European Journal of Clinical Pharmacology

, Volume 74, Issue 12, pp 1567–1574 | Cite as

Clopidogrel utilization in patients with coronary artery disease and diabetes mellitus: should we determine CYP2C19*2 genotype?

  • Saoussen ChoucheneEmail author
  • Rym Dabboubi
  • Haythem Raddaoui
  • Hela Abroug
  • Khaldoun Ben Hamda
  • Sondess Hadj Fredj
  • Fatma Abderrazak
  • Mayssa Gaaloul
  • Marwa Rezek
  • Fadoua Neffeti
  • Ilhem Hellara
  • Mouna Sassi
  • Linda Khefacha
  • Asma Sriha
  • Semir Nouira
  • Mohamed Fadhel Najjar
  • Faouzi Maatouk
  • Taieb Messaoud
  • Mohsen Hassine



Clopidogrel non-responsiveness is multifactorial; several genetic and non-genetic factors may contribute to impaired platelet inhibition. The goal of this study is to determine the effect of the cytochrome P450 CYP2C19*2 polymorphism on the platelet response to clopidogrel in patients with and without diabetes mellitus (DM).


We conducted an observational study in patients with coronary artery disease and consequent exposure to clopidogrel therapy (75 mg/day for at least 7 consecutive days). We have analyzed two groups of patients: group I (DM patients) and group II (non-diabetes mellitus patients). Platelet reactivity was assessed by the VerifyNow P2Y12 assay and high on clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) ≥ 208. Genotyping for CYP2C19*2 polymorphism was performed by PCR-RFLP.


We have included 150 subjects (76 DM and 74 non-diabetes mellitus patients). The carriage of CYP2C19*2 allele, in DM patients, was significantly associated to HPR (odds ratio (OR) 4.437, 95% confidence interval (CI) 1.134 to 17.359; p = 0.032). Furthermore, 8.4% of the variability in percent inhibition by clopidogrel could be attributed to CYP2C19*2 carrier status. However, in non-diabetes mellitus patients, there was no significant difference in platelet response to clopidogrel according to the presence or absence of CYP2C19*2 allele carriage (OR 1.260, 95% CI 0.288 to 5.522; p = 0.759).


Our study suggests that the carriage of CYP2C19*2 polymorphism, in DM patients, might be a potential predictor of persisting HPR in these high-risk individuals.

Trial registration

Clinical NCT03373552 (Registered 13 December 2017)


Clopidogrel Cytochrome P-450 CYP2C19 Coronary artery disease Diabetes mellitus 



The authors are very grateful to all patients who participated in this study.

Contributions of authors

SC designed the study, performed data analysis, and wrote the manuscript. HR, MG, and MR included the patients. RD and SHF performed genetic analysis and reviewed the manuscript. HA and AS conducted the statistical analysis. FA, FN, IH, MS, and LK supervised results. SN, KBH, FM, MFN, TM, and MH revised critically the intellectual content of the manuscript.

Compliance with ethical standards

The study protocol was approved by the Ethics Committee for Clinical Research at our center and all subjects gave informed consent for study participation.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

228_2018_2530_MOESM1_ESM.docx (52 kb)
Table S1 is supplementary data associated with this article, in the online version. (DOCX 52 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Saoussen Chouchene
    • 1
    Email author return OK on get
  • Rym Dabboubi
    • 2
  • Haythem Raddaoui
    • 3
  • Hela Abroug
    • 4
  • Khaldoun Ben Hamda
    • 3
  • Sondess Hadj Fredj
    • 2
  • Fatma Abderrazak
    • 1
  • Mayssa Gaaloul
    • 1
  • Marwa Rezek
    • 1
  • Fadoua Neffeti
    • 5
  • Ilhem Hellara
    • 5
  • Mouna Sassi
    • 6
  • Linda Khefacha
    • 6
  • Asma Sriha
    • 4
  • Semir Nouira
    • 7
  • Mohamed Fadhel Najjar
    • 5
  • Faouzi Maatouk
    • 3
  • Taieb Messaoud
    • 2
  • Mohsen Hassine
    • 1
  1. 1.Hematology DepartmentFattouma Bourguiba University HospitalMonastirTunisia
  2. 2.Biochemistry and Molecular Biology Laboratory (LR00SP03), Children’s Hospital Bechir HamzaTunisTunisia
  3. 3.Cardiology DepartmentFattouma Bourguiba University HospitalMonastirTunisia
  4. 4.Epidemiology and Preventive Medicine DepartmentFattouma Bourguiba University HospitalMonastirTunisia
  5. 5.Biochemistry DepartmentFattouma Bourguiba University HospitalMonastirTunisia
  6. 6.Biology Department, Maternity and Neonatal Medicine CenterFattouma Bourguiba University HospitalMonastirTunisia
  7. 7.Research Laboratory (LR12SP18)University of MonastirMonastirTunisia

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