Clinical Significance of Genetic Variations in CYP2D6 Investigated in HF Patients

The authors analyzed a variety of publications discussing the effects of CYP2D6 polymorphism on metoprolol and carvedilol tolerance and efficacy
The authors analyzed a variety of publications discussing the effects of CYP2D6 polymorphism on metoprolol and carvedilol tolerance and efficacy

According to a recently published review, further research is required to determine the clinical significance and effect CYP2D6 polymorphisms have on heart failure (HF) patients requiring therapy with carvedilol or metoprolol.

According to HF guidelines, beta-blockers must be titrated to a specific target dose in order to obtain their morbidity and mortality benefit in HF patients. Of the 3 beta-blockers recommended for use in HF patients, 2 are metabolized by CYP2D6, "a highly polymorphic enzyme of the P450 family." Because of this, these agents are subject to varying therapeutic concentrations and effects. The authors explain, "Metoprolol relies almost exclusively on this enzyme for degradation to inactive metabolites, whereas carvedilol relies on this enzyme only partially for metabolism, and the portion of drug that is metabolized by CYP2D6 becomes active metabolites."

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The authors analyzed a variety of publications discussing the effects of CYP2D6 polymorphism on metoprolol and carvedilol tolerance and efficacy. Unfortunately, their literature analysis yielded varying results, inconsistent data, and a general lack of consensus. Leading the authors to conclude that further research in this area is required prior to making any strong recommendations concerning HF treatment. "The clinical significance of genetic variations in CYP2D6 in heart failure patients requiring treatment with carvedilol and metoprolol remains unclear," they write.

They did note however, that those of European and Asian ancestry may be at a greater risk of intolerance to guideline-directed doses of metoprolol. Additionally, some evidence indicates that HF patients of North African ancestry may have a lower risk of metoprolol intolerance.  

The authors conclude, "Due to the significant prevalence of CYP2D6 enzyme variations among all ethnicities, it may be reasonable to consider switching to carvedilol for patients who are unable to fully titrate metoprolol."

Reference

Ingram A, Valente M. Genetic Variation of Hepatic Enzymes Influence on β-Blocker Dose in Patients With Reduced Ejection Fraction Heart Failure. Journal of Pharmacy Practice. 2018. DOI: 10.1177/0897190018782794.