Generic Name

Tirzepatide

Mechanism

• Dual GIP/GLP‑1 receptor agonist
• Mimics endogenous glucose‑dependent insulinotropic polypeptide (GIP) and glucagon‑like peptide‑1 (GLP‑1).
• Enhances insulin secretion and suppresses glucagon in a glucose‑dependent manner.
• Delays gastric emptying via GLP‑1 receptor activity, improving satiety.
• Promotes β‑cell proliferation and decreases lipolysis, contributing to weight loss.

Pharmacokinetics

• Route: Subcutaneous injection; 2 mL volume.
• Absorption: Peak plasma concentration (Cmax) ~ 4 days post‑dose.
• Half‑life: 5–9 days (steady state ~ 28 days with weekly dosing).
• Protein binding: ~ 97 % to serum albumin.
• Metabolism: Proteolytic cleavage via intestinal peptidases; minimal hepatic metabolism.
• Elimination: Primarily renal (urine), < 1 % excreted unchanged; no active metabolites.
• Food effect: Non‑significant; can be administered with or without food.

Indications

• Type 2 Diabetes Mellitus (HbA1c > 8 %)
• Adjunct to diet, exercise, and other antidiabetic agents.
• Obesity (BMI ≥ 30 kg/m²) or overweight (BMI 25–29.9 kg/m²)
• For weight reduction ≥ 5 % over 68 weeks, adjunct to lifestyle modifications.
• Potential Off‑Label: Non‑diabetic individuals seeking substantial weight loss—under close monitoring.

Contraindications

• Known hypersensitivity to tirzepatide or excipients (PEG‑prodrug backbone).
• Severe renal or hepatic impairment: dose adjustment not established.
• History of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia type 2 (MEN 2):
• Warning: Animal studies show increased C‑cell tumor risk.
• Active diabetic retinopathy: May accelerate progression.
• Suspected pancreatitis or gallbladder disease: Use with caution; monitor abdominal pain and serum amylase/lipase.
• Pregnancy/Breastfeeding: Pregnancy category N; not recommended.

Dosing

• Initiation: 5 mg SC once weekly (every Sunday).
• Titration (weekly increments):
• 5 mg → 10 mg → 15 mg.
• Escalation after 4 weeks at each dose if HbA1c/weight goals unmet.
• Maximum: 15 mg weekly; 10 mg or 7.5 mg weekly for patients on insulin or metformin if weight goal  24 h later, skip and resume next scheduled dose.

Adverse Effects

• Diabetic Hypoglycemia: Low incidence when used alone; ↑ risk with insulin or sulfonylureas.
• Pancreatitis: Monitor for persistent abdominal pain; obtain serum amylase/lipase if symptomatic.
• Gallbladder Disease: Report gallstone or cholecystitis symptoms.

Monitoring

• Baseline: HbA1c, fasting plasma glucose, weight, BP, serum lipids, liver enzymes, renal profile, amylase/lipase, thyroid‑stimulating hormone, and ophthalmologic exam for diabetic retinopathy.
• Follow‑up:
• HbA1c every 12 weeks; weight at each visit.
• Lipid profile, liver enzymes, and renal function every 3–6 months.
• Serum amylase/lipase if pancreatitis suspected.
• Monitor for nascent visual changes in patients with pre‑existing retinopathy.

Clinical Pearls

• Weight‑loss “driver”: The dual agonist profile yields greater weight reduction than GLP‑1‑only analogues; ideal for patients needing > 5 % loss.
• Titration patience: It may take 4–6 weeks at each dose before evaluating efficacy; premature dose escalation can under‑utilize benefit.
• Nausea as tolerance indicator: Mild GI upset often resolves; use anti‑emetics only if severe—this may mask impending pancreatitis.
• Insulin combo: When combined with basal insulin, switch basal type‑1 to Gla‑70/300 to reduce hypoglycemia risk.
• No drug interaction: Tirzepatide has minimal CYP interaction; no dose adjustments needed for most concurrent medicines.
• Lifestyle synergy: Maximum benefit with caloric restriction and structured exercise; consider behavioral support for adherence.

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