What is tirzepatide (a dual Glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) receptor agonist)?

Tirzepatide: A Dual GIP/GLP-1 Receptor Agonist

Tirzepatide is a first-in-class dual receptor agonist that acts on both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, providing superior glycemic control and weight reduction compared to single-target GLP-1 receptor agonists. 1

Mechanism of Action

Tirzepatide works through a unique dual-hormone mechanism:

• GLP-1 Receptor Activity: Similar to other GLP-1 receptor agonists, tirzepatide:

  • Stimulates glucose-dependent insulin secretion from pancreatic β-cells
  • Inhibits glucagon secretion in hyperglycemic states
  • Delays gastric emptying
  • Promotes satiety through central nervous system pathways 1, 2

• GIP Receptor Activity: Additionally, tirzepatide activates GIP receptors which:

  • Enhances insulin secretion in response to rising glucose levels
  • Augments glucagon secretion during euglycemia/hypoglycemia (reducing hypoglycemia risk)
  • Inhibits glucagon secretion during hyperglycemia 1, 3

Notably, tirzepatide's affinity for the GIP receptor is higher than for the GLP-1 receptor, with its GLP-1 receptor affinity approximately five times less than endogenous GLP-1. 1

Pharmacokinetics

• Administration: Subcutaneous injection once weekly 1, 4
• Half-life: Approximately 5 days 5
• Molecular structure: Acylated synthetic peptide with a C20 fatty-diacid portion that binds to albumin, extending its duration of action 4, 5
• Metabolism: Modified to prevent rapid inactivation by dipeptidyl peptidase-4 (DPP-4) 1

Clinical Efficacy

Glycemic Control

• Produces unprecedented HbA1c reductions of 1.24-2.58% in type 2 diabetes 3
• 23-62.4% of patients achieve normoglycemia (HbA1c <5.7%) 3
• Superior glycemic control compared to selective GLP-1 receptor agonists like semaglutide 3, 6

Weight Management

• Obesity treatment: FDA-approved for chronic weight management in November 2023 1

• Weight loss efficacy:

  • 15% mean weight loss at 72 weeks with 5 mg dose
  • 19.5% with 10 mg dose
  • 20.9% with 15 mg dose (compared to 3.1% with placebo) 1
  • 20.7-68.4% of patients lose >10% of baseline body weight 3

• Comparative efficacy: 15 mg weekly tirzepatide produces greater weight loss than:

  • Semaglutide 2.4 mg weekly (difference: 5.1%)
  • Liraglutide 3 mg daily (difference: 13.0%) 1

Cardiovascular Benefits

• Improves cardiovascular risk factors 3, 6
• Meta-analysis of clinical trials shows favorable cardiovascular safety profile 3
• Ongoing SURPASS-CVOT trial investigating long-term cardiovascular outcomes 6

Approved Indications

• Type 2 diabetes management 3, 4
• Chronic weight management in adults with obesity or overweight with weight-related comorbidities 1, 7

Dosing

• Available in 5 mg, 10 mg, and 15 mg doses for weekly subcutaneous injection 7, 6
• Typically initiated at lower doses and titrated upward to minimize gastrointestinal side effects 1

Adverse Effects

Similar to other GLP-1 receptor agonists, with gastrointestinal effects being most common:

• Nausea and vomiting
• Dyspepsia
• Diarrhea
• Constipation
• Gastrointestinal reflux 1

Clinical Considerations and Cautions

• Avoid in gastroparesis due to effects on gastric emptying 1
• Start at low dose and titrate slowly to minimize gastrointestinal side effects 1
• Long-term therapy required: Weight regain occurs when therapy is discontinued 1
• Cost considerations: Higher cost compared to some other anti-obesity medications 6
• Monitoring needed: For cardiac arrhythmia/tachycardia in susceptible patients 1

Tirzepatide represents a significant advancement in metabolic medicine, offering unprecedented efficacy in both glycemic control and weight management through its innovative dual-receptor mechanism of action.