Months Of Simvastatin Therapy Research Articles

The effect of APOE, CETP, and PCSK9 polymorphisms on simvastatin response in Thai hypercholesterolemic patients.

To investigate the effect of apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP) and proprotein convertase subtilisin kexin type 9 (PCSK9) polymorphisms on the lipid-lowering response to simvastatin therapy in Thai hypercholesterolemic patients. Two hundred and twenty-five hypercholesterolemic patients in southern Thailand were enrolled and treated with simvastatin 20 or 40mg per day for 3months. Serum lipids were measured before and after the therapy. APOE, CETP TaqIB, and PCSK9 (R46L, I474V, and E670G) polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). After 3months of simvastatin therapy, subjects with APOE2 (Total cholesterol [TC]: -30.89% vs-13.56%, P<.05, LDL-C: -45.00% vs -17.73%, P<.05) and APOE3 carriers (TC: -26.22% vs -13.56%, P<.05, LDL-C: -37.14% vs -17.73%, P<.05) had greater TC and LDL-C reduction compared to APOE4 carriers, whereas CETP TaqIB B2B2 genotype showed lower TC (-16.37% vs -24.92%, P=.016) and LDL-C (-22.54% vs -35.19%, P=.028) reduction compared to CETP TaqIB B1 carriers. In addition, PCSK9 474IV carriers showed greater LDL-C (-50.57% vs -32.99%) reduction compared to PCSK9 474II carriers. Combined effect analyses showed that individuals carrying more risk alleles tended to have lower TC and LDL-C (P for trend=.000 and .000, respectively) reduction in response to simvastatin therapy. APOE4 carriers and the CETP TaqIB B2B2 genotype were associated with a decreased response, but PCSK9 474IV carriers tended to be associated with an increased response to simvastatin therapy in Thai hypercholesterolemic patients.

Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: A randomized controlled trial

BackgroundPleiotropic effects of statins decrease intrahepatic resistance and portal hypertension. AimWe evaluated the effects of simvastatin on hepatic venous pressure gradient (HVPG) and azygos vein blood flow in cirrhotic patients. MethodsA 3-month prospective, randomized, triple-blind trial with simvastatin (40mg/day) vs. placebo was conducted in patients with cirrhotic portal hypertension. HVPG and azygos blood flow, measured by colour Doppler endoscopic ultrasound, were assessed before and after treatment. The primary endpoint was a decrease in the HVPG of at least 20% from baseline or to ≤12mmHg after the treatment. Results34 patients were prospectively enrolled, and 24 completed the protocol. In the simvastatin group 6/11 patients (55%) presented a clinically relevant decrease in the HVPG; no decrease was observed in the placebo group (p=0.036). Patients with medium/large oesophageal varices and previous variceal bleeding had a higher response rate to simvastatin. HVPG and azygos blood flow values were not correlated. No significant adverse events occurred. ConclusionSimvastatin lowers portal pressure and may even improve liver function. The haemodynamic effect appears to be more evident in patients with severe portal hypertension.

Statin therapy, myopathy and exercise--a case report

In a bid to reduce the morbidity and mortality associated with coronary artery disease, statin therapy has become a cornerstone treatment for patients with dyslipideamia. Statins, or HMG-CoA reductase inhibitors, are effective in blocking hepatic synthesis of cholesterol and are generally regarded as safe. Although rare, severe adverse side effects such as rhabdomyolysis have been reported, however, the more common complaint from patients is that related to myopathy. There is also mounting evidence that exercise may exacerbate these side effects, however the mechanisms are yet to be fully defined and there is controversy regarding the role that inflammation may play in the myopathy. This paper reports a patients experience during 6 months of simvastatin therapy and provides some insight into the white cell count (inflammation) following two bouts of moderate intensity exercise before and during statin therapy. It also highlights the need for rehabilitation practitioners to be aware of the adverse effects of statins in exercising patients.

