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GLP-1 Receptor Agonists (GLP-1RAs)

Summary

GLP-1 receptor agonists (GLP-1RAs) are therapeutic agents that mimic the action of glucagon-like peptide 1 (GLP-1), a hormone involved in insulin secretion and satiety. This drug class, which includes semaglutide and the dual GLP-1/GIP agonist tirzepatide, has become a cornerstone in obesity and type 2 diabetes management. Pharmacogenetic research by the Auton Lab has identified genetic variations in GLP1R and GIPR that predict individual responses to these therapies.

Clinical Indications and Efficacy

  • Obesity and Overweight: Used for long-term weight management. Tirzepatide generally demonstrates greater weight loss efficacy than semaglutide (median BMI loss of 4.75 vs 3.71 $\text{kg/m}^2$, $P = 9.7 \times 10^{-29}$ as of 2026-04-08).
  • Type 2 Diabetes (T2D): Originally developed to improve glycemic control by promoting glucose-dependent insulin secretion.

Mechanism of Action

  • Semaglutide: A selective GLP1R agonist that enhances insulin secretion, suppresses glucagon release, delays gastric emptying, and acts on hypothalamic pathways to reduce appetite.
  • Tirzepatide: A dual agonist of both the GLP1R and GIPR receptors. GIP receptor activation acts synergistically with GLP-1 signaling in the brain, enhancing efficacy and mitigating gastrointestinal side effects.

Pharmacogenetics and Side Effects

Inter-individual variability in response and tolerability is partly determined by genetic variation: - Efficacy: Associated with the GLP1R variant rs10305420. - Gastrointestinal Side Effects: Moderate-to-severe nausea and vomiting are common, affecting up to 25.1% and 8.4% of users, respectively (as of 2026-04-08). Risk of vomiting is modulated by variants in GLP1R and GIPR (specifically rs1800437 in tirzepatide users).

Citations