Pharmacogenetic considerations for cardiovascular drugs discusses several drugs where genetic factors can influence drug response, including clopidogrel, warfarin, and statins. For clopidogrel, CYP2C19 metabolizer status is important as poor metabolizers have lower drug levels and diminished effects. Warfarin dosing is affected by variants in CYP2C9, VKORC1, and CYP4F2. Statins like simvastatin are affected by SLCO1B1 variants which influence drug transport and risk of muscle symptoms. Clinical guidelines provide recommendations on genotype-guided dosing for these drugs.

1. Pharmacogenetic considerations
for cardiovascular drugs
Presenter
Dr. Nipa Mendapara
Junior Resident (Academic)
Dept. Of Pharmacology
AIIMS, New Delhi

2. Outline
• Introduction to pharmacogenetics
• Need for pharmacogenetic testing
• Example of cardiovascular drugs under pharmacogenetic considerations
1. Clopidogrel
2. Warfarin
3. Statins
4. Beta-blocker
5. Hydralazine
6. Anti-arrhythmics
• Benefits and limitations of pharmacogenetic study
2

3. Pharmacogenetics
• A field aimed at understanding the genetic contribution to inter-patient variability in
drug efficacy and toxicity
• “Pharmacogenetics” term used in reference to studies focusing on single gene’s
variability and it’s contribution to differences in drug response
• “Pharmacogenomics” term used to describe approaches that evaluate polymorphism
in numerous gene (or the genome) for their contribution to variable drug response
3
Jullie A, 2001

4. Single Nucleotide Polymorphism (SNP)
4
M.Roy et al., 2010
It’s a variation at a single position in a DNA sequence among individuals

5. Sequence variant nomenclature
Ex. Solute carrier organic anion transporter
(SLCO1B1) for statins encodes by SLCO1B1
c.521T>C (rs4149056)
• SLCOB1- gene
• “c” Reference sequence used (c for coding DNA)
• “521” Position of the nucleotide(s) affected
• “T>C” Change (a C changed to T)
• “rs4149056” rs ID, reference SNP ID number
5
https://varnomen.hgvs.org/bg-material/simple/

6. Allele star nomenclature
• Alleles : alternative forms of a gene
• Different alleles arise due to SNPs
Ex - CYP2C9*3
Star allele system to convey information for each variant
allele
• Fully functional reference allele is referred as *1
• Star alleles are numbered consecutively in order of
discovery irrespective of impact on function
• Thus, the *3 allele for any gene may represent 1 (or
sometimes >1) variant compared with the reference
and may or may not confer altered functional status of
the gene product
6
https://www.genome.gov/genetics-glossary/Recessive
CYP2C9*1/*1 CYP2C9*1/*3 CYP2C9*3/*3

7. It is divided into two broad area :
1. Polymorphism that alter drugs
pharmacokinetics (eg. metabolizing
enzymes, transporters)
2. Polymorphism that affects encoding
drug receptors and action of the
drug, independent of drug
concentration which alters drugs
pharmacodynamic
7
Roden DM, et al., 2018
Classification of Pharmacogenetics

8. 8
Genotypic variation affects
Pharmacokinetic
Duarte JD, 2021 and Dan M. Rode , 2011
Pro drug Active drug
Genotypic variation affects
Pharmacodynamic

9. 9
Jullie A, 2010
Examples of cardiovascular drugs with evidence of association between genetics and efficacy or toxicity

10. Levels of evidence for Gene - drug pair associations
CPIC(Clinical Pharmacogenetics Implementation Consortium) categorizes gene–drug
pairs
• Level- A Genetic information should be used to change prescribing of affected drug
• Level- B Genetic information could be used to change prescribing of the affected
drug because alternative therapies/dosing are extremely likely to be as effective and
as safe as non-genetically based dosing
• Level- C There are published studies at varying levels of evidence, some with
mechanistic rationale, but no prescribing actions are recommended
• Level- D There are few published studies, clinical actions are unclear, substantial
conflicting data. If the genes are not widely tested for clinically, evaluations are not
needed
Currently, 26 CPIC guidelines have been published, all for gene–drug pairs ranked as
level A
10
https://cpicpgx.org/prioritization-of-cpic-guidelines/

