Younger age, higher body mass index and lower adiponectin concentration predict higher serum thromboxane B2 level in aspirin-treated patients with type 2 diabetes: an observational study.

BACKGROUND: Evidence from the literature suggests diminished acetylsalicylic acid (ASA) treatment efficacy in type 2 diabetes (DM2). High on-aspirin platelet reactivity (HAPR) in DM2 has been linked to poor glycemic and lipid control. However, there are no consistent data on the association between HAPR and insulin resistance or adipose tissue metabolic activity. The aim of this study was to assess the relationship between laboratory response to ASA and metabolic control, insulin resistance and adipokines in DM2. METHODS: A total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median. RESULTS: Significant trends in age, body mass index (BMI), HOMA-IR, HMW adiponectin concentration, C-reactive protein concentration and the frequency of achieving target triglyceride levels were observed across increasing quartiles of TXB2. In a multivariate analysis, only younger age and higher BMI were independent predictors of TXB2 concentration above the upper quartile, while younger age and lower HMW adiponectin concentration were predictors of TXB2 concentration above the median. CONCLUSIONS: These results suggest that in DM2, the most important predictor of HAPR is younger age. Younger DM2 patients may therefore require total daily ASA doses higher than 75 mg, preferably as a twice-daily regimen, to achieve full therapeutic effect. Higher BMI and lower HMW adiponectin concentration were also associated with less potent ASA effect. This is the first study to demonstrate an association of lower adiponectin concentration with higher serum TXB2 level in patients treated with ASA.

New single nucleotide polymorphisms associated with differences in platelets reactivity in patients with type 2 diabetes treated with acetylsalicylic acid: genome-wide association approach and pooled DNA strategy.

The objective of this study was to use genome-wide association approach and pooled DNA strategy to search for new genomic loci associated with inter-individual differences in platelet reactivity in the diabetic patients during acetylsalicylic acid (ASA) treatment. Study cohort consisted of 297 diabetic patients who had been taking ASA (75 mg daily) for at least 3 months. We tested association of single nucleotide polymorphisms (SNPs) genotyped using high density microarray platform with several platelet reactivity assays, followed by individual genotyping of most significant SNPs identified in the microarray genomic scan. The highest statistical significance (p value of 0.0001-0.008 in individual genotyping) was observed for SNP located within the regulatory G-protein signaling (RGS) 7 gene (rs2502448) using recessive genetic model. The diabetic patients on ASA treatment and homozygotes for its minor allele were characterized by increased odds ratio of at 3.45 (confidence interval: 1.82-6.53) for high on ASA platelet reactivity (i.e. impaired ASA response) when compared with homozygotes for wild-type allele. The genome-wide approach might provide an opportunity to identify novel candidate genes and pathways related to platelet activation in diabetic patients.

Effect of common single-nucleotide polymorphisms in acetylsalicylic acid metabolic pathway genes on platelet reactivity in patients with diabetes.

BACKGROUND: Platelet reactivity in patients on acetylsalicylic acid (ASA) therapy can be influenced by physiological or pathological conditions affecting ASA pharmacokinetics or pharmacodynamics. The mechanism of such variability in the therapeutic response to ASA, particularly in diabetic patients, is poorly understood. The rate of elimination of ASA and its metabolite, salicylic acid (SA), is likely a major factor determining drug efficacy. The objective of this study was to investigate the effect of genetic polymorphisms in the selected candidate genes within the ASA metabolic pathway on the platelet reactivity and concentration of ASA and thromboxane A(2) (TxA(2)) metabolites in a population of patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: The study cohort consisted of 287 Caucasians with T2DM who had been taking ASA tablets at the dose of 75 mg per day for at least 3 months. Platelet reactivity analyses were performed using VerifyNow Aspirin and PFA-100 assays. The measured ASA metabolite included salicylic acid (ASA), and TxA(2) metabolites included serum TxB(2) and urinary 11-dh-TxB(2). Genotyping for the selected 18 single-nucleotide polymorphisms (SNPs) within 5 genes of the ASA metabolic pathway was performed using a Sequenom iPLEX platform. RESULTS: No statistically significant association was observed between the investigated SNPs genotypes, platelet reactivity, and measured metabolites in the investigated cohort of patients. CONCLUSIONS: The results of our study failed to confirm that the selected variants in the genes within the ASA metabolic pathway might contribute to platelet reactivity in a diabetic population treated with ASA.

