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Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner.
Theusch, E, Kim, K, Stevens, K, Smith, JD, Chen, YI, Rotter, JI, Nickerson, DA, Medina, MW
The pharmacogenomics journal. 2017;(3):222-229
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Abstract
Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR=15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho=0.32, q=0.11) was driven by men (interaction P=0.0055). rs73161338 was associated with INSIG1 expression changes (P=5.4 × 10-5) and TG response in two statin clinical trials (P=0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P=5.6 × 10-6). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.
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Simvastatin therapy decreases MMP-9 levels in obese women.
Andrade, VL, do Valle, IB, Sandrim, VC
Journal of clinical pharmacology. 2013;(10):1072-7
Abstract
Statins exert cholesterol-independent beneficial effects on multiple targets including the cardiovascular system, in addition to modulating matrix metalloproteinases (MMPs) expression. The purpose of this study was to assess the effects of simvastatin treatment in obese women without comorbidities. We recruited 33 obese women that received placebo or simvastatin at 20 mg/day for 45 days. Plasma MMP-9, MMP-2, TIMP-1, and TIMP-2 levels were measured using an enzyme-linked immunosorbent assay (ELISA). Cardiovascular risk was assessed by the Framingham risk score and Castelli indexes I and II. Treatment with simvastatin significantly reduced MMP-9 levels and the MMP-9/TIMP-1 ratio (P < .05) when compared to the placebo group (P > .05). Conversely, we found no effect on MMP-2, TIMP-1, and TIMP-2 levels or on the MMP-2/TIMP-2 ratio (P > .05). The Framingham risk score and Castelli I and II indexes were significantly reduced in the simvastatin-treatment group (P < .05), while we found no effect on the placebo group. These findings may have clinical importance since simvastatin therapy reduced cardiovascular risk and MMP-9 levels in obese woman without comorbidities, indicating a potentially new therapeutic approach.
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CYP3AP1*3 allele is associated with lipid-lowering efficacy of simvastatin and atorvastatin in Chinese women.
Li, YP, Zhang, LR, Jia, M, Hu, XJ
Journal of clinical pharmacology. 2011;(2):181-8
Abstract
Response to statin therapy for cardiovascular disease is variable among different individuals. The authors aimed to investigate the effect of the CYP3AP1*3 polymorphism on the lipid-lowering efficacy of statins. They recruited 379 unrelated hyperlipidemic patients: 202 (103 men) treated with simvastatin and 177 (87 men) with atorvastatin as single-agent therapy (20 mg day(-1) orally) for 4 weeks. CYP3AP1*3(-44G>A) was genotyped using the PCR restriction fragment-length polymorphism method. Serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) were determined before and after treatment. The frequency of the CYP3AP1*3 variant allele in Chinese hyperlipidemic patients was 70.6%. In the simvastatin treatment group, the percentage reduction of LDL-C level was greater in the CYP3AP1*3/*3 carriers than in the CYP3AP1*1 carriers. This difference was statistically significant for women but not for men. In contrast, the authors found no significant association between the lipid-lowering efficacy of atorvastatin and the CYP3AP1*3 polymorphism in all participants. However, in women, the percentage change of the TC level was significantly lower in the CYP3AP1*3/*3 carriers than in the CYP3AP1*1 carriers. These findings suggest that the CYP3AP1*3 allele may be a biomarker for the lipid-lowering efficacy of simvastatin and atorvastatin in Chinese women with hyperlipidemia.
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Lymphocyte-suppressing effect of simvastatin in mixed dyslipidemic patients but not impaired glucose tolerance patients.
Krysiak, R, Okopień, B
Pharmacological reports : PR. 2011;(1):95-101
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Abstract
This study compared the effect of simvastatin on lymphocyte secretory function between patients with impaired glucose tolerance (IGT) (n=30) and mixed dyslipidemia (n=29). Lipid profile, glucose metabolism markers (fasting and 2-h post-glucose challenge glucose levels, HOMA-IR and glycated hemoglobin), plasma CRP levels and the release of interleukin-2 and interferon-γ by phytohemagglutinin-stimulated T lymphocytes were determined before and after 30 and 90 days of simvastatin administration (20 mg daily). Phytohemagglutinin-stimulated T cells from both IGT and mixed dyslipidemic subjects released significantly higher amounts of both cytokines than lymphocytes of 30 dyslipidemia-free individuals with normal glucose tolerance. Despite improving the lipid profile, simvastatin produced no effects on glucose metabolism markers in either treatment groups. The drug normalized the lymphocyte cytokine release and plasma hsCRP in mixed dyslipidemic patients but not in IGT patients. Our study indicates that the presence of mixed dyslipidemia and IGT is associated with the enhanced secretory function of human lymphocytes. Simvastatin is an effective lymphocyte-suppressing agent in mixed dyslipidemic patients but not in IGT patients.