11. CPIC guidelines of cardiovascular drugs
11
GENE DRUG CURRENT CPIC LEVEL* STATUS
CYP2C19 Clopidogrel A Published
CYP2C9,VKORC1,
CYP4F2
Warfarin A Published
SLCO1B1 Statin A Published
NAT2 Hydralazine A/B -
CYP2D6 B-blockers (carvedilol,
metoprolol,
propranolol, timolol)
B/C In progress
CYP2D6 Antiarrhythmics
(quinidine, flecainide,
propafenone)
B -

12. ANTI PLATELET DRUGS
12
• Clopidogrel, ticagrelor or prasugrel are adenosine
diphosphate (ADP) antagonists that bind selectively to the
P2Y12 receptor to inhibit platelet function
• Standard of care with aspirin as (DAPT) in patients with
acute coronary syndromes (ACS) and following
percutaneous coronary intervention (PCI) to reduce the risk
of major adverse cardiovascular events
• Prasugrel and ticagrelor exhibit more prompt, potent and
consistent platelet inhibition compared with clopidogrel
but associated with higher rates of bleeding, and both have
higher cost and discontinuation rates than clopidogrel
Klein MD et al. 2019 ; Noé Corpataux, 2020
--CYP3A4, CYP2B6 &
CYP2C19 CYP3A4
--CYP2C19

13. Clopidogrel mechanism of action and metabolism
13
Duarte JD, 2021
CSE1- Carboxylesterase 1
PON1- Paraoxonase 1

14. 14
GENE GENETIC VARIANT PK/PD EFFECT RECOMMENDATION POPULATION
CYP2C19 Most common LOF are CYP2C19*2
(rs4244285, c.681G>A, splicing defect) &
CYP2C19*3 (rs4986893, c.636G>A,
premature stop codon
*3 are common among Asian
Less common LOF alleles include
CYP2C19*4, *5, *6, *7, and *8
*17 a/w increased enzyme function
PMs and IMs : lower
plasma concentrations
of the active
metabolite and
diminished inhibition of
platelet aggregation
PMs-Avoid clopidogrel if
possible. Consider an
alternative P2Y12 inhibitor
IMs - Consider an
alternative P2Y12 inhibitor
RMs or UMs- No
recommendation
IMs and PMs -≈30%
Similar in Africa,
Middle East, Europe,
US.
In Asian ≈57% and
Oceanian with 94%
population carrying a
LOF allele
CES1 Gly143Glu (rs71647871),
reduces CES1 activity
Increase exposure to
clopidogrel active
metabolites and
enhances antiplatelet
effects
---- ----
ABCB1
(P-gp)
C3435T in ABCB1 Reduced bioavailability
of clopidogrel but
have conflicting
evidence
----- ----
PON1 PON1 Q192R Glu (Q, wild type) to Argi (R,
variant) reduced PON1 activity
Early stent thrombosis
more frequent in
QQ192 compared with
QR192 and RR192
----- ----
CLOPIDOGREL
CPIC guidelines 2022

15. CYP2C19 metabolizer phenotypes by geographic region
Klein MD et al. 2019

16. https://products.sanofi.us/plavix/plavix.pdf
FDA-boxed warning on clopidogrel label
16

17. CLOPIDOGREL
• Clinical variables : Advanced age, BMI,
chronic kidney disease, and diabetes mellitus
are associated with high on-treatment
residual platelet aggregation
• In addition, use CYP2C19 inhibitors(proton
pump inhibitors )/inducers(Rifampicin) may
also affect clopidogrel response
• ABCD-GENE validated as a predictor of
cardiovascular events after PCI
• In patients with a high score, long-term oral
P2Y12 inhibitors other than clopidogrel
should be considered
17
Duarte JD, 2021 & Angiolillo DJ, 2020