Assessment of postural stability in women with hip osteoarthritis: A case-control study.

OBJECTIVE: The aim of the study was to assessment the impact of hip osteoarthritis on postural stability. METHODS: One hundred and twenty-five randomly selected women 20-85 years old (mean age of 49 ± 24.4 years) were assigned to three groups based on age, health status and activity level. Group 1 (cases) - elderly women with diagnosed hip osteoarthritis, group 2 (control) - women without hip osteoarthritis, and group 3 (control) - healthy young women. Assessment of postural stability were measured using a WIN-POD Pel 38 electronic podometer. Statistica 10 software was used to perform t-test resulting in significance level of p < 0.05. RESULTS: Significant differences in pedobarographic balance measurements were observed between the study groups with eyes opened or closed (deviation length eyes open: group 1-3 and 2-3 p < 0.0001; eyes closed group 1-2 p = 0.19; 1-3 and 2-3 p < 0.0001; deviation area eyes open: group 1-3 and 2-3 p < 0.0001; eyes closed group 1-3 and 2-3 p < 0.0001; deviation velocity eyes open: group1-3 and 2-3 p < 0.0001; eyes closed group 1-2 p < 0.010, 1-3 and 2-3 p < 0.0001). The poorest postural stability was observed in patients with hip osteoarthritis (deviation length eyes open vs eyes closed 180.8/201.7 p = 0.028, deviation area 128.7/145.7 p = 0.771, deviation velocity 5.1/6.1 p < 0.0001), and the best postural stability was observed in young women (deviation length 111.3/137.5 p < 0.0001, deviation area 57/76.9 p = 0.003, deviation velocity 3.4/4.2 p < 0.0001). CONCLUSION: (1) Osteoarthritic degeneration of the hip joint results in a significant disturbance in proprioception. This finding was reflected by the inferior stability parameters collected from subjects with hip osteoarthritis when asked to stand with their eyes closed. These finding were not observed in the other groups. (2) The disorder of the body stability of people with osteoarthritis may be a relative indication for the implantation of hip arthroplasty.

Association of adipokines and inflammatory markers with lipid control in type 2 diabetes.

INTRODUCTION: Data regarding the effect of certain adipokines on lipid metabolism are equivocal. OBJECTIVES: The aim of this study was to evaluate the association of lipid control with adipokines and inflammatory markers in patients with type 2 diabetes. PATIENTS AND METHODS: The analysis included 195 patients with type 2 diabetes. The achievement of treatment targets in terms of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides was assessed in accordance with the current guidelines. Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) index as well as concentrations of highmolecular-weight (HMW) adiponectin, leptin, resistin, high-sensitivity C-reactive protein, interleukin 6, and tumor necrosis factor α (TNF-α) were measured in all patients. Logistic regression analyses were performed to determine the risk factors for inadequate lipid control. RESULTS: Optimal control in terms of total cholesterol, LDL, HDL, and triglycerides was achieved in 61%, 43%, 53%, and 68% of the patients, respectively. In multivariate analyses, female sex, lower resistin concentrations, and the absence of statin treatment were predictors of total cholesterol levels above the treatment target; older age and lower statin dose--of LDL cholesterol levels above the treatment targets; female sex, higher HOMA-IR index, lower HMW adiponectin concentrations, and higher TNF-α concentration-o-f HDL levels below the treatment targets; and higher HOMA-IR, lower HMW adiponectin concentration, and the absence of statin treatment--of triglycerides above the treatment target. CONCLUSIONS: In type 2 diabetes, lower HMW adiponectin concentrations are associated with inadequate triglyceride and HDL control; higher TNF-α, with inadequate HDL control, and lower resistin concentrations, with inadequate total cholesterol control.

