The effect of obesity and serum leptin levels on clopidogrel resistance

Doğan, Ali; Kahraman, Serkan; Usta, Emrah; Özdemir, Emrah; Görmüş, Uzay; Çıftçı, Çavlan

doi:10.5543/tkda.2016.44459

Cited by 6 publications

(4 citation statements)

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“…All of the abovementioned mechanisms are potentially responsible for a decreased reactivity of clopidogrel. 29 , 30 As such, we speculate that the CC genotype of GNAS rs7121 regulates clopidogrel resistance, thereby affecting the responsiveness of related drugs via inflammation related to body obesity.…”

Section: Discussionmentioning

confidence: 91%

Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population

Zhong

Zheng

et al. 2021

Clinical Laboratory Analysis

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Background: Due to the loss of responsiveness to insulin, diabetes mellitus (DM) patients develop increased platelet reactivity and reduced response to antiplatelet agents. Nevertheless, the relationship between the single-nucleotide polymorphisms (SNP) of the signal pathway gene of insulin secretion and the effect of clopidogrel is elusive.Methods: Blood samples were collected from patients administered with dualantiplatelet therapy (clopidogrel, 75 mg, once daily and aspirin, 100 mg, once daily) after 5 days and completed test within 4 h. The VerifyNow P2Y12 assay was used to measure the platelet functions, and the results were expressed as a P2Y12 reaction unit (PRU). Notably, the selected SNPs were analyzed to demonstrate the functionality of genetic variants.Results: Analysis of the study population showed that old age, lower plasma albumin (ALB) level, higher creatinine (CREA) level, higher uric acid (UA) level, lower platelet (PLT) count, and lower plateletcrit (PCT) potentially increased the risk of clopidogrel resistance. In a single-nucleotide polymorphism rs6056209 of the PCLB1 gene, the AG genotype was a risk factor for clopidogrel resistance (p < 0.05, OR = 1.574).Similarly, the CC and AG genotype in GNAS rs7121 and CCKAR rs1800857 were protective factors (p < 0.05, OR = 0.094; p <0.05, OR = 0.491). TT was a protective factor in rs10814274 of the CREB3 gene (p < 0.05, OR = 0.444). In the RAPGEF4 gene polymorphism rs17746510, TG was the protective genotype, and the TT genotype was a risk factor for clopidogrel resistance. GCG rs5645 was confirmed; there was a relationship between genotypes containing A or G and clopidogrel resistance. Conclusion:Single-nucleotide polymorphisms of insulin secretion signaling pathway genes trigger clopidogrel resistance.

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Section: Discussionmentioning

confidence: 91%

Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population

Zhong

Zheng

et al. 2021

Clinical Laboratory Analysis

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“…Many clinical studies have shown that obesity and hyperlipidemia are closely related to cardiovascular diseases such as hypertension and atherosclerosis. Doğan et al 22 found a significantly increased incidence of clopidogrel resistance in patients with BMI > 30. Comparison of the baseline data in the present study identified significant differences between the two Han groups in cholesterol and BMI levels, which is consistent with the results of Doğan et al's study; however, significant differences were not found between the two Hui groups.…”

Section: Discussionmentioning

confidence: 99%

The Correlation Between MDR1 Gene Polymorphism and Clopidogrel Resistance in People of the Hui and Han Nationalities

