All peptide guides
Weight Loss

Tirzepatide

Dual GIP/GLP-1 Receptor Agonist - Clinical Guide

Clinical Disclaimer: This guide is for educational purposes only and does not constitute medical advice. Prescribers should exercise independent clinical judgment and verify all information before making treatment decisions.

What is Tirzepatide?

Tirzepatide is a novel dual-action peptide that activates both GIP and GLP-1 receptors, representing a significant advancement in metabolic therapeutics. It is FDA-approved as Mounjaro (for type 2 diabetes) and Zepbound (for chronic weight management).

Structure: 39-amino acid synthetic peptide with modifications for extended half-life

Half-life: Approximately 5 days, allowing once-weekly dosing

Mechanism of Action

Dual Incretin Receptor Activation

Unlike single-target GLP-1 agonists, tirzepatide activates both incretin pathways:

GIP Receptor Effects:

  • Enhances insulin secretion in a glucose-dependent manner
  • Promotes beta-cell function and survival
  • May enhance fat oxidation and energy expenditure
  • Contributes to appetite regulation

GLP-1 Receptor Effects:

  • Stimulates glucose-dependent insulin release
  • Suppresses glucagon secretion
  • Slows gastric emptying
  • Reduces appetite through central mechanisms

Metabolic Benefits

  • Superior glycemic control compared to GLP-1 mono-agonists
  • Enhanced weight loss through complementary mechanisms
  • Improved lipid profiles
  • Potential cardiovascular benefits (under investigation)

Central Appetite Regulation

  • Acts on hypothalamic appetite centers
  • Reduces food intake and cravings
  • Promotes satiety signaling
  • May affect food reward pathways

Clinical Applications

FDA-Approved Indications

Type 2 Diabetes (Mounjaro):

  • Adjunct to diet and exercise for glycemic control
  • Demonstrated superior HbA1c reduction vs. comparators
  • Cardiovascular outcomes trial ongoing (SURPASS-CVOT)

Chronic Weight Management (Zepbound):

  • BMI ≥30 kg/m² (obesity)
  • BMI ≥27 kg/m² with weight-related comorbidity
  • Demonstrated up to 20%+ weight loss in trials

Off-Label Considerations

  • Metabolic syndrome
  • NAFLD/NASH (under investigation)
  • Polycystic ovary syndrome (PCOS)

Dosing Protocols

FDA-Approved Titration Schedule

Starting Dose:

  • 2.5 mg subcutaneously once weekly for 4 weeks

Titration:

  • Week 5: Increase to 5 mg weekly
  • May increase by 2.5 mg increments every 4 weeks
  • Available doses: 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg

Maintenance:

  • Minimum effective dose: 5 mg weekly
  • Maximum dose: 15 mg weekly
  • Target dose based on glycemic/weight goals and tolerability

Administration

  • Subcutaneous injection (abdomen, thigh, or upper arm)
  • Same day each week; can adjust day if needed
  • With or without food
  • Rotate injection sites

Patient Selection Criteria

Ideal Candidates

  • BMI ≥27 with comorbidities or BMI ≥30
  • Type 2 diabetes inadequately controlled on current therapy
  • Motivated for comprehensive lifestyle modification
  • No contraindications to GLP-1/GIP therapy
  • Previous insufficient response to GLP-1 mono-agonists

Contraindications

Absolute:

  • Personal or family history of medullary thyroid carcinoma (MTC)
  • Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
  • Known hypersensitivity to tirzepatide

Relative:

  • History of pancreatitis
  • Severe gastroparesis
  • End-stage renal disease
  • Pregnancy or planned pregnancy
  • Active gallbladder disease

Safety Profile

Common Adverse Effects (≥5%)

  • Nausea (most common, typically decreases over time)
  • Diarrhea
  • Vomiting
  • Constipation
  • Abdominal pain
  • Dyspepsia
  • Injection site reactions
  • Decreased appetite

Serious Adverse Effects (Rare)

  • Pancreatitis (discontinue if suspected)
  • Gallbladder disease/cholecystitis
  • Hypoglycemia (primarily with sulfonylureas/insulin)
  • Acute kidney injury (usually dehydration-related)
  • Hypersensitivity reactions/anaphylaxis
  • Thyroid C-cell tumors (boxed warning based on rodent studies)

GI Management Strategies

  • Slow titration schedule
  • Smaller, more frequent meals
  • Avoid high-fat foods initially
  • Stay well-hydrated
  • Consider anti-emetics if needed

Monitoring Parameters

Baseline Assessment

  • HbA1c, fasting glucose
  • Complete metabolic panel including renal function
  • Lipid panel
  • Thyroid examination and history
  • Weight, BMI, waist circumference
  • Blood pressure
  • Pregnancy test (reproductive-age females)

Ongoing Monitoring

Every 4 weeks during titration:

  • Weight and tolerability assessment
  • GI symptom review
  • Hypoglycemia assessment

Every 3-6 months at maintenance:

  • HbA1c (diabetics)
  • Weight and BMI
  • Renal function
  • Lipid panel
  • Blood pressure
  • Assessment for GI and other adverse effects

Drug Interactions

Clinical Significance

Insulin and Sulfonylureas:

  • Increased hypoglycemia risk
  • Reduce sulfonylurea dose by 50% when starting tirzepatide
  • Consider insulin dose reduction

Oral Medications:

  • Delayed gastric emptying may affect absorption
  • Take oral contraceptives at least 1 hour before tirzepatide or switch to non-oral methods
  • Monitor narrow therapeutic index drugs

Warfarin:

  • Monitor INR more frequently when starting or adjusting dose

Compounding Considerations

Quality Requirements

  • Certificate of Analysis (identity, purity, potency)
  • Sterility and endotoxin testing
  • Proper cold chain maintenance
  • Appropriate beyond-use dating

Storage

  • Refrigerate at 2-8°C (36-46°F)
  • May be stored at room temperature for up to 21 days (if needed)
  • Protect from light
  • Do not freeze

Regulatory Note

Compounded tirzepatide is NOT FDA-approved. Prescribers should inform patients of this distinction and document informed consent.

Regulatory Status

  • FDA-approved as Mounjaro (type 2 diabetes, 2022)
  • FDA-approved as Zepbound (weight management, 2023)
  • Available through compounding pharmacies
  • Patent-protected until 2036

Clinical Pearls

  1. Expect superior efficacy: Tirzepatide shows greater weight loss and HbA1c reduction than GLP-1 mono-agonists in head-to-head trials
  2. GI effects are frontloaded: Nausea typically peaks early and decreases; slower titration helps
  3. Hydration is critical: Emphasize fluid intake to prevent dehydration and AKI
  4. Adjust diabetes medications: Reduce sulfonylureas 50%, monitor insulin needs closely
  5. Set realistic timelines: Maximum efficacy typically seen at 40-72 weeks
  6. Consider switching from GLP-1s: Patients who plateau on semaglutide may respond to tirzepatide's dual mechanism

References

  1. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216.
  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. Rosenstock J, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1). Lancet. 2021;398(10295):143-155.
  4. FDA Prescribing Information for Mounjaro and Zepbound.