Effect of Statin on the Reference Segments after Bare-Metal Stent Implantation

Effect of Statin on the Reference Segments after Bare-Metal Stent Implantation

Improvement of Endothelial Dysfunction with Simvastatin in Patients with Autosomal Dominant Polycystic Kidney Disease

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Endothelial dysfunction (ED), which is an early manifestation of vascular injury, has been shown in patients with ADPKD. Statins have a beneficial effect in the reversal of ED. The aim of this study was to investigate the effects of a statin, simvastatin, on ED in patients with ADPKD. Sixteen patients with ADPKD having well-preserved renal function were included in the study. Endothelial function of the brachial artery was evaluated by using high-resolution vascular ultrasound. Endothelial-dependent dilatation (EDD) was expressed as the percentage change in the brachial artery diameter from baseline to reactive hyperemia. After the baseline evaluations of EDDs, patients were started treatment with simvastatin at a dose of 40 mg/day and were treated for six months. EDDs were recalculated after one and six months of therapy. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein were also measured as markers of inflammation. Baseline EDD was 11.3 ± 6.9% in patients with ADPKD. After one month of simvastatin treatment, EDD increased significantly to 14.6 ± 4.6 % (P = 0.016 versus baseline). Endothelial-dependent dilatation further increased significantly to 18.9 ± 7.5 % (P = 0.011 versus baseline, P = 0.048 versus first month) after six months of therapy. There was also a significant decrease in the level of IL-6 from 21.6 ± 21.7 pg/mL to 9.1 ± 3.5 pg/mL (P= 0.002).Six months of simvastatin therapy resulted in a significant improvement of ED in patients with ADPKD. This finding may be in part related to the pleiotropic effects of simvastatin.

Cholesterol-lowering therapy evokes time-limited changes in serotonergic transmission

A number of studies have reported an increased risk for violent deaths and depression in subjects with reduced serum cholesterol concentrations. Links with hypothesized impairment of serotonin neurotransmission have not been satisfactorily tested. In this investigation, the serum and membrane cholesterol, microviscosity of erythrocyte membranes, platelet serotonin uptake, and clinical parameters were determined during pharmacotherapy of 17 hypercholesterolemic patients. A significant decrease in serum cholesterol and a nonsignificant decrease in membrane cholesterol concentration were found after 2 months of simvastatin therapy. Serotonin transporter (SERT) activity was significantly increased following 1 month of simvastatin; the tendency to decrease the initial increase in SERT activity was evident following 2 months of therapy. Both membrane cholesterol and SERT activity returned to pre-treatment levels after more than 1 year of therapy. Microviscosity of plasma membranes, impulsivity, empathy, adventure, sensation seeking, and depressed mood were not markedly changed. These data indicate that long-term therapy has different effects on serotonin transmission from short-term (1- to 2-month) therapy. A significant increase in SERT activity was detected only during the first month of simvastatin therapy. This finding suggests that within this period some patients could be vulnerable to depression, violence, or suicide.

Influence of Simvastatin on Aspects of Thrombogenesis in CAPD Patients

Patients on continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. Statins show beneficial effects on serum lipids and thrombogenesis in various groups of patients, but prospective studies have so far not been performed on CAPD patients. To determine the effects of 6 months' treatment with simvastatin on platelet function and some hemostatic parameters, markers of endothelial cell injury, in 14 CAPD patients with hypercholesterolemia. Simvastatin was given in a dose of 10 mg at bedtime. Commercially available kits were used for all determinations. Cholesterol and low density lipoprotein fell significantly as early as after 1 month of the therapy (p < 0.001). Platelet aggregation in whole blood and platelet-rich plasma was transiently decreased by simvastatin therapy. The fibrinolytic activity index increased significantly after 6 months of simvastatin administration (p < 0.05), reaching values observed in the control group, whereas euglobulin clot lysis time, which was also significantly shortened after 6 months (p < 0.05), did not reach values obtained in healthy volunteers. Vascular cell adhesion molecule, thrombomodulin, and protein Z decreased significantly after 3 months of the therapy (p < 0.05, p < 0.05, and p < 0.01, respectively), whereas intercellular adhesion molecule decreased after 6 months (p < 0.05). Vascular endothelial growth factor and its receptor, protein Z, total tissue factor pathway inhibitor (TFPI),TFPI/Xa complexes, and thrombin activatable fibrinolysis inhibitor concentration and activity fell significantly after 6 months of treatment with simvastatin (all p < 0.05). Tissue plasminogen activator concentration increased after 1 month (p < 0.01 after 1 month, p < 0.05 after 3 and 6 months), whereas total homocysteine fell after 6 months of simvastatin therapy (p < 0.05). Truncated TFPI decreased significantly as early as after 1 month of therapy (p < 0.05 after 1 month, p < 0.01 after 3 and 6 months). Simvastatin is an effective hypolipemic agent in CAPD patients. It favorably affects platelet aggregation and the extrinsic coagulation pathway, improves fibrinolysis, and ameliorates endothelial dysfunction. Simvastatin might reduce the risk of thrombotic complications in CAPD patients.

