Pharmacogenetic factors affecting β-blocker metabolism and response

ABSTRACT

Introduction

β-blockers are among the most widely prescribed of all drugs, used for treatment of a large number of cardiovascular diseases. Herein we evaluate literature pertaining to pharmacogenetics of β-blocker therapy, provide insight into the robustness of the genetic associations, and determine the appropriateness for translating these genetic associations into clinical practice.

Areas covered

A literature search was conducted using PubMed to collate evidence on associations between CYP2D6, ADRB1, ADRB2, and GRK5 genetic variation and drug-response outcomes in the presence of β-blocker exposure. Pharmacokinetic, pharmacodynamic, and clinical outcomes studies were included if genotype data and β-blocker exposure were documented.

Expert opinion

Substantial data suggest that specific ADRB1 and GRK5 genotypes are associated with improved β-blocker efficacy and have potential for use to guide therapy decisions in the clinical setting. While the data do not justify ordering a CYP2D6 pharmacogenetic test, if CYP2D6 genotype is available in the electronic health record, there may be clinical utility for understanding dosing of β-blockers.

KEYWORDS:

• Beta-blockers
• CYP2D6
• beta-adrenergic receptors
• pharmacogenomics
• precision medicine
• chronic heart failure
• essential hypertension
• coronary artery disease

Article highlights

• ADRB1, ADRB2, GRK5, and CYP2D6 have been extensively studied for their associations with efficacy, adverse effects and or clinical outcomes resulting from treatment with β-blockers. We summarize this literature and discuss the potential clinical utility of genotype-guided approaches to β-blocker treatment.

• CYP2D6 intermediate and poor metabolizers have significantly higher plasma drug concentrations than others at an equal dose. This may result in greater heart rate response, or effective β-blockade at lower than usual doses, but otherwise CYP2D6 genotype/phenotype has minimal clinical impact, including that it appears to have minimal to no impact on β-blocker–related adverse effects. If CYP2D6 genotype data are already available to the prescribing clinician, they may provide clinical utility given patients who are poor or intermediate metabolizers may achieve the target HR response at a lower than expected dose. Ordering a CYP2D6 test to guide β-blocker therapy is not recommended.

• Numerous studies suggest greater β-blocker efficacy in those with the ADRB1 Arg389Arg genotype, including for cardiovascular outcomes, the latter of which appear to be due to higher risk for cardiovascular events in this genotype group, which is offset with β-blocker therapy.

• Similarly, GRK5 Gln41Gln is associated with increased risk of adverse cardiovascular outcomes, which is offset by treatment with a β-blocker therapy, resulting in this genotype group being more responsive to β-blockers.

• Data generally do not suggest an important role of ADRB2 variability influences responses to β-blockers.

• Current evidence is consistent with the potential clinical use of ADRB1 and GRK5 genotype to guide β-blocker therapy and development of Clinical Pharmacogenetics Implementation Consortium guidelines should be considered.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

C Thomas is supported by an NIH grant (T32 HG008958) and J Johnson’s effort is partially supported by an NIH grant (U01 HG007269).