TIRZEPATIDE |

Lakshay Agarwal^*

^{*PG Resident , Department of Medicine, Lady Hardinge Medical College, New Delhi}

Tirzepatide is a novel medication that is FDA approved for the treatment of type 2 diabetes mellitus. Given its potent weight loss properties, Tirzepatide be used off-label for obesity treatment. It works as a dual GLP-1 agonist and GIP agonist to maximize similar benefits that are seen with GLP-1 medications such as Semaglutide. It is currently implemented as a second-line diabetes medication, similar to GLP-1 medications, and given as a once-a-week subcutaneous injectable. The FDA approved Tirzepatide in May 2022.

Indications

Tirzepatide is FDA-approved for treating type 2 diabetes mellitus. It is important to note that Tirzepatide is not approved for treating type-1 diabetes mellitus and has not been studied in patients with pancreatitis.

The FDA approved Tirzepatide in May 2022. Tirzepatide can also be used off-label for treating obesity. It is currently implemented as a second-line diabetes medication, similar to GLP-1 medications like Semaglutide.

Given its weight loss properties and lack of liver toxicity, it is likely to play an indirect role in the treatment of nonalcoholic fatty liver disease (NAFLD) as well; however, further research is needed before it is approved for NAFLD.

Mechanism of Action

Tirzepatide is a synthetic peptide; and a dual gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. It is composed of 39 amino acids and is an analog of the gastric inhibitory polypeptide. Functionally, it stimulates insulin release from the pancreas and leads to a reduction of hyperglycemia. In addition, Tirzepatide also increases the levels of adiponectin. Its dual agonism ability leads to a more significant reduction of hyperglycemia than GLP-1 agonist agents alone and lowers the user’s appetite.

Pharmacokinetics

Absorption: Tirzepatide has a bioavailability of approximately 80%. The time it takes to reach peak serum levels can range from 8 to 72 hours.

Distribution: The mean apparent steady-state volume of distribution (Vd) of Tirzepatide is approximately 10.3 L. Tirzepatide is highly bound to plasma albumin (99%).

Metabolism: Once injected, the peptide structure undergoes proteolytic cleavage. In addition, the C20 fatty diacid composition undergoes beta-oxidation and amide hydrolysis.

Excretion: Tirzepatide has a half-life of 5 days, allowing once-weekly dosing, and is cleared in urine and feces in the form of metabolites.

Administration

Tirzepatide is administered subcutaneously via an injection. It is not available in oral form at this time. It is available in various dosages: 2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5 mL, 12.5 mg/0.5 mL, 15 mg/0.5 mL. Standard dosing is once weekly, with the usual initiation

Adverse Effects

Below are the adverse drug reactions reported by System Organ Class (SOC).

Gastrointestinal: Decreased appetite is often reported. Nausea and diarrhea may occur in up to 10% of patients, in addition to some infrequent reports of vomiting and acid reflux. Constipation has also been reported in some users.

Cardiovascular: Sinus tachycardia has been reported but may be blunted by concurrent medication use.

Renal: Infrequent cases of acute kidney injury have been reported, likely secondary to dehydration from gastrointestinal losses.

Dermatologic: Hypersensitivity reactions have been infrequently reported at the injection site. The prevalence is not higher than those reported by patients using GLP-1 agonists.

Pancreatitis: GLP-1 medications are a known risk factor for acute pancreatitis. The risk level for Tirzepatide is similar to GLP-1 agonist medications. Patients should be advised to seek care at the local emergency department if they develop severe abdominal pain while on Tirzepatide therapy. Asymptomatic elevation of lipase and amylase may also be seen in some patients.

Hepatobiliary: There have been reports of cholelithiasis and cholecystitis occurring in patients on Tirzepatide therapy.

Endocrine: There is a small risk of hypoglycemia and dose-dependent. This risk is more significant for those on insulin therapy and/or those utilizing sulfonylureas. Patients should be advised on the potential symptoms of hypoglycemia.

Contraindications

Boxed Warning: Data in animal studies has demonstrated the potential of developing medullary thyroid carcinoma. It is unknown whether this would also occur in humans at this time. Given the theoretical risk, Tirzepatide should be avoided in those with a personal or family history of medullary thyroid carcinoma. Patients with a history of MEN 2 (multiple endocrine neoplasia syndrome type-2) should also avoid Tirzepatide.

Patients with other thyroid cancer-related risk factors should be advised of the theoretical risks. Furthermore, patients who experience a hypersensitivity reaction should avoid using Tirzepatide any further. Other relative contraindications also exist, such as gallbladder disease or diabetic retinopathy.

REFERENCES

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Collins L, Costello RA. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jan 13, 2023. Glucagon-like Peptide-1 Receptor Agonists. [PubMed]
Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA. 2022 Feb 08;327(6):534-545. [PMC free article] [PubMed]
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jun 20, 2022. Tirzepatide. [PubMed]
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