An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT-HF Substudy

Abstract

To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

“…In the largest study to date of CYP2D6 genetic polymorphisms and beta-blocker effects (n = 1,533 total with n = 513 metoprolol treated), Bijl et al reported that CYP2D6 PM were treated with significantly lower doses of metoprolol (39) and that CYP2D6 *4 was significantly associated with heart rate, bradycardia, and diastolic blood pressure in patients treated with metoprolol (39). In contrast to our findings and those reported by Rau et al and Bijl et al , Batty et al did not find a significant association between CYP2D6 *4 and metoprolol dose in their pharmacogenetic sub-study of the MERIT-HF trial (11). As the only study reported on the association of CYP2D6 *4 and clinical outcomes, the study reported by Batty et al did not find significant differences among CYP2D6* 4 genotypes in all-cause mortality or rate of hospitalization (11).…”

“…In contrast to our findings and those reported by Rau et al and Bijl et al , Batty et al did not find a significant association between CYP2D6 *4 and metoprolol dose in their pharmacogenetic sub-study of the MERIT-HF trial (11). As the only study reported on the association of CYP2D6 *4 and clinical outcomes, the study reported by Batty et al did not find significant differences among CYP2D6* 4 genotypes in all-cause mortality or rate of hospitalization (11). The lack of association between CYP2D6 *4 and clinical outcomes reported by Batty et al may have been secondary to an inherent decrease in statistical power (decreased sample size and increased number of comparison groups) characteristic of retrospective genetic sub-study analyses.…”

“…Although several studies have found a significant association between CYP2D6 genetic polymorphisms and beta-blocker dose or patient response to metoprolol or carvedilol (6,10–12,32–40), an almost equal number of studies have reported null findings (9,11,13,33,41–45). Our findings regarding carvedilol dose are consistent with the reported findings of Baudhuin et al (32).…”

G Protein–Coupled Receptor Kinase 5 Gene Polymorphisms Are Associated With Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting in Patients Receiving β-Blockers

“…After correcting for the multiple testing, none of them qualified as significant. Furthermore, among the 19 imputed SNPs, the non-functional variant of the CYP2D6 gene ( CYP2D6*4; rs3892097) identified by other investigators 44, 45 was also tested, but it did not show a significant association with risk for postoperative AF, despite perioperative BB prophylaxis (MAF = 0.15; OR = 0.86; 95% CI: 0.56-1.34; P = 0.51). Several reasons may account for this negative replication for CYP2D6 including variation in study design, the use of imputed data, dose and/or type of BBs used.…”

Cardiovascular Pharmacogenomics—Implications for Patients With CKD

“…Significantly higher drug plasma concentrations of metoprolol and carvedilol have been reported among CYP2D6 poor metabolizers compared to those with other phenotypes. 55–58 While the poor metabolizer phenotype has also been associated with greater heart rate and diastolic blood pressure response to β-blockers, results are inconsistent. 56–61 Inconsistent associations between genotype with clinical response to metoprolol is likely a reflection of the wide therapeutic index of β-blockers where differences in plasma concentrations may or may not result in clinically significant effects.…”