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Prior simvastatin treatment is associated with reduced thrombin generation and platelet activation in patients with acute ST-segment elevation myocardial infarction.
Pastuszczak, M, Kotlarz, A, Mostowik, M, Zalewski, J, Zmudka, K, Undas, A
Thrombosis research. 2010;(5):382-6
Abstract
BACKGROUND It has been reported that statin therapy produces additional effects including impaired activation of blood coagulation. It is not clear whether statins can affect hemostasis in patients with acute coronary syndrome. The aim of this study was to investigate the effect of prior statin treatment on thrombin generation and platelet activation in patients with ST-segment elevation myocardial infarction (STEMI). METHODS We studied 53 consecutive STEMI patients admitted within 12 hours of pain onset, including 19 treated with simvastatin (40 mg/d) (simvastatin group) at least one month prior to STEMI, and 34 not receiving any statins (no-statin group) on admission. Thrombin-antithrombin (TAT) complexes generation and soluble CD40 ligand (sCD40L) release were determined in 60-second blood samples collected at the site of microvascular injury. RESULTS There were no significant intergroup differences with respect to clinical and laboratory variables, including plasma TAT and sCD40L levels, except lower total cholesterol and low-density lipoprotein cholesterol in the simvastatin group. The mean maximum rate of TAT generation was 47.5% lower (p=0.0002) and sCD40L release 33.3% lower (p=0.0006) in the simvastatin group. Total amounts of TAT (p<0.0001) and sCD40L (p=0.002) collected within 5 minutes of bleeding were lower in simvastatin-pretreated patients. By multivariate regression analysis, variables describing local TAT and sCD40L profiles in the whole group were independently associated with simvastatin pretreatment (p<0.0001), but not with cholesterol, platelet count or troponin levels. CONCLUSIONS Prior simvastatin use is associated with lower thrombin generation and platelet activation following vascular injury in the early phase of STEMI.
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Simvastatin increases clot permeability and susceptibility to lysis in patients with LDL cholesterol below 3.4 mmol/l.
Undas, A, Topór-Madry, R, Tracz, W
Polskie Archiwum Medycyny Wewnetrznej. 2009;(6):354-9
Abstract
INTRODUCTION Statins produce additional beneficial effects, including attenuation of prothrombotic mechanisms. In patients at high cardiovascular risk, who have markedly elevated low-density lipoprotein (LDL) cholesterol levels, simvastatin can reduce thrombin generation. Moreover, we have described simvastatin-induced improvement of fibrin clot properties, the formation of which represents the final step of blood coagulation. OBJECTIVES The aim of the present study was to assess the effect of simvastatin on fibrin features observed in subjects with LDL cholesterol <3.4 mmol/l. PATIENTS AND METHODS Thirty subjects (24M, 6F) aged <70 years with LDL cholesterol <3.4 mmol/l with no history of cardiovascular events were enrolled in the study. Patients were excluded if they had diabetes mellitus, chronic inflammatory diseases and renal insufficiency. Prior to and following a 3-month treatment with simvastatin (40 mg/d), ex vivo plasma fibrin clot permeability and efficiency of clot lysis were measured. RESULTS Simvastatin led to a significant decrease in total cholesterol, LDL cholesterol, triglycerides and C-reactive protein (CRP), while fibrinogen levels remained unaltered. There were posttreatment increase in clot permeability by 4.4% (p<0.001) and shortening of clot lysis by 11.2% (p<0.001) compared to pretreatment values. These changes were correlated with reduction in CRP following simvastatin. Simvastatin-induced increase in clot permeability was associated only with age and decrease in CRP levels (R2 for the model = 0.61), while shortening of clot lysis time observed following simvastatin use was predicted only by reduction of triglycerides and CRP (R2 for the model = 0.62). CONCLUSIONS Simvastatin exerts unique properties involving enhanced fibrin clot lysis and increased clot permeability in subjects with LDL cholesterol <3.4 mmol/l, which is associated with its anti-inflammatory effects. Altered fibrin clot function might contribute to clinical benefits of statins.
