Where Are we in the Genetic Information Guided Drug Therapy?
There has been a marked increase in the incidence and prevalence of cardiovascular disease in recent years (1) (2) (3) (4). 44% (17.9 million) of deaths due to non-communicable diseases (NCDs) in the world are due to cardiovascular diseases, 22% (9 million) to cancers, 9% (3.8 million) to asthma and chronic obstructive pulmonary diseases and 4% (1.6 million) are due to diabetes (5). NCD-related deaths increased from 31 million in 2000 to 38 million in 2012. It is estimated that this number will be 52 million in 2030 (6).
The situation in Turkey is not different. Ischemic heart diseases and stroke are also at the top ranks in Turkey in terms of the number of patients exposed to the disability-adjusted life years (DALY). (Figure 1.).
Figure 1. Top 10 DALY Reasons in 2019 (7).
Aspirin is a cyclooxygenase-1 (COX-1) inhibitor at low doses and inhibits thromboxane A2 (TXA2)-dependent platelet aggregation in human platelets. However, it has been shown that the addition of a second antiplatelet agent to the treatment in the prevention of ischemic complications provides further benefit as a result of further suppression of platelet activation (2) (4) (8) (9).
In this context, many antiplatelet agents have been developed over time. Most of these are oral preparations and are classified as P2Y12 inhibitors. By selectively inhibiting the binding of adenosine diphosphate (ADP) to P2Y12 receptors, this class of drugs inhibits glycoprotein GPIIb/IIIa complex-mediated platelet activation and consequent platelet aggregation. Among these drugs, clopidogrel, ticagrelor and prasugrel, cilostazol and dipyridamole can be listed.
Clopidogrel is the most commonly used P2Y12 blocker with aspirin in patients undergoing percutaneous coronary intervention (with or without a stent) or coronary artery bypass surgery, and in TIA or minor ischemic stroke in Turkey (Figure 2). Treatment with this drug is generally continued as monotherapy 21 days after the onset of the ischemic event.
Figure 2 IMS – TPI 2022 data (2022 Absolute)
In patients with coronary artery stent, hospitalized with the diagnosis of acute coronary syndrome, myocardial infarction or unstable angina, patients with heart valve prosthesis, coronary artery disease, occlusive peripheral artery disease, or a documented cerebral ischemic event (ischemic stroke), clopidogrel is used for both short-term and long-term. If provided, it can be prescribed for a period of 12 months and can be repeated when necessary.
Clopidogrel is a prodrug. Since it is biotransformed in the liver to its active metabolite, a first-pass effect is essential for this prodrug to be effective. The enzyme that converts this drug to its active form in the liver is cytochrome (CYP) P450 P2C19. However, the response to clopidogrel is largely influenced by a single nucleotide polymorphism (SNP). In patients with SNPs, the effect of clopidogrel either disappears, decreases, or increases excessively and may occur in such a way as to cause bleeding (4).
Clopidogrel and Single Nucleotide Polymorphism (SNP)
The effect of clopidogrel, as mentioned above, has a complex background in which chromosomal changes are involved. In humans, drug metabolizing enzymes are commonly found on chromosome ten (10q24) (10) (11). The metabolic fate of this prodrug is also highly dependent on gene expression on chromosome 10q24, the gene encoding the CYP2C19 enzyme. However, this gene also has a common single nucleotide polymorphism (SNP) in CYP2C19, leading to a protein synthesis with low enzymatic activity (12). Several studies have shown that genetic variation in CYP2C19 resulting in reduced activity may result in decreased metabolic activation of clopidogrel, decreased antiplatelet effect, and increased risks of cardiovascular events (eg, stent thrombosis, etc.) (4) (13).
The CYP2C19 gene encodes a 490 amino acid protein that is expressed on the long arm of chromosome 10 (10q24) and predominantly in the liver and to a lesser extent in the small intestine. The most common non-functional allele, CYP2C19*2, has an allele frequency of about 15% in Europeans and Africans and about 30% in Asians (13). The CYP2C19*2 allele (681G>A) encodes a malfunctioning enzyme that causes protein premature termination (13).
Clopidogrel, which is metabolized in the liver, is prescribed to almost 99% of these patients in Turkey (Figure 2). In other words, considering the CYP2C19*2 allele (681G>A) (13), which has an estimated minor allele frequency (MAF) of approximately 30% in Asians, recurrent stent thrombosis risk seems to be a major problem that may lead to an increased risk of mortality.
Although clopidogrel is prescribed at a rate of 94% in Turkey, it is estimated that the proportion of patients carrying the CYP2C19*2 allele (681G>A) may be quite high as per predicted from the previous studies. Considering that these patients may be poor metabolizers or ultra-rapid metabolizers, it should be considered that the treatment applied without determining the genotype may not produce the desired results (12) (4) (13).
Most of the approximately 3 million patients in Turkey are under clopidogrel treatment.
When we summarize all this information, almost 94% of nearly 3 million patients in Turkey are prescribed clopidogrel, which is metabolized in the liver (Figure 2). Considering the CYP2C19*2 allele (681G>A) (13), which has an estimated minor allele frequency (MAF) of approximately 30% in Asians, the risk of recurrent stent thrombosis may be an important problem. It is known that the treatment to be applied without SNP analysis may bring some risks. However, there is no gene data-guided treatment algorithm in the world yet. Obviously, this is extremely important. The money to be spent on these tests will be far below the treatment costs of ischemic heart diseases, stroke, etc., which are the first causes of mortality in Turkey. It will make a great contribution to the rational treatment of ischemic cardiovascular events.
