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

Abstract

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.

• Authors: Steven G Terra, Daniel F Pauly, Craig R Lee, J Herbert Patterson, Kirkwood F Adams, Richard S Schofield, Bernadette S Belgado, Karen K Hamilton, Juan M Aranda, James A Hill, Hossein N Yarandi, Joseph R Walker, Michael S Phillips, Craig A Gelfand, Julie A Johnson
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 77 Issue 3 Pg. 127-37 (Mar 2005) ISSN: 0009-9236 [Print] United States
• PMID: 15735607 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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