Introduction
Tirzepatide is a novel once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved by the FDA in May 2022. It represents the first medication in its class that simultaneously activates both GIP and GLP-1 receptors, offering a unique mechanism for managing type 2 diabetes mellitus and, more recently, chronic weight management.
Mechanism of Action
Tirzepatide functions as a dual agonist at both GIP and GLP-1 receptors, which are incretin hormones involved in glucose homeostasis. The drug enhances glucose-dependent insulin secretion, suppresses glucagon secretion, slows gastric emptying, and reduces food intake. The GIP receptor activity appears to augment the effects of GLP-1 receptor activation, potentially explaining its superior efficacy compared to selective GLP-1 receptor agonists.
Indications
- Type 2 Diabetes Mellitus: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- Chronic Weight Management: For chronic weight management in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity
Dosage and Administration
Initial dose: 2.5 mg subcutaneously once weekly Maintenance dose: Increase by 2.5 mg every 4 weeks until reaching the target maintenance dose of 5 mg, 10 mg, or 15 mg once weekly based on clinical response and tolerability Administration:- Administer subcutaneously in the abdomen, thigh, or upper arm
- Can be administered with or without meals
- Rotate injection sites with each administration
- If a dose is missed, administer within 4 days; if more than 4 days have passed, skip the missed dose and administer the next scheduled dose
- Renal impairment: No dosage adjustment necessary for mild to moderate impairment; use with caution in severe impairment
- Hepatic impairment: No dosage adjustment necessary
- Geriatric patients: No dosage adjustment necessary
Pharmacokinetics
Absorption: Peak plasma concentrations reached in 8-72 hours; bioavailability approximately 80% Distribution: Volume of distribution ~10.3 L; >99% plasma protein bound Metabolism: Proteolytic degradation into smaller peptides and amino acids Elimination: Half-life approximately 5 days; primarily eliminated via catabolism with renal and fecal excretion of metabolitesContraindications
- History of serious hypersensitivity reaction to tirzepatide or any component of the formulation
- Personal or family history of medullary thyroid carcinoma
- Patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
Warnings and Precautions
Boxed Warning: Risk of thyroid C-cell tumors- Pancreatitis: Discontinue if pancreatitis is suspected
- Hypoglycemia: Increased risk when used with insulin secretagogues or insulin
- Acute Kidney Injury: Monitor renal function in patients reporting severe gastrointestinal reactions
- Diabetic Retinopathy: Rapid improvement in glucose control may temporarily worsen diabetic retinopathy
- Acute Gallbladder Disease: Has been reported with GLP-1 receptor agonists
Drug Interactions
Significant interactions:- Insulin secretagogues or insulin: Increased risk of hypoglycemia; consider dose reduction of these agents
- Oral medications: May delay gastric emptying and affect absorption of orally administered drugs
- Warfarin: Monitor INR more frequently when initiating or changing tirzepatide dose
Adverse Effects
Most common (≥10%):- Nausea (17-20%)
- Diarrhea (13-17%)
- Vomiting (9-11%)
- Constipation (9-12%)
- Abdominal pain (7-9%)
- Decreased appetite (6-12%)
- Pancreatitis
- Severe hypersensitivity reactions
- Acute kidney injury
- Gallbladder disease
- Hypoglycemia (when used with other glucose-lowering agents)
Monitoring Parameters
- Glycemic control: HbA1c every 3 months until stable, then every 6 months
- Renal function: Serum creatinine at baseline and as clinically indicated
- Weight: Regular monitoring
- Pancreatitis symptoms: Monitor for persistent severe abdominal pain
- Thyroid nodules: Regular neck examination
- Hypoglycemia: Especially when used with other antidiabetic agents
Patient Education
- Administration: Proper injection technique and site rotation
- Gastrointestinal effects: Nausea and diarrhea are common initially but often improve over time
- Hypoglycemia: Recognize signs and symptoms, especially when using with other diabetes medications
- Missed dose: Instructions for handling missed doses
- Storage: Refrigerate unused pens; may be stored at room temperature for up to 21 days
- Pregnancy planning: Discuss with healthcare provider before conception
- Concomitant medications: Inform all providers of tirzepatide use due to potential absorption effects
References
1. FDA Prescribing Information: Mounjaro (tirzepatide) injection. 2022 2. Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515 3. Del Prato S, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4). Lancet. 2021;398(10313):1811-1824 4. Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021;12(1):143-157 5. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216 6. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1)