Zhang

Dong

Bian

et al. 2022

Clin Appl Thromb Hemost

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To investigate the differences in the correlation between multidrug resistance protein 1 ( MDR1) ( ABCB1) gene polymorphism and clopidogrel resistance in patients of the Hui and Han nationalities with percutaneous coronary intervention (PCI). A total of 377 subjects (154 people of Hui nationality, 223 people of Han nationality) with PCI were enrolled in the study. Each patient's platelet aggregation rate was induced by adenosine diphosphate and measured using light turbidimetry. Based on the results, the patients were divided into two groups: a clopidogrel resistance (CR) group and a non-clopidogrel resistance (NCR) group. Restrictive fragment-length polymorphism polymerase chain reaction technology was then used to determine the genotype and alleles at two loci (C3435 T[rs1045642] and C1236 T[rs1128503]), calculate the frequencies of the genotype and alleles at these two loci, and conduct correlation analysis. The incidence rate of clopidogrel resistance was 23.4%, and the frequencies of the TT genotype and T allele at C3435 T for patients of both nationalities were significantly higher in the CR group than in the NCR group (P < 0.05). There were no significant differences between the two groups in genotype or allele frequency at C1236 T. There was a significant difference in the distribution of C1236 T polymorphism between the two nationalities (P < 0.05), but there was no significant difference between the two nationalities in C3435 T polymorphism. Patients with a T allele at MDR1 C3435 T are more likely to show clopidogrel resistance, and no significant differences were identified in C3435 T gene polymorphism between the two nationalities.

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“…It is well known that obesity is associated with a large number of co‐morbidities, with the most prominent being Type 2 diabetes mellitus and metabolic syndromes. Clinical research studies demonstrated that obesity is an independent risk factor for attenuated responses of platelets to clopidogrel in clinical settings (Dogan et al, 2016; Gajos & Mostowik, 2015; Norgard & Monte, 2017). However, sporadic and incomplete evidence indicated that diminished P450‐mediated metabolic activation of clopidogrel, augmented CES1‐catalyzed hydrolysis of the drug, the inflammatory status related to obesity, increased platelet turnover, and enhanced platelet reactivity all would contribute to poor responses to clopidogrel, to an extent that may vary in each patient involved (Norgard & Monte, 2017).…”

Section: Discussionmentioning

confidence: 99%

Is platelet responsiveness to clopidogrel attenuated in overweight or obese patients and why? A reverse translational study in mice

Jiang

et al. 2021

British J Pharmacology

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Background and Purpose Overweight or obese patients exhibit poorer platelet responses to clopidogrel. However, the mechanisms behind this phenotype remain to be elucidated. Here, we sought to discover whether and why obesity could affect the metabolic activation of and/or platelet response to clopidogrel in obese patients and high‐fat diet‐induced obese mice. Experimental Approach A post hoc stratified analysis of an observational clinical study was performed to investigate changes in residual platelet reactivity with increasing body weight in patients taking clopidogrel. Furthermore, high‐fat diet‐induced obese mice were used to reveal alterations in systemic exposure of clopidogrel thiol active metabolite H4, ADP‐induced platelet activation and aggregation, the expression of genes involved in the metabolic activation of clopidogrel, count of circulating reticulated and mature platelets, and proliferation profiles of megakaryocytes in bone marrow. The relevant genes and potential signalling pathways were predicted and enriched according to the GEO datasets available from obese patients. Key Results Obese patients exhibited significantly attenuated antiplatelet effects of clopidogrel. In diet‐induced obese mice, systemic exposure of clopidogrel active metabolite H4 was reduced but that of its hydrolytic metabolite was increased due to down‐regulation of certain P450s but up‐regulation of carboxylesterase‐1 in the liver. Moreover, enhanced proliferation of megakaryocytes and elevated platelet count also contributed. Conclusion and Implications Obesity attenuated metabolic activation of clopidogrel and increased counts of circulating reticulated and mature platelets, leading to impaired platelet responsiveness to the drug in mice, suggesting that clopidogrel dosage may need to be adjusted adequately in overweight or obese patients.

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The effect of obesity and serum leptin levels on clopidogrel resistance

Abstract: Clopidogrel resistance is more common in obese and hyperleptinemic patients. Dosage should be individualized in these populations.

Cited by 6 publications

References 0 publications

Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population

Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population

The Correlation Between MDR1 Gene Polymorphism and Clopidogrel Resistance in People of the Hui and Han Nationalities

Is platelet responsiveness to clopidogrel attenuated in overweight or obese patients and why? A reverse translational study in mice

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