Effects of Long-Term Treatment with Simvastatin on Some Hemostatic Parameters in Continuous Ambulatory Peritoneal Dialysis Patients

Background/Aim: Disturbances in serum lipids, hemostasis and platelet functions are frequent features in uremia and may contribute to the progression of atherosclerosis and its thrombotic complications. Recently, attention has been paid to beneficial effects of statins on serum lipids and hemostasis in uremic patients. Peritoneally dialyzed (continuous ambulatory peritoneal dialysis; CAPD) subjects are particularly prone to dyslipidemia and have a high risk of cardiovascular death. The purpose of this work was to assess platelet functions, some hemostatic parameters and serum lipids in 8 hyperlipidemic CAPD patients treated with simvastatin (Zocor, MSD) for 6 months. Methods: Platelet aggregation in whole blood and in platelet-rich plasma (PRP) induced by collagen (2 µg/ml for whole blood and PRP), arachidonic acid (0.75 mM for whole blood and PRP), ADP (10 µM for whole blood and 5 µM for PRP) and ristocetin (0.75 mg/ml for whole blood and 1.5 mg/ml for PRP) was studied before and after 1, 3 and 6 months of simvastatin (dose: 10 mg at bedtime) treatment. Results: Whole-blood platelet aggregation induced by collagen decreased significantly after 3 and 6 months of the therapy, whereas in PRP, platelet aggregation induced by collagen and ADP decreased significantly after 6 months. Ristocetin-induced platelet aggregation in PRP decreased significantly after 3 and 6 months of simvastatin therapy. P-selectin remained unaltered by 6 months of simvastatin therapy. The fibrinolytic activity index was significantly higher after 3 months of the therapy when compared to the baseline values. Thrombomodulin, a marker of endothelial cell injury, was significantly lower after 3 and 6 months of the therapy. Prothrombin fragments 1 + 2 did not change significantly during 6 months of simvastatin administration. Cholesterol and LDL fell significantly as early as after 1 month and remained lowered during further months of the therapy. Conclusion: Simvastatin is an effective hypolipemic agent and favorably affects platelet aggregation, endothelial function and fibrinolysis in CAPD patients.

Effect of Simvastatin Therapy on Paraoxonase Activity and Related Lipoproteins in Familial Hypercholesterolemic Patients

