CYP2D6 Metabolizer Status and Mortality in Metoprolol Users

CYP2D6

CYP2D6 metabolizer status driving metoprolol exposure and associated with risk of death

Pharmacogenomic associations are extensively documented on pharmacokinetic and pharmacodynamic endpoints, far less on survival. The authors used the Montreal Heart Institute Hospital Cohort, with single random plasma samples from 996 patients receiving metoprolol tartrate, quantification by liquid chromatography-tandem mass spectrometry, and CYP2D6 metabolizer status assigned by standardised classifications. Over a median follow-up of 101.4 months, 24.3% of patients (n = 242) had died. Higher metabolizer status was associated with a lower risk of death in Cox models adjusted for age, sex, cardiovascular history, concomitant medications and CYP2D6 inhibitors (HR = 0.82; 95% CI 0.67-0.99; p = 0.04). Metoprolol concentrations were no longer associated with mortality after adjustment for confounders.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The value of this work is to move the CYP2D6-metoprolol pair from pharmacokinetics towards a hard endpoint, all-cause mortality, which almost every claimed pharmacogenomic association lacks. Caution is warranted: the upper confidence bound touches 0.99 with p = 0.04, in a single-centre hospital cohort where the indication for metoprolol is not homogeneous, and the direction of effect, better survival among faster metabolizers, deserves testing against residual confounding by underlying cardiovascular status. This is a signal to replicate in large cohorts rather than an argument for genotyping before a beta-blocker.

Analysis by Dr Thibaut Benquey