Tirzepatide

Tirzepatide is a first-in-class glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor co-agonist. It consists of a 39 amino acid linear synthetic peptide whose sequence is based on endogenous GIP, conjugated to a C20 fatty diacid moiety via a hydrophilic linker at the lysine residue at position 20. This modification enables high albumin binding (~99%), which slows absorption and extends half-life to approximately 5 days, supporting once-weekly dosing.

Mechanism of Action

Tirzepatide binds with high affinity to both the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR). Both receptors are G-protein-coupled receptors linked to adenylyl cyclase; ligand binding increases intracellular cAMP, stimulating glucose-dependent insulin secretion from pancreatic beta cells. In vitro, tirzepatide has comparable GIPR binding affinity to native GIP, and approximately five-fold lower GLP-1R affinity than native GLP-1.

Effects mediated through dual receptor agonism include:

• Glucose-dependent insulin secretion: stimulates first- and second-phase insulin release from pancreatic beta cells only when blood glucose is elevated.
• Glucagon suppression: reduces glucagon levels in a glucose-dependent manner, preserving counter-regulatory response to hypoglycemia.
• Delayed gastric emptying: lowers fasting and postprandial glucose concentrations.
• Appetite reduction and decreased food intake: activates anorexigenic pathways, reducing caloric intake and promoting weight loss.
• Improved insulin sensitivity: contributes to metabolic benefit beyond insulin secretion alone.

The exact contribution of GIPR agonism to glycemic and weight outcomes is still under investigation; co-administration of GIP and a GLP-1R agonist demonstrated more pronounced insulin response and glucagon suppression than either alone in clinical studies.

Pharmacokinetics

• Bioavailability: mean absolute bioavailability ~80% after subcutaneous administration.
• Tmax: 8–72 hours after subcutaneous injection.
• Cmax: 108–397 ng/mL over the 1–5 mg dose range.
• Volume of distribution: mean steady-state Vd 9.5–10.3 L.
• Protein binding: 99% bound to plasma albumin (via C20 fatty diacid conjugation).
• Metabolism: proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis; unchanged drug not detected in urine or feces.
• Half-life: approximately 5 days (~120 hours).
• Clearance: mean apparent clearance 0.056–0.061 L/h.
• Excretion: primarily urine and feces as metabolites.
• Steady state: achieved after approximately 4 weeks of once-weekly dosing.

In the SURPASS clinical trial program in type 2 diabetes, tirzepatide demonstrated:

• HbA1c reduction: up to 2.5% from baseline.
• Weight loss: 7–12 kg with active comparators; 15–22% body weight reduction at the highest doses in obesity studies.
• Cardiovascular outcomes: reduced cardiovascular risk factors, lower blood pressure, improved lipid profiles.
• Superior glycemic and weight outcomes compared to semaglutide 1 mg, dulaglutide, and basal insulin in head-to-head trials.

• Type 2 diabetes mellitus (Mounjaro): as an adjunct to diet and exercise to improve glycemic control in adults, as monotherapy or in combination with other antidiabetic medications.
• Chronic weight management (Zepbound): in adults with obesity (BMI ≥30 kg/m²), or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, dyslipidemia), combined with reduced-calorie diet and increased physical activity.
• Moderate obstructive sleep apnea (Zepbound): as an adjunct to diet and exercise in adults with obesity and moderate-to-severe obstructive sleep apnea.

• Hypersensitivity to tirzepatide or any of the excipients.
• Personal or family history of medullary thyroid carcinoma (MTC).
• Multiple endocrine neoplasia syndrome type 2 (MEN 2).
• History of severe gastrointestinal disease.
• Pregnancy and breastfeeding.
• Age under 18 years.

Use with caution: history of pancreatitis, renal impairment, diabetic retinopathy, history of angioedema or anaphylaxis with other GLP-1 receptor agonists.

Very Common (>10%): nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, abdominal pain.

Common (1–10%): injection site reactions, fatigue, hypoglycemia (with insulin or sulfonylureas), increased heart rate, increased lipase and amylase, alopecia, eructation, gastroesophageal reflux disease.

Uncommon (<1%): acute pancreatitis, severe hypersensitivity reactions, acute gallbladder disease.

Most gastrointestinal effects occur during dose escalation and decrease over time.

• Insulin and insulin secretagogues: may increase hypoglycemia risk; consider dose reduction.
• Oral medications: delayed gastric emptying may affect absorption of co-administered oral drugs requiring rapid GI absorption.
• Oral contraceptives: no clinically significant interaction in studies to date.

Do not mix tirzepatide with other medications in the same injection.

Tirzepatide is administered once weekly by subcutaneous injection (abdomen, thigh, or upper arm). It can be taken at any time of day, with or without meals. Do not inject intravenously or intramuscularly.

Dose Escalation

• Weeks 1–4: 2.5 mg once weekly (initiation dose, not therapeutic).
• Week 5 onwards: 5 mg once weekly (minimum maintenance dose).
• May increase in 2.5 mg increments after at least 4 weeks if additional control is needed: 7.5 mg, 10 mg, 12.5 mg, up to a maximum of 15 mg once weekly.

The day of weekly administration may be changed if needed, provided there are at least 3 days between doses.

Missed Dose

• If ≤4 days late: administer as soon as possible.
• If >4 days late: skip the missed dose and resume the regular schedule.

Do not administer two doses within 3 days of each other.

Pancreatitis Risk

Discontinue if pancreatitis is suspected (severe persistent abdominal pain, pain radiating to the back, nausea and vomiting). Do not restart if pancreatitis is confirmed.

Thyroid C-Cell Tumors

In animal studies, tirzepatide caused thyroid C-cell tumors. Counsel patients on symptoms (neck mass, hoarseness, dysphagia, dyspnea). Use is contraindicated in patients with personal or family history of medullary thyroid carcinoma or MEN type 2.

Hypoglycemia

Risk increases when used with insulin or insulin secretagogues. Patients should monitor blood glucose and recognize hypoglycemia symptoms.

Diabetic Retinopathy

Rapid improvement in glucose control may transiently worsen diabetic retinopathy. Monitor patients with a history of retinopathy.

Renal Function and Hydration

Gastrointestinal side effects may lead to dehydration and acute kidney injury. Ensure adequate hydration, especially in patients with renal impairment.

Pregnancy Planning

Discontinue at least 2 months before planned pregnancy due to the long washout period.

Effect on Driving

May cause dizziness or fatigue. Use caution when driving or operating machinery, especially when combined with medications that cause hypoglycemia.

Unopened pens: store in a refrigerator at 2–8°C, in the original carton. Do not freeze. Protect from light.

After first use: store at room temperature (not exceeding 30°C) or refrigerated (2–8°C). Use within 21 days. Keep the cap on when not in use.

Dispose of used pens in a sharps container according to local regulations.

2 years when stored properly. Do not use after the expiry date.

Prescription required.