Human paraoxonase (PON1) is a calcium-dependent esterase closely associated with high density lipoprotein (HDL)-containing apolipoprotein AI (apoAI), which has been shown to confer antioxidant properties to HDL. PON1 has been recently implicated in the pathogenesis of atherosclerosis. Low PON1 activities have been found in familial hypercholesterolemia (FH) and diabetes mellitus. We have undertaken a study of the effect of the lipid-lowering drug simvastatin on serum PON1 activity (in relation to paraoxon and arylesterase activity), on apoAI-containing and apolipoprotein B (apoB)-containing lipoproteins, and on lipid peroxide concentrations in 64 (39 women and 25 men) unrelated FH patients. We have also analyzed the influence of the PON1-192 and PON1-55 genetic polymorphisms on the response of PON1 activity to simvastatin therapy. A venous blood sample for a baseline analysis and another after 4 months of simvastatin therapy at a dosage of 20 mg per day were taken. The major effect of simvastatin on lipid traits was to decrease serum cholesterol, low density lipoprotein (LDL) cholesterol, and lipid peroxide concentrations by 19.9%, 26.3%, and 37.3%, respectively. There was also a significant decrease in serum apoB, LDL apoB, and triglyceride concentrations (20.5%, 21.1%, and 15.6%, respectively). Conversely, simvastatin had no significant influence on very low density lipoprotein-lipid content, HDL cholesterol, apoAI concentrations, and lipoprotein AI and AI:AII particles. Remarkably, serum PON1 activity toward paraoxon significantly increased during treatment with simvastatin (168. 7+/-100.3 U/L before therapy versus 189.5+/-116.5 U/L after therapy, P:=0.005). Arylesterase activity displayed only a nonsignificant trend to increase after therapy. Whereas PON1 activity levels were significantly lower in FH patients before simvastatin therapy compared with those of 124 normolipidemic subjects (168.7+/-100.3 versus 207.6+/-125.2 U/L, respectively; P:<0.05), this difference disappeared after simvastatin therapy. After simvastatin therapy, a significantly negative correlation between PON1 activity and lipid peroxide concentration was observed (r=-0.35, P:=0.028). The latter also strongly correlated with LDL cholesterol concentration (r=0.64, P:<0.001). Serum PON1 activity levels were significantly lower in the low-activity PON1-192 QQ and PON1-55 M carriers than in R carriers and in LL carriers, respectively. No significant differences were found in the therapeutic response of PON1 activity between genotype groups (8.5% and 11.1% increase for QQ homozygous and R-carrier FH patients, respectively, and 12.7% and 9.5% increase for LL homozygotes and M carriers, respectively). We conclude that simvastatin may have important antioxidant properties through increasing serum PON1 activity, perhaps as a consequence of reducing oxidative stress, by a mechanism independent of apoAI-containing lipoprotein concentration and without the influence of PON1-192 and PON1-55 genetic polymorphisms. Further studies are clearly warranted to clarify the precise mechanism by which simvastatin therapy is associated with increased PON1 activity.

Effect of simvastatin treatment on the electronegative low-density lipoprotein present in patients with heterozygous familial hypercholesterolemia

Most described modifications of low-density lipoprotein (LDL) cholesterol share an increase in its negative electric charge; in fact, an electronegative form of LDL can be identified and isolated from plasma. Although the exact nature of the chemical modification of electronegative LDL is still controversial, its toxicity on endothelial cells has been demonstrated. Statins have protective effects against cardiovascular disease that are independent of their lipid-lowering action and which could be due, at least in part, to the prevention of LDL modification. We evaluated the effect of 6 months of simvastatin therapy (40 mg/day) on electronegative LDL proportion and LDL susceptibility to in vitro induced oxidation in 21 patients with heterozygous familial hypercholesterolemia (FH). Eleven normolipemic subjects were analyzed as a control group. Total cholesterol as well as LDL and very low density lipoprotein cholesterol, triglycerides, and apoprotein B decreased 30% after the first month of therapy, with no further decreases thereafter. LDL susceptibility to oxidation was similar in FH patients and controls and did not change throughout the treatment. Electronegative LDL proportion was 35.1 ± 9.9% in FH patients and 9.1 ± 2.4% in control subjects (p <0.0001) but, in contrast to total LDL cholesterol and the rest of lipid parameters, it decreased to 28.6 ± 9.1% in the third month and to 21.2 ± 7.7% in the sixth month of therapy. The decrease in these cytotoxic particles may be a relevant mechanism by which simvastatin protects against cardiovascular disease.

Lipid-lowering therapy corrects endothelial cell dysfunction in a short time but does not affect hypercoagulable state even after long-term use in hyperlipidemic patients.

