How does GLP (Glucagon-Like Peptide) work in the treatment of type 2 diabetes?

How GLP-1 (Glucagon-Like Peptide) Works in Type 2 Diabetes Treatment

GLP-1 receptor agonists work through multiple mechanisms including glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and increased satiety, making them highly effective for both glycemic control and weight management in type 2 diabetes.

Mechanism of Action

GLP-1 receptor agonists function through several complementary pathways:

• Pancreatic effects:

  • Stimulate glucose-dependent insulin secretion from pancreatic β-cells 1
  • Inhibit glucagon secretion from pancreatic α-cells (only when blood glucose is normal or elevated) 2
  • Increase insulin biosynthesis, improving β-cell function 3

• Gastrointestinal effects:

  • Delay gastric emptying, particularly with short-acting GLP-1 receptor agonists 4
  • Reduce gastrointestinal motility and secretions 1

• Central nervous system effects:

  • Increase satiety and reduce appetite via action on the hypothalamus 1, 3
  • Promote weight loss independent of nausea effects 4

Clinical Benefits in Type 2 Diabetes

GLP-1 receptor agonists provide multiple benefits:

• Glycemic control:

  • Reduce HbA1c by approximately 0.8-2.0% depending on the specific agent 4, 5
  • Provide greater HbA1c reduction than DPP-4 inhibitors, sulfonylureas, and some other oral agents 4

• Weight management:

  • Produce substantial weight loss (3-10% of body weight) 1, 4
  • Weight loss effects persist during long-term treatment 4

• Cardiovascular benefits:

  • Reduce major adverse cardiovascular events (MACE) in patients with established cardiovascular disease 6, 2
  • Liraglutide demonstrated 13% relative risk reduction in cardiovascular death, non-fatal MI, or stroke 6
  • Semaglutide showed 26% relative risk reduction in similar outcomes 6

• Low hypoglycemia risk:

  • Insulin stimulation and glucagon suppression are glucose-dependent, minimizing hypoglycemia risk when used as monotherapy 1, 2

Types of GLP-1 Receptor Agonists

GLP-1 receptor agonists are classified based on their duration of action:

• Short-acting agents (exenatide BID, lixisenatide):

  • Administered once or twice daily
  • More pronounced effect on postprandial glucose via stronger gastric emptying delay
  • Less effect on fasting glucose 4

• Long-acting agents (liraglutide, semaglutide, dulaglutide, exenatide once-weekly, albiglutide):

  • Administered once daily or once weekly
  • More profound effects on fasting glucose and overall HbA1c
  • Greater weight loss effects, particularly with semaglutide 4
  • Some tachyphylaxis of gastric emptying effects over time 4

Place in Treatment Algorithm

According to current guidelines:

• GLP-1 receptor agonists are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment 6, 7
• They can be effectively combined with basal insulin for enhanced glycemic control 1
• Particularly beneficial in patients with established atherosclerotic cardiovascular disease 6, 2
• Preferred in patients where weight loss is a priority 1

Common Adverse Effects

• Gastrointestinal effects:

  • Nausea, vomiting, and diarrhea are most common 6, 2
  • Usually transient and diminish over time
  • Less common with long-acting formulations and with slow dose titration 4

• Other considerations:

  • Low risk of hypoglycemia when used as monotherapy 2
  • Caution in patients with history of pancreatitis 2
  • Injection site reactions may occur 8

Clinical Pearls

• Start with lower doses and titrate gradually to minimize gastrointestinal side effects 1
• Long-acting GLP-1 receptor agonists generally provide better adherence due to less frequent dosing 4
• The glucose-lowering effect is immediate but weight loss may take several weeks to become apparent 4
• Effects on β-cell function do not persist after discontinuation of treatment 5
• Consider perioperative risks due to delayed gastric emptying, which may increase aspiration risk 6

GLP-1 receptor agonists represent a significant advancement in type 2 diabetes management, offering benefits beyond glycemic control including cardiovascular protection and weight reduction, with a favorable safety profile when properly prescribed.