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Pharmacogenetics to guide cardiovascular drug therapy

Abstract

Over the past decade, pharmacogenetic testing has emerged in clinical practice to guide selected cardiovascular therapies. The most common implementation in practice is CYP2C19 genotyping to predict clopidogrel response and assist in selecting antiplatelet therapy after percutaneous coronary intervention. Additional examples include genotyping to guide warfarin dosing and statin prescribing. Increasing evidence exists on outcomes with genotype-guided cardiovascular therapies from multiple randomized controlled trials and observational studies. Pharmacogenetic evidence is accumulating for additional cardiovascular medications. However, data for many of these medications are not yet sufficient to support the use of genotyping for drug prescribing. Ultimately, pharmacogenetics might provide a means to individualize drug regimens for complex diseases such as heart failure, in which the treatment armamentarium includes a growing list of medications shown to reduce morbidity and mortality. However, sophisticated analytical approaches are likely to be necessary to dissect the genetic underpinnings of responses to drug combinations. In this Review, we examine the evidence supporting pharmacogenetic testing in cardiovascular medicine, including that available from several clinical trials. In addition, we describe guidelines that support the use of cardiovascular pharmacogenetics, provide examples of clinical implementation of genotype-guided cardiovascular therapies and discuss opportunities for future growth of the field.

Key points

  • Substantial evidence supports CYP2C19 genotyping to predict the effectiveness of clopidogrel after percutaneous coronary intervention.

  • Data strongly support genetic associations with warfarin dose requirements and risk of simvastatin-induced myopathy, but the use of genotyping in clinical practice to guide prescribing of these drugs is limited.

  • Limited evidence exists to support genetic testing to guide the use of other cardiovascular drugs at present.

  • Modern computational approaches can harness large multi-origin data to elucidate genetic predictors of the response to drug treatment for diseases requiring multiple medications targeting various pathogenic pathways.

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Fig. 1: Mechanisms by which variation in genes encoding drug-metabolizing enzymes can affect cardiovascular drug pharmacokinetics.
Fig. 2: Clopidogrel metabolism.
Fig. 3: Sites of action for pharmacogenes involved in the response to warfarin.

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Acknowledgements

J.D.D. and L.H.C. are supported by NIH grant NIH/NHGRI U01 HG00729. L.H.C. is supported by grants NIH/NHLBI R01 HL149752 and NIH/NCATS UL1TR001427.

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J.D.D. and L.H.C. researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Larisa H. Cavallari.

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Duarte, J.D., Cavallari, L.H. Pharmacogenetics to guide cardiovascular drug therapy. Nat Rev Cardiol 18, 649–665 (2021). https://doi.org/10.1038/s41569-021-00549-w

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