Effect of common single nucleotide polymorphisms in COX-1 gene on related metabolic activity in diabetic patients treated with acetylsalicylic acid.

INTRODUCTION: The objective of this study was to investigate the effect of common single nucleotide genomic polymorphisms in the cyclooxygenase-1 (COX-1) gene on the thromboxane A2 (TxA2) metabolite concentrations in serum and urine, as well as on prostaglandin F2α (PGF2α) urinary excretion in the diabetic population on acetylsalicylic acid (ASA) therapy. MATERIAL AND METHODS: The study cohort consisted of 284 Caucasians with diabetes type 2 who had been taking ASA tablets at the dose of 75 mg/day for at least 3 months. Genotyping for the 4 selected SNPs within the COX-1 gene (two nonsynonymous-coding variants, rs3842787 [C50T, P17L] and rs5789 [C174A, L237M]; and two other synonymous SNPs, rs3842788 [G128A, Q41Q] and rs5788 [C644A]) was performed using the Sequenom iPLEX platform. RESULTS: No statistically significant results were observed for the investigated SNPs and measured metabolites in the investigated cohort of patients. Statistically significant differences in S-TxB2 could however be observed for rs5788 in the subgroup of patients with very high S-TxB2 concentrations. In particular, more patients who were carriers of the minor allele for this polymorphism were observed in the group with S-TxB2 levels > 95(th) percentile, when compared with similar carriers in the group with S-TxB2 < 95(th) percentile (20% vs. 1.1%, respectively, p < 0.001, Mann-Whitney test). CONCLUSIONS: The results of our study suggest that the four investigated common SNPs in the COX1 gene are not associated with obviously altered TxA2 metabolism and PGF2α synthesis in the investigated diabetic cohort treated with ASA.

Effect of ASA dose doubling versus switching to clopidogrel on plasma inflammatory markers concentration in patients with type 2 diabetes and high platelet reactivity: the AVOCADO study.

BACKGROUND: The aim of the study was to compare the effects of 2 strategies of antiplatelet treatment (i.e., 150 mg ASA vs. 75 mg clpoidogrel) on plasma level of inflammatory markers in type 2 diabetes mellitus (T2DM) patients with high platelet reactivity (HPR). METHODS: Study cohort consisted of 304 T2DM patients on chronic ASA therapy (75 mg per day) participating in the Aspirin Versus/Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes (AVOCADO) study. Patients with HPR defined as Platelet Function Analyzer (PFA)-100 collagene/epinephrine closure time (CEPI-CT) < 193 s (n = 80) were randomized to 150 mg of ASA or 75 mg of clopidogrel in 2:3 ratio, respectively. Concentrations of the selected inflammatory markers, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, solubleCD40 ligand (sCD40L), and high sensitivity C-reactive protein (hsCRP), were measured and compared in both treatment groups before and after 8 weeks of treatment in both groups. RESULTS: Out of 234 patients included into final analysis, the total of 34.2% (n = 80) patients displayed HPR, of which 14.1% (n = 33) were randomized into 150 mg of ASA group and 20.1% (n = 47) into 75 mg of clopidogrel group. Treatment with clopidogrel was a positive predictor (stepwise multiple regression analysis) of reduction of sCD40L concentration (odds ratio [OR] 4.15; p = 0.013), while treatment with 150 mg ASA was a positive predictor of reduction of IL-6 concentration (OR 4.38; p = 0.033). There was no statistically significant differences between clopidogrel and ASA 150 mg treatment in respect to predictive value for decreased hsCRP concentrations or increased TNF-α concentrations. CONCLUSIONS: Increasing the dose of ASA from 75 mg to 150 mg daily or switching ASA 75 mg to clopidogrel 75 mg daily may reduce concentrations of some inflammatory markers (in particular hsCRP, IL-6 and CD40L) in T2DM patients with HPR treated previously with 75 mg of ASA.

Association of plasma concentrations of salicylic acid and high on ASA platelet reactivity in type 2 diabetes patients.