18. Strategies for dual antiplatelet therapy after PCI
De-escalation of P2Y12 inhibitors:
• Unguided de-escalation
• Platelet function testing (PFT)-guided
de-escalation
• Genotype-guided de-escalation
(presence of the CYP2C19*2 and *3
allele)
18
Claassens DM,
2020

19. Oral anticoagulants -WARFARIN
19
Duarte JD, 2021
VKORC1-Vitamin K epoxide reductase complex 1
GGCX- γ-glutamyl carboxylase
Vit KH2- vitamin K hydroquinone

20. 20
GENE GENETIC VARIANT PK/PD EFFECT DOSE MODIFICATION POPULATION
CYP2C9 CYP2C9*2, *3, *5,
*6, *8 and *11 LOF
alleles
Reduce S-warfarin
(the more active
enantiomer)
metabolism
Dose reductions
requires
*2 and *3 alleles m/c
in European
*5, *6, *8 and *11
m/c in African
VKORC1 −1639 G>A,
(rs9923231)
Alters a transcription
factor binding site
and leads to lower
protein (VKORC1)
expression
Lower doses generally
observed in Asian
higher doses observed
in individuals of African
–1639 AA (highly
sensitive) in Asian
–1639 GG (highly
resistant)
in African
CYP4F2 *3 allele
(rs2108622) LOF
allele
Higher concentrations
of vitamin K1 being
available for
reduction to vitamin
K hydroquinone
higher warfarin dose
requirements
European and Asian
No association in
African
WARFARIN
CPIC 2017 update

21. 21
US-FDA LABEL OF WARFARIN, 2011
Johnson JA, 2013

22. Factors contributing to the interindividual variation in
warfarin maintenance dose requirements
International Warfarin
Pharmacogenetics Consortium (IWPC)
has developed Dosing algorithms
• It Includes genotype (VKORC1
−1639G>A, CYP2C9*2 and CYP2C9*3
alleles)
• Clinical variables that influence the
response to warfarin (for example,
age, height, weight and use of
CYP2C9 inhibitors (, miconazole)
amiodarone, fluconazole/CYP2C9
inducers(like Rifampicin,
carbamazepine)
22
Daniel E. Jonas, 2009

23. 23
CPIC GUIDELINES 2017 UPDATE

24. STATINS
First-line choice in Lipid-lowering therapy to reduce
cardiovascular risk
• More hydrophilic compounds require active transport into
the liver, are less metabolized by the cytochrome P450
(CYP) family, and exhibit more pronounced active renal
excretion
• ex. Rosuvastatin and Pitavastatin and Pravastatin,
• Less hydrophilic compounds are transported by passive
diffusion and are better substrates for both CYP enzymes
and transporters involved in biliary excretion
ex. Lovastatin, Fluvastatin, Simvastatin and Atorvastatin
Some of key genes that affect statin pharmacokinetics include
SLCO1B1, ABCG2, CYP3A4, HMGCR
24
• Solute carrier organic anion transporters
(SLCO’s)- influx transporter
• ATP-Binding Cassette Transporters (ABC
Transporters ) efflux transporter
Ahangari N et al., 2020

