beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure

Clin Pharmacol Ther. 2005 Mar;77(3):127-37. doi: 10.1016/j.clpt.2004.10.006.


Objective: beta-Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate beta-blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure. We also tested whether polymorphisms in the beta(2)-adrenergic receptor, G-protein alpha s subunit (G(s)alpha), and cytochrome P450 (CYP) 2D6 genes or S-metoprolol plasma concentrations were associated with beta-blocker tolerability.

Methods: Sixty-one beta-blocker-naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period.

Results: The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the beta(2)-adrenergic receptor or G(s)alpha polymorphisms with decompensated heart failure.

Conclusions: Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during beta-blocker titration and thus may require more frequent follow-up during titration.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cytochrome P-450 CYP2D6 / drug effects
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Delayed-Action Preparations / administration & dosage
  • Delayed-Action Preparations / pharmacokinetics
  • Drug Administration Schedule
  • Drug Resistance / drug effects
  • Drug Resistance / genetics
  • Exercise Tolerance / drug effects
  • Exercise Tolerance / genetics
  • GTP-Binding Protein alpha Subunits, Gs / drug effects
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Genotype
  • Heart Failure / diagnosis
  • Heart Failure / drug therapy*
  • Humans
  • Male
  • Metoprolol / administration & dosage*
  • Metoprolol / pharmacokinetics
  • Metoprolol / therapeutic use
  • Middle Aged
  • Pharmacogenetics / methods
  • Phenotype
  • Polymorphism, Genetic / drug effects*
  • Polymorphism, Genetic / genetics
  • Polymorphism, Genetic / physiology
  • Receptors, Adrenergic, beta / drug effects*
  • Receptors, Adrenergic, beta / genetics*
  • Receptors, Adrenergic, beta / physiology
  • Time and Motion Studies
  • Treatment Outcome


  • Delayed-Action Preparations
  • Receptors, Adrenergic, beta
  • Cytochrome P-450 CYP2D6
  • GTP-Binding Protein alpha Subunits, Gs
  • Metoprolol