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Simvastatin and ezetimibe in addition to nonpharmacological risk factor modification for achieving new low-density lipoprotein cholesterol targets.
Liska, B, Khattab, AA, Herrmann, L, Abdel-Wahab, M, Westphal, R, Tölg, R, Geist, V, Richardt, G
Herz. 2008;(5):362-7
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Abstract
BACKGROUND Though guidelines emphasize low-density lipoprotein cholesterol (LDL-C) lowering as an essential strategy for cardiovascular risk reduction, achieving target levels may be difficult. PATIENTS AND METHODS The authors conducted a prospective, controlled, open-label trial examining the effectiveness and safety of high-dose fluvastatin or a standard dosage of simvastatin plus ezetimibe, both with an intensive guideline-oriented cardiac rehabilitation program, in achieving the new ATP III LDL-C targets in patients with proven coronary artery disease. 305 consecutive patients were enrolled in the study. Patients were divided into two groups: the simvastatin (40 mg/d) plus ezetimibe (10 mg/d) and the fluvastatin-only group (80 mg/d). Patients in both study groups received the treatment for 21 days in addition to nonpharmacological measures, including advanced physical, dietary, psychosocial, and educational activities. RESULTS After 21 days of treatment, a significant reduction in LDL-C was found in both study groups as compared to the initial values, however, the reduction in LDL-C was significantly stronger in the simvastatin plus ezetimibe group: simvastatin plus ezetimibe treatment decreased LDL-C to a mean level of 57.7 +/- 1.7 mg/ml, while fluvastatin achieved a reduction to 84.1 +/- 2.4 mg/ml (p < 0.001). In the simvastatin plus ezetimibe group, 95% of the patients reached the target level of LDL-C < 100 mg/dl. This percentage was significantly higher than in patients treated with fluvastatin alone (75%; p < 0.001). The greater effectiveness of simvastatin plus ezetimibe was more impressive when considering the optional goal of LDL-C < 70 mg/dl (75% vs. 32%, respectively; p < 0.001). There was no difference in occurrence of adverse events between both groups. CONCLUSION Simvastatin 40 mg/d plus ezetimibe 10 mg/d, on the background of a guideline-oriented standardized intensive cardiac rehabilitation program, can reach 95% effectiveness in achieving challenging goals (LDL < 100 mg/dl) using lipid-lowering medication in patients at high cardiovascular risk.
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[Effect of long-term cardiac training on lipids concentration in patients with chronic heart ischemic disease treated with simvastatin].
Kałka, D, Sobieszczańska, M, Kopka, L, Marciniak, W, Zawadzka-Bartczak, E, Bak, A, Popielewicz-Kautz, A, Korzeniowska, J, Janczak, J, Adamus, J
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2007;(128):101-6
Abstract
UNLABELLED Dyslipidemia worsens a prognosis in patients with chronic heart ischemic disease, who underwent myocardial infarction. Therefore, new methods, besides drugs, are being sought, for optimizing a serum concentration of lipid fractions. THE AIM An effect of 6-month of ambulatory long-term cardiac rehabilitation on the lipidogram fractions concentration in patients with chronic heart ischemic disease treated with simvastatin, as well as a correlation between lipids changes and cardiac training intensity was assessed. MATERIAL AND METHOD Rehabilitation was performed in 66 patients with previous myocardial infarction treated invasively (27 CABG and 39 PTCA), who constituted group I. A control group (group II) consisted of 32 patients with previous myocardial infarction also treated invasively (24 CABG and 8 PTCA), but not subjected to rehabilitation. The two analyzed groups did not differ significantly from each other as to age, applied drug regimen, current clinical status, echocardiographic parameters and BMI values. Group I was subjected to 6-month cardiac rehabilitation program, comprising 45-minute training on cycle ergometer (three times per week) and generally improving exercises (2 times per week). Blood concentration of lipidogram fractions was assessed: total cholesterol (TC), HDL- and LDL-cholesterol, and triglicerides (TG) at the onset and upon completion of the rehabilitation cycle. RESULTS The both patient groups were comparable concerning the initial concentration of the lipid fractions. After finishing the rehabilitation program, in the group I, a statistically significant reduction of TC, LDL and TG concentration was found out. In addition, a significant increase of HDL concentration was noted. In contrary, in the group II (without rehabilitation), the only significant change concerned a concentration of HDL fraction, which decreased. Furthermore, in the group I, it was noted a negative, statistically significant correlation between intensity of cardiac training, expressed by training workload and delta of work, and a difference in blood concentration of triglicerides, measured just before the training onset and after the program was finished. CONCLUSION It was revealed that long-term ambulatory cardiac rehabilitation has a profitable effect on serum concentration of the all lipid fractions in patients with chronic heart ischemic disease cured with simvastatin, regardless of training intensity. It was also ascertained that an extent of changes in triglicerides serum concentration was related to an intensity of the cardiac training applied to the patients.
