What is the role of GLP-1 (Glucagon-Like Peptide-1) vs GIP (Glucose-dependent Insulinotropic Polypeptide) in type 2 diabetes management?

GLP-1 vs GIP in Type 2 Diabetes Management

GLP-1 receptor agonists are superior to GIP-only agents for type 2 diabetes management due to their established cardiovascular protection, superior glycemic control, and weight reduction benefits, while dual GLP-1/GIP receptor agonists like tirzepatide offer even greater efficacy when maximal glycemic control and weight loss are needed. 1

Mechanisms of Action

GLP-1 (Glucagon-Like Peptide-1)

• Released from intestinal L-cells in response to meals 2
• Primary actions:
  • Stimulates glucose-dependent insulin secretion from pancreatic beta cells
  • Suppresses glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production
  • Slows gastric emptying, reducing postprandial glucose excursions
  • Promotes satiety and reduces food intake, leading to weight loss
  • Lowers fasting and postprandial glucose concentrations 2, 3

GIP (Glucose-dependent Insulinotropic Polypeptide)

• Released from intestinal K-cells in response to meals 2
• Primary actions:
  • Stimulates glucose-dependent insulin secretion
  • Does not suppress glucagon secretion as effectively as GLP-1
  • Has less effect on gastric emptying and appetite compared to GLP-1
  • Has reduced effectiveness in patients with type 2 diabetes 1, 2

Clinical Efficacy Comparison

GLP-1 Receptor Agonists

• Reduce all-cause mortality and major adverse cardiovascular events (MACE) compared to usual care (high confidence of evidence) 4
• Reduce stroke (high confidence of evidence) 4
• Reduce serious adverse events and severe hypoglycemia compared to insulin or sulfonylureas 4
• Promote significant weight loss 1, 3
• Have low risk of hypoglycemia when used as monotherapy 3
• Cardiovascular benefits: 13% relative risk reduction in MACE with liraglutide in patients with established cardiovascular disease 1

GIP-only Agents

• Less evidence supporting their use in diabetes management
• Less effective than GLP-1 receptor agonists for glycemic control and weight reduction 1
• Cardiovascular benefits not as well established as with GLP-1 receptor agonists

Dual GLP-1/GIP Receptor Agonists (e.g., Tirzepatide)

• Demonstrate greater HbA1c reductions and weight loss compared to GLP-1 receptor agonists alone
  • Tirzepatide achieves up to 20.9% weight loss at higher doses over 72 weeks 1
  • Provides 5.1% more weight loss than semaglutide 2.4mg weekly 1
• Associated with lower risk of major adverse cardiovascular events compared to semaglutide (hazard ratio 0.54,95% CI 0.38-0.76) 1
• Currently recommended when maximal glycemic control and weight loss are needed 1

Clinical Applications

When to Use GLP-1 Receptor Agonists

• As second-line therapy after metformin for patients requiring improved glycemic control with weight loss benefits 5
• For patients with established atherosclerotic cardiovascular disease or at high cardiovascular risk 1, 6
• For patients not achieving HbA1c targets on basal insulin 7
• For patients with metabolic dysfunction-associated steatotic liver disease (MASLD) 1

When to Consider Dual GLP-1/GIP Receptor Agonists

• When maximal glycemic control and weight loss are needed 1
• For patients with obesity or overweight with at least one weight-related comorbidity 1
• For patients who may benefit from once-weekly dosing instead of daily administration 1

Safety Considerations

Common Adverse Effects

• Gastrointestinal issues (nausea, vomiting, diarrhea, constipation) - more common with short-acting GLP-1 receptor agonists than long-acting ones 1, 3
• Potential risk of pancreatitis 1
• Delayed gastric emptying may increase risk of aspiration during anesthesia 1

Contraindications

• Personal or family history of medullary thyroid carcinoma
• Multiple Endocrine Neoplasia syndrome type 2
• Known hypersensitivity to the medication or its components 1

Practical Considerations

• Short-acting GLP-1 receptor agonists (exenatide BID, lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose but maintain their effect on gastric emptying during long-term treatment 3
• Long-acting GLP-1 receptor agonists (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c 3
• Consider withholding GLP-1 receptor agonists for at least three half-lives before elective surgical procedures due to delayed gastric emptying 1

Key Takeaways

1. GLP-1 receptor agonists are preferred over GIP-only agents due to established cardiovascular and glycemic benefits
2. Dual GLP-1/GIP receptor agonists like tirzepatide offer enhanced efficacy for both glycemic control and weight loss
3. The American Diabetes Association and European Association for the Study of Diabetes recommend GLP-1 receptor agonists over GIP-only agents for diabetes management 1
4. Consider patient-specific factors such as cardiovascular risk, need for weight loss, and renal function when selecting therapy