Don't Skip a Beat: Familiarize Yourself With Updates in Cardiovascular Pharmacogenomics

Pharmacogenomics is an ever evolving and advancing field which holds significant promise in terms of providing more individualized patient care. The genetic variations that exist from person to person contribute to the differences that arise in medication efficacy and tolerability.¹ There have been several drug–gene associations that have been discovered with more discoveries continuing to be made. Not only are drug-metabolizing enzymes of interest in the pharmacogenomic realm, but drug transporters and receptors are also crucial because they represent an equally important role in affecting individuals’ responses to certain medications.²

There are several classes of cardiology medications with pharmacogenomic implications, including statins, beta-blockers, and antiplatelets/anticoagulants.²

Statins are very common and effective medications prescribed for indications such as hyperlipidemia management. Unfortunately, there remains some hesitancy around statin use due to the potential for adverse effects, which may result in some patients refusing or discontinuing therapy altogether. Statin-associated musculoskeletal symptoms (SAMS) are most common. There are several genes that have been discovered to provide utility in selecting more appropriate statins and doses from initiation to promote greater tolerability and thereby efficacy. These genes include SLCO1B1, ABCG2, and CYP2C9.³

SLCO1B1 encodes the transmembrane protein that works to transport statins into the liver for their breakdown. Therefore, if there is decreased function of this SLCO1B1 transporter, there is greater risk of SAMS due to increased systemic exposure to the statin. Of course, statin lipophilicity plays a role in this as well: the more lipophilic a statin is, there will be a greater risk for SAMS with decreased or poor SLCO1B1 function.⁴ Alternatively, the more hydrophilic a statin is, there will be reduced risk for SAMS with decreased or poor SLCO1B1 function.4 Recommendations around SLCO1B1 function are broadly applicable to all statins. See Table 1⁴ for the SLCO1B1 genotype-phenotype pairs, Figure 1⁴ for SAMS risk across statin intensity groups according to statin and dose in SLCO1B1 decreased function, and Figure 2⁴ for SAMS risk across statin intensity groups according to statin and dose in SLCO1B1 poor function.

Table 4:⁴ SCO1B1 genotypes and resulting phenotypes

Figure 1:⁴ SAMS risk across statin intensity groups according to statin and dose in SLCO1B1 decreased function

Figure 2:⁴ SAMS risk across statin intensity groups according to statin and dose in SLCO1B1 poor function

The Adenosine Triphosphate (ATP) Binding Cassette G2 (ABCG2) is a transporter that is found in several different tissues, including the liver. It helps in the exportation of compounds back out into the extracellular space. At this time, recommendations around ABCG2 function are applicable only to rosuvastatin.⁵ See Table 2 below for ABCG2 genotype-phenotype pairs and Table 3 for rosuvastatin dosing recommendations.

Table 2:⁵ ABCG2 genotypes and resulting phenotypes

Table 3:⁵ Rosuvastatin dosing recommendations in relation to ABCG2 activity (phenotype)

Fluvastatin is metabolized by CYP2C9 and, therefore, this enzyme’s activity becomes an important component to consider when initiating fluvastatin therapy.^6,7 See Table 4^6,7 below for CYP2C9 genotype-phenotype pairs and Table 5^6,7 for fluvastatin dosing recommendations.

Table 4:^6,7 CYP2C9 genotypes and resulting phenotypes

Table 5:^6,7 Fluvastatin dosing recommendations in relation to CYP2C9 enzyme activity (phenotype)

The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline update in 2022 regarding statin therapy provided the recommendations noted in Table 6 for those already on statin therapy, detailing when a transition to a different statin and/or dose would be recommended versus continuing current therapy.⁵

Table 6:⁵ Recommendations for patients already on statin therapy that is either high or moderate risk of SAMS according to the individual's pharmacogenomic results

In terms of beta-blocker pharmacogenomics, an individual’s CYP2D6 enzyme activity becomes important because this enzyme is involved in the metabolism of several beta-blockers including metoprolol, propranolol, bisoprolol, carvedilol, nebivolol, betaxolol, and acebutolol. Current guidelines do not provide specific beta-blocker dosing recommendations depending on one’s CYP2D6 phenotype, but rather more vaguely state that poor CYP2D6 metabolizers will have greater systemic circulation of those beta-blockers that rely on CYP2D6 for metabolism. In addition, it would be expected that poor CYP2D6 metabolizers would then be at greater risk for adverse effects which warrant close monitoring and dose titrations.^8,9 The CPIC guideline regarding beta-blockers is expected to be released in early 2024.

Lastly, it is well understood that clopidogrel is a pro-drug requiring CYP2C19 to mediate the bioactivation step. Notably, if this bioactivation step does not take place, the parent drug will remain inactive, making one’s CYP2C19 phenotype particularly important. There is CPIC guidance around clopidogrel and CYP2C19 which can be found in Table 7.^10-12 The current literature indicates that CYP2C19 intermediate and poor metabolizers have an increased risk of cardiovascular death, myocardial infarction, and stroke when taking clopidogrel. However, those intermediate metabolizers could take a higher daily dose of clopidogrel, 225 mg daily, to overcome the loss of function and this may be considered if an alternative antiplatelet agent is not feasible for the patient for one reason or another. This recommendation, however, does not apply to those CYP2C19 poor metabolizers.^10-12

Table 7:^10-12 Clopidogrel dosing recommendations based on CYP2C19 phenotype

It is not hard to see that pharmacogenomic information can be used to more selectively choose medications and doses that are more appropriate for each individual. There are several pharmacogenomic implications across the various classes of cardiology medications, and it will be important to stay up to date as the guidelines continue to evolve for these commonly prescribed medications.

Rferences

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2. Pharmacogenomics – What does it mean for your health? CDC. Reviewed May 20, 2022. Accessed March 10, 2024. https://www.cdc.gov/genomics/disease/pharma.htm#:~:text=Pharmacogenomics%20is%20an%20important%20example,way%20you%20respond%20to%20drugs.

3. Turner RM, Pirmohamed M. Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic, and Muscle Components. J Clin Med. 2020; 9:1-37.

4. Ward NC, Watts GF, Eckel RH. Response by Ward et al to Letter Regarding Article, “Statin Toxicity: Mechanistic Insights and Clinical Implications.” Circulation Research 2019; 124:121-122.

5. Cooper De-Hoff RM, Niemi M, Ramsey LB et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 Genotypes and Statin-Associated Musculoskeletal Symptoms. Clinical Pharmacology & Therapeutics 2022; 111:1007-1021.

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8. Zisaki A, Miskovic L, Hatzimanikatis V. Antihypertensive Drugs Metabolism: An Update to Pharmacokinetic Profiles and Computational Approaches. Current Pharmaceutical Design 2015; 21:806-822.

9. Table of Pharmacogenetic Associations. U.S. Food and Drug Administration (FDA). Reviewed October 26, 2022.

10. Sangkuhl K, Klein TE, Altman RB. Clopidogrel Pathway. Pharmacogenet Genomics 2010; 20:463-465.

11. Scott SA, Sangkuhl K, Stein CM et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update. Clinical Pharmacology & Therapeutics 2013; 94:317-323.

12. Lee CR, Luzum JA, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clinical Pharmacology & Therapeutics 2022; 112:959-967.