Why the study?
Genetic variability in pharmacokinetic and pharmacodynamic genes has been studied regarding beta-blocker exposure and response, prompting an evaluation of evidence to provide therapeutic recommendations.
Does CYP2D6 or pharmacodynamic gene variation alter beta-blocker exposure and response enough to warrant genotype-guided prescribing in cardiovascular disease?
Systematic Review
Does CYP2D6 or pharmacodynamic gene variation alter beta-blocker exposure and response enough to warrant genotype-guided prescribing in cardiovascular disease?
This CPIC guideline provides actionable recommendations to initiate metoprolol with the lowest recommended starting dose and monitor for bradycardia in known CYP2D6 poor metabolizers to avoid supratherapeutic exposure.
Prompts lowest-dose metoprolol initiation with bradycardia monitoring in known CYP2D6 poor metabolizers; confirms high-evidence associations and supports CPIC guidance.
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).
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Duarte et al. (2024) conducted a systematic review in Patients receiving or considered for beta-blocker therapy (e.g., for heart failure, myocardial infarction, cardiac arrhythmias, hypertension). CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 genotypes vs. Normal metabolizers/wild-type genotypes was evaluated. CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers, prompting CPIC genotype-guided dosing recommendations.
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