Zeptide

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
  As an adjunct to diet and exercise to improve glycemic control in adults with T2DM.
• Chronic Weight Management (Obesity or Overweight):
  In adults with a body mass index (BMI) ≥30 kg/m² (obesity) or ≥27 kg/m² (overweight) with at least one weight-related comorbidity (e.g., hypertension, dyslipidemia, or T2DM), as an adjunct to reduced-calorie diet and increased physical activity.

Important Off-label or Investigational Uses:

• Non-alcoholic Steatohepatitis (NASH):
  Being studied for potential benefit in improving liver histology in patients with NASH.
• Cardiovascular Risk Reduction:
  Investigated for reducing major adverse cardiovascular events (MACE) in patients with type 2 diabetes and established cardiovascular disease or risk factors.

Route: Subcutaneous injection (abdomen, thigh, or upper arm)
Frequency: Once weekly, at the same time each week, with or without meals.

Adults with Type 2 Diabetes or Obesity:

• Starting Dose: 2.5 mg once weekly for 4 weeks (for tolerability)
• Titration: Increase in 2.5 mg increments every 4 weeks, as tolerated
• Maintenance Dose Range: 5 mg to 15 mg once weekly
• Maximum Dose: 15 mg once weekly

Elderly:
No dose adjustment required based on age alone; monitor renal function.

Pediatrics:
Not approved for pediatric use.

Renal Impairment:

• Mild to Moderate: No dosage adjustment needed.
• Severe or ESRD: Use with caution; limited data available.

Hepatic Impairment:

• No clinically relevant difference in pharmacokinetics; no dose adjustment required.

Missed Dose:
Administer within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip and resume at the next scheduled dose.

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. It binds to and activates both GIP and GLP-1 receptors, enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, slowing gastric emptying, and promoting satiety. These actions result in improved glycemic control and significant reductions in body weight. The dual agonism mimics endogenous incretin hormones, improving both postprandial and fasting glucose regulation while also reducing appetite and food intake.

• Absorption:
  Slowly absorbed after subcutaneous injection; peak plasma concentrations occur in ~8–72 hours.
• Bioavailability:
  High subcutaneous bioavailability (not significantly affected by injection site).
• Distribution:
  Volume of distribution: ~10.3 L. Highly protein-bound.
• Metabolism:
  Metabolized via proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty acid moiety. Not reliant on CYP450 enzymes.
• Elimination:
  Primarily excreted unchanged in urine and feces.
  Elimination half-life: ~5 days (allows once-weekly dosing).
• Steady-State:
  Achieved in 4–5 weeks.

• Pregnancy:
  Tirzepatide should not be used during pregnancy. Discontinue at least 1 month prior to conception. Adverse fetal outcomes have been observed in animal studies.
• Lactation:
  Unknown if tirzepatide is excreted in human breast milk. Because of the potential for hypoglycemia or gastrointestinal effects in breastfed infants, a risk-benefit decision should be made. Use with caution.
• Contraception:
  Women of reproductive potential should use effective contraception during treatment and for 1 month after the last dose.

• Primary Class: Dual Incretin Receptor Agonist
• Subclass: GIP and GLP-1 receptor agonist (first-in-class)

• Known hypersensitivity to tirzepatide or any of its components
• Personal or family history of medullary thyroid carcinoma (MTC)
• Patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Severe gastrointestinal disease (e.g., gastroparesis)

• Thyroid C-cell Tumors:
  Black box warning: Risk of thyroid C-cell tumors observed in rodents. Human relevance unknown.
• Pancreatitis:
  Risk of acute pancreatitis; discontinue if suspected.
• Gastrointestinal Effects:
  May cause severe nausea, vomiting, and diarrhea, particularly during dose escalation.
• Hypoglycemia Risk:
  Increased when used with insulin or sulfonylureas; dose adjustment of these agents may be necessary.
• Acute Kidney Injury:
  Monitor renal function in patients with dehydration, nausea, or vomiting.
• Retinopathy Complications:
  Caution in patients with diabetic retinopathy due to rapid glucose improvement.
• Immunogenicity:
  Potential for development of anti-drug antibodies.

Common (≥5%)

• Gastrointestinal: Nausea, vomiting, diarrhea, constipation, decreased appetite, dyspepsia
• Metabolic: Hypoglycemia (when combined with insulin/sulfonylurea)
• General: Fatigue, injection site reactions

Less Common

• Cardiovascular: Increased heart rate, orthostatic hypotension
• Renal: Dehydration-associated acute kidney injury
• Endocrine: Potential thyroid neoplasia

Serious or Rare

• Pancreatitis
• Gallbladder disease (e.g., cholelithiasis, cholecystitis)
• Anaphylaxis and angioedema (rare hypersensitivity)

• Insulin or Sulfonylureas:
  Increased risk of hypoglycemia; dose reduction may be necessary.
• Oral Medications:
  Delayed gastric emptying may impact absorption; monitor drugs with narrow therapeutic index.
• No CYP450 involvement:
  Minimal drug-drug interactions via hepatic metabolism.
• Alcohol:
  May enhance the hypoglycemic effect; use caution.

• FDA Approval for Weight Management (2024):
  Tirzepatide received expanded indication for chronic weight management in obese/overweight adults.
• Ongoing Cardiovascular Outcomes Trials (e.g., SURPASS-CVOT):
  Interim results suggest reduction in MACE; full data expected soon.
• Guidelines Integration (ADA 2024, AACE):
  Tirzepatide now recommended as first-line therapy in obese T2DM patients or those with high cardiovascular risk.

• Unopened Pens:
• Store refrigerated at 2°C to 8°C
• Do not freeze
• Protect from light
• In-Use Pens:
• May be stored at room temperature up to 30°C for up to 21 days
• Do not refrigerate after first use
• Keep pen cap on when not in use
• Handling:
• Do not shake
• Inspect visually for particulate matter or discoloration before use