BACKGROUND: The objective of this study was to investigate the association between plasma concentrations of salicylic acid (SA) and other minor acetylsalicylic acid (ASA) metabolites and high on ASA platelet reactivity assessed with different methods in type 2 diabetic patients (T2DM). METHODS: Study cohort consisted of 293 T2DM patients on chronic ASA therapy. Platelet function inhibition was analyzed using measurements of serum thromboxane B2 (S-TxB2), VerifyNow Aspirin and Platelet Function Analyzer (PFA)-100 assays. The concentration of ASA metabolites in plasma was measured with a high-performance liquid chromatography (HPLC). RESULTS: In logistic regression analysis both ASA dose/kg of body weight and plasma SA concentration were found to be predictive of S-TxB2 concentrations above 0.72 ng/mL cut-off point (OR 16.9, 95% CI 2.29-125.8, p = 0.006 and OR 5.34, 95% CI 2.67-10.68, p < 0.001, respectively). When using the VerifyNow Aspirin Assay, the concentrations of SA were significantly lower (p = 0.007) in the group with high on ASA platelet reactivity when compared with the group with normal on ASA platelet reactivity. In logistic regression analysis plasma SA concentration was found to be predictive of VerifyNow Aspirin Reaction Units (ARU) ≥ 550 (OR 3.86, 95% CI 1.86-8.00, p < 0.001). CONCLUSIONS: Our study suggests that disturbances of pharmacokinetic mechanisms might contribute to lower plasma SA levels, and subsequently incomplete inhibition of thromboxane A2 synthesis as measured with S-TxB2 concentrations and increased platelet reactivity measured with VerifyNow in T2DM patients.

The effect of doubling the dose of acetylsalicylic acid (ASA) on platelet function parameters in patients with type 2 diabetes and platelet hyperreactivity during treatment with 75 mg of ASA: a subanalysis of the AVOCADO study.

BACKGROUND: Individuals with diabetes are at 2- to 4-fold higher risk of cardiovascular disease than those without diabetes. High platelet reactivity (HPR) plays a pivotal role in atherothrombotic complications of diabetes. Polish and American diabetes associations recommend treating high-risk diabetic patients with low doses of acetylsalicylic acid (ASA) in primary and secondary prevention of cardiovascular events. Unfortunately, some patients show HPR despite treatment with ASA. AIM: To determine the effect of doubling the dose of ASA on platelet reactivity in patients with type 2 diabetes and HPR despite treatment of with 75 mg of ASA. METHODS: 304 type 2 diabetes patients treated with 75 mg of ASA were enrolled into the prospective, randomised, open-label Aspirin Versus/Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes (AVOCADO) study. Platelet reactivity was assessed by Platelet Function Analyser (PFA)-100®, VerifyNow® Aspirin Assay, and serum thromboxane B2 (sTXB2) and urinary 11-dehydrothromboxane B2 (u11dhTXB2) level measurements. Patients with HPR determined by collagen/epinephrine-induced closure time (CEPI-CT) measured by PFA-100® were randomised in a 2:3 ratio to receive 150 mg of ASA (Group 1) or 75 mg of clopidogrel (Group 2), respectively. Platelet reactivity was assessed at baseline and after 8 weeks of treatment. RESULTS: Complete clinical data and blood samples were ultimately available for 260 of 304 patients initially enrolled to the study. Subsequently, six patients were excluded from the analysis based on suspected ASA non-compliance (sTXB2 level > 7200 pg/mL). Among 254 patients finally included into analysis, HPR was found in 90 (35.4%) patients of whom 38 patients were randomised to Group 1 and 52 patients to Group 2. Doubling the dose of ASA resulted in a significant CEPI-CT prolongation (Delta 111 s, p < 0.001) and reduction of sTXB2 level (Delta -101.3 pg/mL, p = 0.001) but did not significantly affect results of other platelet function tests. CONCLUSIONS: Doubling the dose of ASA improved platelet reactivity in patients with type 2 diabetes and HPR.

Lack of effect of common single nucleotide polymorphisms in leukotriene pathway genes on platelet reactivity in patients with diabetes.

