renders the molecule resistant to DPP-IV degradation. It has a C-18 fatty diacid chain linked to the Lys residue at position-26 which binds the molecule to albumin, and subsequently, accounts for the drug’s long half-life. Semaglutide therapy lowers hemoglobin A1c by 1.5-1.8%. In one of the clinical trials, an increased incidence of diabetic retinopathy was observed in the semaglutide-treated group, which was attributed to the rapid decrease in glucose level upon administering the drug. Semaglutide is co-formulated with sodium N-[8(2-hydroxybenzoyl) amino] caprylate, a gastrointestinal absorption enhancer that allows oral administration. The oral bioavailability is ~ 0.4% to 1% [31, 32].

The most frequent adverse reactions of GLP-1 receptor agonists, particularly at high doses, are nausea (~11-40%), diarrhea (~9-17%), and vomiting (~4-13%). Generally, agonists of GLP-1 receptor may increase the pancreatitis risk. Acute renal injury and renal impairment have been reported in patients taking exenatide. Several GLP-1 agonists were also reported to stimulate thyroidal C-cell tumors in rodents. The drugs are contraindicated in patients with a previous family or medical history of multiple endocrine neoplasia syndrome type 2 or medullary thyroid cancer [5, 16, 17, 31, 32].

3. THE NEW ADDITION: TIRZEPATIDE (MOUNJARO®)

3.1. Chemistry

Tirzepatide is a 39-amino acid peptide analog of GIP. It contains a C-terminal amide, two noncoded amino acids of aminoisobutyric acid at positions-2 and -13, and Lys residue at position-20 that is attached to 1,20-eicosanedioic acid via a linker, a glutamic acid and two (2-(2-aminoethoxy)-ethoxy)-acetic acid units (Fig. 1). Its molecular weight is 4813.53 Da [33]. These structural features resulted in a long half-life. The synthesis of tirzepatide was reported by E. Lilly & Comp. using the standard solid phase peptide synthesis. In this protocol an allyl-oxycarbonyl protecting group on position-20 Lys residue was introduced to permit a series of chemical transformations in which the sidechain amine of that Lys is decorated with a lipid fragment [34]. Large-scale synthesis was also reported [35].

Fig. (1).

Fig. (1).

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The chemical structure of tirzepatide.

3.2. Pharmacology: Pharmacodynamics and Pharmacokinetics

Tirzepatide has a high affinity to both the GLP-1 receptor and GIP receptor. This dual agonism mechanism appears to lead to a greater decrease of hyperglycemia than that achieved by a selective GLP-1 receptor agonist. Tirzepatide is reported to lower postprandial and fasting glucose concentration, reduce body weight, and decrease food intake in patients with T2DM. Tirzepatide decreases glucagon levels and increases 1st and 2nd -phase insulin secretion, both in glucose- dependent fashion. Furthermore, tirzepatide has also been shown to increase adiponectin level, an adipokine important for the regulation of lipid and glucose metabolism, with a maximum increase of 26% from baseline, at the 10 mg dosage, after 26 weeks. The molecule is administered as a weekly SC injection [33].

The pharmacokinetics of the drugs was found to be similar between healthy individuals and patients with T2DM. Steady-state plasma concentrations were obtained after four weeks of once weekly administration. Its exposure increases in a dose-proportional fashion. Following SC administration, the drug’s bioavailability is ~ 80%. The time to maximum plasma concentration is from 8 to 72 hours. Its apparent volume of distribution is ~ 10.3 L. Tirzepatide tightly binds to plasma albumin (99%). The apparent clearance of tirzepatide is 0.061 L/h and its half-life is about 120 hours. Tirzepatide is not detected in feces or urine. The primary routes of its metabolites’ excretion are via feces and urine [33].

3.3. Approval and Use

Tirzepatide was approved for therapeutic use in the US on May 13, 2022, as an adjunct therapy to exercise and diet to improve glycemic control in T2DM adults. The drug is not indicated for patients with T1DM. It was not evaluated for use in individuals with a history of pancreatitis [33].

3.4. Adverse Effects and Contraindication

Preclinical studies as well as phases I and II clinical trials, have indicated that tirzepatide shows similar adverse effects to other GLP-1 receptor agonists. The most frequent adverse effects are GIT symptoms of nausea, diarrhea, and vomiting. Other side effects were dizziness, dyspepsia, abdominal pain, constipation, and hypoglycemia. Patients also reported deceased appetite to a lesser extent. The number of dropout patients also increased as the dosage increased, with 25% discontinuation rate for 15 mg-patients vs 5.1% rate for 5 mg-patients and 11.1% rate for patients taking dulaglutide [36].

The drug is contraindicated in patients with a family or personal history of multiple endocrine neoplasia syndrome types 2 or medullary thyroid cancer. It is also contraindicated in individuals with known critical hypersensitivity to the drug or the excipients in the marketed formulation.

3.5. Warning and Precautions

In a 2-year study at clinically relevant concentrations, tirzepatide led to a treatment duration and dose-dependent increase in the incidence of thyroid C-cell tumors (carcinomas and adenomas) in both sexes of rats. Regarding acute pancreatitis, including necrotizing pancreatitis as well as nonfatal and fatal hemorrhagic pancreatitis, 14 events were confirmed in 13 out of N = 5415 tirzepatide-treated patients (0.23 patients/100 years of exposure) versus 3 events in 3 out of N = 2354 comparator-treated patients (0.11 patients/100 years of exposure) [37]. Furthermore, simultaneous use of tirzepatide with an insulin or insulin secretagogue may raise the hypoglycemia risk, including severe hypoglycemia. Other warnings include hypersensitivity reactions, diabetic retinopathy complications, acute gallbladder disease, severe gastrointestinal disease, and acute kidney injury [33].

3.6. Drug Interactions and Use in Specific Populations

Tirzepatide delays gastric emptying and thus, has the ability to affect the absorption of simultaneously taken oral medications. Additionally, tirzepatide may cause fetal harm based on animal study. Therefore, female patients using oral contraceptives are advised to add a barrier method of contraception or to shift to a nonoral contraceptive method, for 4 weeks after initiation and 4 weeks after each dose increase [33].

CONCLUSION

Tirzepatide is a novel, first-in-class, subcutaneous, and dual-acting treatment for T2DM. FDA recently approved the drug, and it is the first and only approved once-weekly single molecule that activates GIP and GLP-1 receptors in the body. It is indicated as an adjunct therapy to exercise and diet to improve glycemic control in T2DM adults.

FUNDING

RAAH is supported by the National Institute of General Medical Sciences of the National Institute of Health under award number SC3GM131986.

LIST OF ABBREVIATIONS

GFR

Glomerular Filtration Rate

GIP

Glucose-Dependent Insulinotropic Polypeptide

GLP-1

Glucagon-Like Peptide-1

T2DM

Type II Diabetes Mellitus

Footnotes

CONFLICT OF INTEREST

The authors declare no conflict of interest with the work being reported here. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutions.

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