25. 25
GENE VARIANT DRUG PK/PD EFFECT RECOMMENDATION POPULATION
SLCO1B1 SLCO1B1*5 & *15
(rs4149056)
(c.521T>C)
decreased function
of transporter
Simvastatin,
followed by
Pitavastatin,
Lovastatin
Atorvastatin
Rosuvastatin
Increased exposure for most
statins
risk of SAMS(Statin-
associated muscle symptoms)
in CC genotype
Strong
Recommendations
based on this
variant’s effects on
PK and SAMS only
not LDL lowering
---
ABCG2 c.421C>A
(rs2231142)
decreased function
of transporter
Rosuvastatin
Atorvastatin,
Pitavastatin,
Fluvastatin
Lovastatin
Associated with increased
exposure to statin in poor
function phenotype (AA)
Weak to moderate
evidence
Higher levels
of
rosuvastatin
observed in
Asian
CYP3A4
&
CYP3A5
CYP3A4*1B &
CYP3A5*3
Atorvastatin Neither variant has been
shown to predict myopathy, it
predicts the severity of how
high the CK may go
Weak evidence
No
recommendations
-----
HMGCR rs17244841 A>T &
rs17238540 T>G
Various statins Reduce response to statin
(less reduction of LDL and TC)
No recommendation -----
STATINS
CPIC guidelines 2022

26. β-BLOCKERS
I. Metoprolol : Most extensively metabolized by CYP2D6
(70–80% of its metabolism)
II. Carvedilol, nebivolol, propranolol, and alprenolol :
Contribution of CYP2D6 is lower than for metoprolol
III. Atenolol : eliminated largely unchanged by glomerular
filtration, and their elimination is therefore independent of
CYP2D6 activity
• Evidence supporting the use of genetic information in
prescribing β-blockers is weak (CPIC level B/C)
• Three other genes have been studied in relation to β-blocker
response: ADRB1, ADRB2 and GRK5
26
Metoprolol and CYP2D6 genotype
Bijl MJ et al. 2009

27. 27
GENE GENETIC VARIANT PK/PD EFFECT CLINICAL OUTCOME
CYP2D6 • Functional alleles *1, *2
• m/c LOF CYP2D6*3,*4,*5,*6
• CYP2D6*4 is the most
common (>75% of PMs)
Poor metabolizers (PMs)
Extensive metabolizers (EMs)
Intermediate metabolizer (IMs)
Ultrarapid metabolizers (UMs)
PMs a/w increased plasma
concentration of drug, so
higher risk of bradycardia
ADRB1 encodes
β1-adrenergic
receptor
Ser49Gly (rs1801252) &
Arg389Gly (rs1801253)
Decrease receptor activity through
receptor downregulation and decreased
signal transduction, respectively.
Greater DBP response
Patients with the Ser49Ser and
Arg389Arg have a greater risk
reduction from β-blockers than
individuals with other
genotypes for indications
including heart failure, atrial
fibrillation and hypertension
ADRB2
β2-adrenergic
receptor
Arg16Gly (rs1042713) & Gln27Glu
(rs1042714)
Not associated with consistent finding.
Conflicting results
---
GRK5 G protein-
coupled receptor
kinase-5
Gln41Leu (rs2230345) Increases GRK5 function (intracellularly to
blunt signalling from the β1 and β2
receptors)
A/w reduced mortality in
patients with heart failure or
hypertension, regardless of β-
block
β-BLOCKERS
Bijl MJ et al. 2009 and Duarte JD, 2021

28. HYDRALAZINE
• It metabolized primarily by acetylation, which is mostly accomplished in the liver by
N-acetyltransferase type 2 (NAT2)
• Genetic variation in NAT2 has been associated with the acetylation rate of NAT2 in
humans
I. NAT2*4 the common allele  Rapid acetylator
II. NAT2*5, *6 and *7 alleles  Slow acetylator
III. With one of each allele (Ex. *4/*5 genotype)  Intermediate acetylators
• It’s reported that in Patients with resistant hypertension, only slow acetylators had
notable blood-pressure reductions
• Indirect evidence suggests that slow acetylators might be at higher risk of developing
these lupus-like symptoms if exposed to hydralazine, but these data are far from
conclusive
• Therefore, slow acetylators might have the greatest antihypertensive response to
hydralazine, probably due to increased drug exposure
28
Duarte JD, 2021