The aim of the present study was to investigate the effect of genetic polymorphisms in candidate genes within the leukotriene (LT) pathway on platelet reactivity and the concentration of selected LTs in diabetic patients treated with acetylsalicylic acid (ASA). The study cohort consisted of 287 Caucasians with type 2 diabetes who had received treatment with ASA tablets (75 mg/day) for at least three months. Platelet reactivity analyses were performed using VerifyNow aspirin and PFA­100 assays. The measured LTs included leukotriene B4 (LTB4) and leukotriene E4 (LTE4). Genotyping for the selected 25 single nucleotide polymorphisms (SNPs) within six genes of the LT pathway was performed using a Sequenom iPLEX platform. No statistically significant association was observed between the investigated SNP genotypes, platelet reactivity and measured LTs in the patient cohort. The results of our study suggest that certain polymorphisms of the LT pathway are not associated with altered platelet reactivity and the measured LTs in diabetic patients treated with ASA.

Do statins influence platelet reactivity on acetylsalicylic acid therapy in patients with type 2 diabetes?

BACKGROUND: Type 2 diabetes (T2DM) patients are at increased risk of cardiovascular events despite long-term acetylsalicylic acid (ASA) therapy. This study was performed to establish the prevalence of high platelet reactivity (HPR) on ASA in T2DM and to identify its predictors. METHODS: The study included 185 T2DM on chronic ASA therapy and to assess platelet reactivity during long-term ASA therapy, we applied the point-of-care method VerifyNow(®) aspirin test (Accumetrics, San Diego, CA, USA). RESULTS: Compared with the low platelet reactivity (LPR) group, patients with HPR had higher triglyceride levels (145 vs. 118 mg/dL, p = 0.041), were less frequently treated with statins (57.1% vs. 75.3%; p = 0.038) and tumor necrosis factor-alpha (TNF-α) concentrations were higher (2.15 vs. 1.74 pg/mL; p = 0.052). In a multivariate analysis only statin therapy (OR 0.375; 95% CI 0.15-0.91; P = 0.030) and lower concentrations of TNF-α (for each 1.0 pg/ml: or 1.3; 95% ci 1.00-1.72; p = 0.046) were predictive of LPR. CONCLUSIONS: Our study provides indirect evidence that the beneficial effect of statins on platelet activity may be related to their non-lipid-mediated, pleiotropic mechanisms of action. This might have been partly related to decreased platelet reactivity in patients receiving statin therapy. In our study in patients with T2DM, platelet reactivity on ASA therapy measured with VerifyNow(®) was associated with TNF-α concentrations and statin therapy. These results may imply a role for subclinical systemic inflammation and a beneficial effect of statins in the development of HPR in T2DM.

Physical activity long-term after liver transplantation yields better quality of life.

BACKGROUND: Transplantation is the only effective method of treatment for end-stage and acute liver failure. Increased average survival time has been observed, and results from improved surgical technique and amended immunosuppression protocols. However, longer survival of patients after orthotopic liver transplantation (OLT) results in higher rate of various complications and ailments (eg, chronic fatigue, anxiousness, social isolation). Hence, gradual deterioration of health-related quality of life (HRQoL) is likely. The goal of this study was to examine the relation between physical activity and quality of life in patients 5 years after OLT. MATERIAL/METHODS: Twenty-six randomly selected patients who survived more than 5 years after orthotopic liver transplantation were included into the study. An SF-36 questionnaire was used for assessment of quality of life. Physical activity was measured subjectively by characterizing its type, duration and frequency per week during the previous 12 months. Patients were divided into 2 groups according to the results of physical activity assessment. Group A consisted of patients who had indicated they had a sedentary life style, and group B of those regularly engaging in physical exercise. RESULTS: Results of the SF-36 questionnaire in 10 categories were compared between the 2 groups. The majority of aspects of health-related quality of life (physical function, body problems, general health, social function, and emotional reaction) were significantly improved in patients who indicated they regularly engaged in physical exercise. CONCLUSIONS: Better quality of life was observed in patients who were physically active after OLT. Improving life quality with regular physical activity could be a valuable supplementation of complex management of OLT recipients.