Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy

Clin Pharmacol Ther. 2024 Oct;116(4):939-947. doi: 10.1002/cpt.3351. Epub 2024 Jul 1.

Abstract

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta-blocker exposure and response. We searched and summarized the strength of the evidence linking beta-blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta-blockers or for any beta-blocker and the other five genes evaluated (updates at www.cpicpgx.org).

Publication types

  • Practice Guideline
  • Systematic Review

MeSH terms

  • Adrenergic beta-Antagonists* / pharmacokinetics
  • Adrenergic beta-Antagonists* / therapeutic use
  • Cytochrome P-450 CYP2D6* / genetics
  • Cytochrome P-450 CYP2D6* / metabolism
  • G-Protein-Coupled Receptor Kinase 5* / genetics
  • Genotype*
  • Humans
  • Metoprolol / pharmacokinetics
  • Pharmacogenetics* / methods
  • Pharmacogenetics* / standards
  • Pharmacogenomic Variants
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, beta-1* / genetics
  • Receptors, Adrenergic, beta-2* / genetics

Substances

  • ADRA2C protein, human
  • ADRB1 protein, human
  • ADRB2 protein, human
  • Adrenergic beta-Antagonists
  • Cytochrome P-450 CYP2D6
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human
  • Metoprolol
  • Receptors, Adrenergic, alpha-2
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2