29. ANTIARRHYTHMIC DRUGS
• Class IC : Flecainide and Propafenone undergo CYP2D6-mediated metabolism
• CPIC level B
• CYP2D6 variation seems to affect the pharmacokinetics of these drugs. Studies have
shown differences in QTc interval response with variations in the CYP2D6 genotype
• Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 enzymes
• FDA-approved labelling for propafenone warns that patients with a CYP2D6 deficiency or
(inhibition secondary to concomitant drug therapy/ CYP2D6 inhibitor ) when combined
with CYP3A4 inhibitor are at greater risk of increased propafenone exposure and
associated proarrhythmia or other adverse events
• No CPIC guidelines exist to address flecainide or propafenone, the DPWG recommends
reducing the flecainide and propafenone doses to 50% and 30% of the standard dose,
respectively, in CYP2D6 PMs
29
Duarte JD, 2021

30. Potential barriers to clinical implementation of pharmacogenetics
Knowledge barriers
• Lack of awareness of the pharmacogenetic data
• Uncertainty about how to interpret a pharmacogenetic test result
• Uncertainly about what action to take based on a pharmacogenetic test result
Logistical/financial barriers
• Remembering when to order a pharmacogenetic test in a busy clinical practice
• Turnaround time for pharmacogenetic test
• Cost of pharmacogenetic test
• Concerns about lack of reimbursement for pharmacogenetic test
Evidence barriers
• Lack of randomized controlled clinical trial data documenting benefit of pharmacogenetic
guided treatment approach
• “Genetic exceptionalism” for genetic and pharmacogenetic tests
30
Johnson JA, 2013

31. References :
• Klein MD, Williams AK, Lee CR, Stouffer GA. Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or
Undergoing Percutaneous Coronary Intervention. Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):647-652.
• Duarte JD, Cavallari LH. Pharmacogenetics to guide cardiovascular drug therapy. Nat Rev Cardiol. 2021 Sep;18(9):649-665.
• Roden DM, Van Driest SL, Wells QS, Mosley JD, Denny JC, Peterson JF. Opportunities and Challenges in Cardiovascular Pharmacogenomics: From Discovery to
Implementation. Circ Res. 2018 Apr 27;122(9):1176-1190.
• Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, Vulto AG, van Gelder T, Stricker BH. Genetic variation in the CYP2D6 gene is associated with a
lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther. 2009 Jan;85(1):45-50.
• Johnson JA, Cavallari LH. Pharmacogenetics and cardiovascular disease--implications for personalized medicine. Pharmacol Rev. 2013 May 17;65(3):987-1009.
• M.Roy , S.Biswas and S. Barman(Mandal) jan 2010
• Jullie A johnsons and Larissa M Humma. Pharmacogenetics of cardiovascular drugs. 2001
• Daniel E. Jonas. Genetic and clinical factors relating to warfarin dosing Genetic and clinical factors relating to warfarin dosing. Pharma sci.2009; Volume 30Issue
7p331-386
• Angiolillo DJ, Capodanno D, Danchin N, Simon T, Bergmeijer TO, Ten Berg JM, Sibbing D, Price MJ. Derivation, Validation, and Prognostic Utility of a Prediction Rule
for Nonresponse to Clopidogrel: The ABCD-GENE Score. JACC Cardiovasc Interv. 2020 Mar 9;13(5):606-617
• Ahangari N, Doosti M, Ghayour Mobarhan M, Sahebkar A, Ferns GA, Pasdar A. Personalised medicine in hypercholesterolaemia: the role of pharmacogenetics in
statin therapy. Ann Med. 2020 Dec;52(8):462-470.
• Claassens DM, Sibbing D. De-Escalation of Antiplatelet Treatment in Patients with Myocardial Infarction Who Underwent Percutaneous Coronary Intervention: A
Review of the Current Literature. J Clin Med. 2020 Sep 15;9(9):2983.
• Dan M. Roden et al. Cardiovascular Pharmacogenomics. Circulation research. 2011
31

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