Cytochrome P450 2D6 Metabolizer Phenotype Is Associated With Metoprolol Pharmacodynamics But Not With Metoprolol Discontinuation: A Retrospective Cohort Study in the All of Us Research Program.

CYP2D6

CYP2D6-mediated metoprolol metabolism, diplotypes called by Cyrius and converted to the CPIC/DPWG activity score

This retrospective All of Us cohort linked whole-genome sequencing to electronic health records in 44,485 metoprolol users with a called CYP2D6 diplotype and at least two dispensings. The primary outcome, time to metoprolol discontinuation, was not associated with metabolizer phenotype (poor vs. normal metabolizers: cause-specific hazard ratio 1.04, 95% CI 0.99-1.09, P = 0.12; reduced-metabolizer contrast 1.01, 95% CI 0.99-1.04). Secondary pharmacodynamic outcomes, by contrast, showed the expected graded effect: lower attained heart rate in poor (-1.85 bpm) and intermediate (-0.84 bpm) metabolizers, higher in ultrarapid metabolizers (+0.79 bpm), increased odds of bradycardia (odds ratio 1.19 in poor, 1.16 in intermediate metabolizers) and lower attained maximum dose in intermediate metabolizers (-6.68 mg). Reclassification for phenoconversion by CYP2D6 inhibitors did not change the primary result.

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

An instructive dissociation between physiology and behaviour: CYP2D6 genotype does shift attained heart rate and dose, but not treatment discontinuation. The authors state the limitation themselves, and it is the right one: discontinuation is a composite behavioural endpoint driven by factors that are not genetic, and it does not exclude a genotype effect on adverse effects not captured here (symptomatic bradycardia, fatigue, dizziness). For practice, these data consolidate the pharmacodynamic basis for genotype-guided metoprolol dosing without providing the hard tolerability endpoint that is still missing.

Analysis by Dr Thibaut Benquey