Lipid-lowering therapy reduces cardiac events to an extent that is disproportionate to the small degree of regression of coronary atherosclerosis observed among hyperlipidemic patients. We prospectively investigated the effects of lipid reduction using simvastatin on the endothelial dysfunction and hypercoagulability found in hyperlipidemic patients. We measured levels of coagulation factors [factor VII (FVII) coagulant activity (FVIIc), FVII antigen (FVIIAg), activated FVII (FVIIa), and fibrinogen], and markers of coagulation activation [prothrombin fragment 1 + 2 (F1 + 2)] and endothelial cell dysfunction [von Willebrand factor (vWF)] in 20 hyperlipidemic patients, 20 hypertensive patients, and 20 normotensive normolipidemic controls. The levels of FVIIa, FVIIc, FVIIAg, F1 + 2, and vWF were all higher in hyperlipidemic patients, but only FVIIa, F1 + 2, and vWF levels were higher in hypertensive patients than in controls. We measured the above parameters in 13 hyperlipidemic patients before and after 1, 3, 6, 12 and 24 months of simvastatin therapy and compared these values with those in 15 hypertensive patients at baseline and after 12 and 24 months. The median (25th-75th percentile) level of total cholesterol was decreased from 259 (255-278) to 206 (176-220) mg/dl after 1 month of simvastatin therapy and this reduction persisted for 2 years. The plasma level of vWF [136% (113-158%)] was not changed after 1 month of administration of simvastatin [132% (115-153%)], but was decreased after 3 months of treatment [114% (96-128%), P<0.01]. This decrease also persisted for 2 years during simvastatin therapy and both of these reductions were significant, compared with levels in hypertensive patients. In contrast, levels of fibrinogen, FVIIc, FVIIAg, FVIIa, and F1 + 2 did not change throughout the 2 years of simvastatin therapy. We conclude that lipid reduction using simvastatin corrects endothelial cell dysfunction but not hypercoagulability in hyperlipidemic patients. The improvement in endothelial cell function brought about by lipid-lowering therapy might contribute to the reduction in cardiac events within a relatively short time period in hyperlipidemic patients.

Dissolution of gallstones with simvastatin, an HMG CoA reductase inhibitor.

The aim of this study was to determine whether 12 months of therapy with Simvastatin, an HMG CoA reductase inhibitor, would dissolve gallstones. Twenty-seven subjects entered the study, all had a fasting oral cholecystogram, ultrasound examination, and fasting serum lipids prior to therapy. In addition, 22 subjects had their gallbladder ejection fraction, after CCK, determined by radionucleotide scanning. Eleven subjects had the cholesterol saturation index (CSI) of bile calculated before and at the end of 12 months of therapy. Of the 27 subjects, 26 completed 12 months of treatment with Simvastatin 20 mg daily. There was a significant fall in the total serum cholesterol (27%, P < 0.0001), LDL cholesterol (31%, P < 0.0001), triglyceride (34%, P < 0.0001) but no change in HDL after 12 months of therapy. Simvastatin treatment resulted in a 28% fall in the CSI of bile at the end of therapy (P < 0.01). The concentrations of individual bile acids did not change with therapy, and apart from a slight but significant increase in arachidonate, there were no other significant changes in the fatty acid composition of the biliary phospholipids. After 12 months of Simvastatin therapy there was a small decrease in the gallstone diameter but complete dissolution of gallstones was not achieved in any subjects. In conclusion 12 months of therapy with Simvastatin was effective in lowering the serum lipids and the CSI of bile but was not effective in dissolving gallstones.

Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG‐CoA reductase inhibitors

To test the possibility that HMG-CoA reductase inhibitors reduce LDL mass by an increased VLDL catabolism, we determined the effect of simvastatin therapy on cellular metabolism of VLDL in 18 patients with primary hypercholesterolaemia. Six months of simvastatin therapy was followed by 26%, 31% and 21% reduction of plasma total cholesterol, LDL-cholesterol and plasma triglyceride levels, respectively. Before therapy, patients' VLDL metabolism in cultured human normal skin fibroblasts was similar to control VLDL. Six months after therapy was initiated, a remarkable 2-5-fold increase in VLDL cell metabolism was found. These effects were even more marked when the VLDL was enriched with exogenous recombinant apo E-3. A comparison of the metabolism of the patients' VLDL to control VLDL and LDL, revealed that simvastatin increased metabolic ratios of 60-70% and 45-95%, respectively. Simvastatin therapy was associated with a decrease of VLDL cholesteryl ester content of 19% and increase of the phospholipid content of 13%. The data strongly indicate that simvastatin therapy stimulates VLDL: cell interactions and catabolism, possibly reflecting alterations of the physico-chemical properties of the particle. It is proposed that in addition to other previously described pathways, HMG-CoA reductase inhibitors decrease LDL mass through a novel mechanism of enhanced VLDL catabolism prior to the conversion to LDL.