Impact of the CYP2D6 Genotype on Metoprolol Tolerance and Adverse Events in Elderly Chinese Patients With Cardiovascular Diseases

Abstract

The latest consensus has changed CYP2D6 genotyping among Chinese population, while its impact on metoprolol tolerance and adverse events in elderly Chinese patients with cardiovascular diseases remains unclear. In this study, we prospectively included elderly patients who started metoprolol treatment for cardiovascular indications. According to the latest consensus on CYP2D6 genotype-to-phenotype translation, the patients were categorized as normal, intermediate, or poor metabolizers (NMs, IMs, or PMs, respectively) by detecting the presence of the CYP2D6*1, *2, *5, *10, and *14. Logistic regression model was used to analyze the correlation between the CYP2D6 phenotype and incidence of adverse events, which were assessed over a 12-week period. In this study, there were 651 (62.7%) NMs, 385 (37.1%) IMs, and 3 (0.3%) PMs. After 12 weeks of follow-up, compared with NMs, IMs had the lower maintenance dose [50.0 (25.0–50.0) mg/day vs. 25.0 (25.0–50.0) mg/day, p < 0.001] and lower weight-adjusted maintenance doses (0.52 ± 0.25 mg/day/kg vs. 0.42 ± 0.22 mg/day/kg, p < 0.001), and had higher incidence of postural hypotension (6.0% vs. 10.9%, p = 0.006), bradycardia (21.5% vs. 28.6%, p = 0.011), asystole (0.8% vs. 3.1%, p = 0.009) and syncope (2.0% vs. 6.2%, p = 0.001). In logistic regression model, the overall incidence of adverse events was 1.37-fold larger in IMs than in NMs (odds ratio = 1.37, 95% confidence interval = 1.05–1.79, p = 0.021). We conclude that IMs have lower tolerance and higher incidence of metoprolol-related adverse events than NMs in elderly Chinese patients with cardiovascular diseases. CYP2D6 genotyping is justifiable in elderly patients to minimize the risk of adverse events and ensure the benefits of metoprolol.

Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes

“…A Dutch study by Bijl and colleagues found an 8.5 bpm decrease in HR, leading to increased risk for bradycardia, in CYP2D6 PMs taking metoprolol compared to CYP2D6 NMs (OR = 3.86, p = 0.0014) [ 25 ]. Recently, Chen and colleagues performed a prospective observational trial of metoprolol tolerance in a Han Chinese population, stratifying adverse events by CYP2D6 phenotype [ 26 ]. While few PMs were enrolled in the study, the study did find a statistically higher incidence of postural hypotension, bradycardia, asystole, and syncope in the IM group compared to the NM group.…”

“…Several studies have also noted a relationship between CYP2D6 phenotype and clinical outcomes and, in general, a decreasing function of CYP2D6 is associated with lower blood pressure (BP) [ 20 , 21 ] and a decreased heart rate (HR) [ 20 , 21 , 22 ]. Despite sound evidence on pharmacokinetic and surrogate outcomes in the literature, an association between CYP2D6 phenotype and patient-reported clinical symptoms in metoprolol users remains uncertain as studies have found both positive [ 23 , 24 , 25 , 26 ] and negative [ 27 , 28 , 29 , 30 ] associations. The Dutch Pharmacogenomics Working Group (DPWG) has published guidelines with clearly delineated recommendations for CYP2D6 [ 2 ].…”