Metoprolol Therapy and Genotype

Metoprolol is a beta-blocker indicated for the treatment of various cardiovascular diseases, including hypertension, arrhythmias, angina, myocardial infarction, and heart failure (HF). Metoprolol selectively blocks beta-adrenoreceptors, which are expressed predominantly in cardiac tissue. The primary therapeutic effect resulting from the blockade of these receptors is a reduction in heart rate and a decrease in the force of heart contractions. Metoprolol is metabolized extensively by the hepatic CYP2D6 enzyme. Approximately 8% of Caucasians and 2% of most other populations have absent CYP2D6 activity and are known as “CYP2D6 poor metabolizers (PM).” In addition, several drugs inhibit CYP2D6 activity, such as bupropion, quinidine, fluoxetine, paroxetine, and propafenone. The FDA-approved drug label for metoprolol states that CYP2D6 PM and normal metabolizers (NM) who concomitantly take drugs that inhibit CYP2D6 will have increased metoprolol blood levels, decreasing metoprolol’s cardioselectivity; co-medication with CYP2D6 inhibitors warrants close monitoring (1). (Table 1) Beta-blockers, such as metoprolol, have been demonstrated in several large clinical trials to be safe and effective for the treatment of individuals with cardiovascular disease. As a mainstay of therapy associated with improvements in quality of life, hospitalization rates, and survival (2, 3), clinical care pathways that might lead to the underutilization of beta-blockers require scrutiny. It is common clinical practice to adjust the dose of metoprolol according to individual heart rate until either the target or maximum tolerated dose is reached. The FDA does not specifically comment on the role of genetic testing for initiating therapy. The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that CYP2D6 PM should initiate metoprolol therapy at the lowest recommended starting dose, and titration should be performed with care and close monitoring for bradycardia. (Table 2) Standard dosing and care are recommended for intermediate metabolizers (IM) and NM of CYP2D6, but no recommendation is made for ultrarapid metabolizers (UM) given the limited data on this phenotype and beta-blocker response. (4) The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association (KNMP) has also published metoprolol dosing recommendations based on genotype. For individuals who have a gene variation that reduces the conversion of metoprolol to inactive metabolites (namely, the IM and PM phenotype), DPWG states that the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia. For CYP2D6 PM or IM, if a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia, DPWG recommends increasing the dose of metoprolol in smaller steps, prescribing no more than 25% (PM) or 50% (IM) of the standard dose, or both. For CYP2D6 UM, DPWG indicates that clinical response is hardly decreased at a dose of 200 mg/day. However, if efficacy is insufficient at this maximum dose, the DPWG recommends increasing the dose based on effectiveness and side effects up to a maximum of 2.5 times the normal dose, or selecting an alternative. (Table 3) (5).