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Statin therapy reduces serum levels of glycosylphosphatidylinositol-specific phospholipase D.
Deeg, MA, Raikwar, NS, Johnson, C, Williams, CD
Translational research : the journal of laboratory and clinical medicine. 2007;(3):153-7
Abstract
Statin therapy is associated with changes in low-density, very low-density, and high- density lipoprotein metabolism. The effect of statin therapy on a minor high-density lipoprotein particle containing glycosylphosphatidylinositol-specific phospholipase D has not been examined. Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) has been implicated in triglyceride metabolism. A double-blind, crossover design comparing the effect of simvastatin (80 mg) and atorvastatin (80 mg) on serum lipid and glycosylphosphatidylinositol-specific phospholipase D levels was conducted in 13 patients with low high-density lipoproteins. Both statins reduced cholesterol, triglycerides, and apolipoprotein B and significantly lowered serum glycosylphosphatidylinositol-specific phospholipase D levels (16%). This statin effect seems to occur in the plasma compartment as neither statin altered GPI-PLD mRNA levels in HepG2 cells. Serum glycosylphosphatidylinositol-specific phospholipase D levels are regulated by statins and may represent an additional biochemical mechanism for affecting serum triglyceride levels.
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Effect of simvastatin on coronary flow reserve in patients with atherosclerosis and hypercholesterolemia: an intracoronary Doppler study.
Jensen, LO, Thayssen, P, Pedersen, KE, Haghfelt, T
Coronary artery disease. 2006;(1):51-6
Abstract
BACKGROUND Early stages of coronary atherosclerosis are accompanied by a functional impairment of coronary vasodilator capacity and endothelial dysfunction. Reduced coronary flow reserve has been reported in patients with hypercholesterolemia, despite angiographically normal coronary arteries. The aim of the study was to evaluate the effect of simvastatin on coronary flow reserve. METHODS The study was an open non-placebo-controlled serial investigation in which every patient acted as his own control: 36 male patients with hypercholesterolemia and a non-significant coronary artery lesion in a not previously revascularized coronary artery. Intracoronary Doppler measurements were performed. Coronary flow reserve, relative coronary flow reserve and average peak velocity were performed at baseline, after 3 months on a lipid-lowering diet (control period), and after another 12 months of simvastatin 40 mg/day. In the same patient cohort, significant reduction in lesion plaque plus media has been demonstrated by intravascular ultrasound. RESULTS Changes in coronary flow reserve were not influenced by either diet or simvastatin (2.5+/-0.6 vs. 2.6+/-0.5 vs. 2.6+/-0.6, P=ns). Maximum hyperemic flow (34.8+/-12.2 vs. 36.7+/-12.5 vs. 42.5+/-13.1, P<0.001) as well as resting flow (14.3+/-5.3 vs. 14.5+/-4.4 vs. 16.6+/-4.6, P<0.001) increased significantly after 12 months simvastatin therapy. CONCLUSION Despite plaque plus media, regression simvastatin therapy for 12 months does not affect coronary flow reserve obtained using serial intracoronary Doppler studies. Simvastatin, however, increases the hyperemic flow velocity.