Long-term Simvastatin Treatment Research Articles

Long-Term Treatment with Simvastatin Leads to Reduced Migration Capacity of Prostate Cancer Cells.

Statins have been shown to improve survival of metastatic prostate cancer (mPCa). Nevertheless, their therapeutic use is still under debate. In the present study, we investigated the short-term effects of three different statins (simvastatin, atorvastatin and rosuvastatin) in various PCa cell lines mimicking androgen-sensitive and -insensitive PCa. Moreover, we generated three new PCa cell lines (LNCaPsim, ABLsim, PC-3sim) that were cultured with simvastatin over several months. Our data showed that the three statins expressed highly diverse short-term effects, with the strongest growth-inhibitory effect from simvastatin in PC-3 cells and almost no effect from rosuvastatin in any of the cell lines. Long-term treatment with simvastatin resulted in a loss of response to statins in all three cell lines, which was associated with an upregulation of cholesterol and fatty acid pathways as revealed through RNA sequencing. Despite that, long-term treated cells exhibited diminished spheroid growth and significantly reduced migration capacity per se and to differentiated osteoclasts. These findings were strengthened by reduced expression of genes annotated to cell adhesion and migration after long-term simvastatin treatment. Notably, mPCa patients taking statins were found to have lower numbers of circulating tumor cells in their blood with reduced levels of PSA and alkaline phosphatase. Our data suggest that long-term usage of simvastatin hampers the metastatic potential of PCa cells and may therefore be a potential therapeutic drug for mPCa.

Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterised by the selective loss of motor neurons, muscular atrophy, and degeneration. Statins, as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely prescribed drugs to lower cholesterol levels and used for the treatment of cardiovascular and cerebrovascular diseases. However, statins are seldom used in muscular diseases, primarily because of their rare statin-associated myopathy. Recently, statins have been shown to reduce muscular damage and improve its function. Here, we investigated the role of statins in myopathy using G93ASOD1 mice. Our results indicated that simvastatin significantly increased the autophagic flux defect and increased inflammation in the skeletal muscles of G93ASOD1 mice. We also found that increased inflammation correlated with aggravated muscle atrophy and fibrosis. Nevertheless, long-term simvastatin treatment promoted the regeneration of damaged muscle by activating the mammalian target of rapamycin pathway. However, administration of simvastatin did not impede vast muscle degeneration and movement dysfunction resulting from the enhanced progressive impairment of the neuromuscular junction. Together, our findings highlighted that simvastatin exacerbated skeletal muscle atrophy and denervation in spite of promoting myogenesis in damaged muscle, providing new insights into the selective use of statin-induced myopathy in ALS.

Biochemical Changes in Erythrocytes as a Molecular Marker of Cell Damage during Long-Term Simvastatin Treatment

Long-term administration of simvastatin to rats, irrespective of the baseline cholesterol levels, induced biochemical changes in erythrocytes attesting to hypoxic damage (accumulation of lactate and 2,3-diphosphoglycerate), disturbances in ATP-dependent mechanisms of ion homeostasis regulation (decrease in total ATPase and Ca(2+)-ATPase activities), and antioxidant enzymes system imbalance. These changes can be considered as a sensitive indicator and molecular basis of cell damage during long-term administration of statins.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.

Analysis of Biochemical Changes in Rat Erythrocytes Induced by Long-Term Simvastatin Treatment

Analysis of metabolic changes in rat erythrocytes against the background of long-term simvastatin treatment revealed an increase in glycolysis metabolite concentrations and glucose-6-phosphate dehydrogenase activity and oppositely directed shifts in antioxidant defense enzyme activities. It was demonstrated that hypoxia and imbalance in the antioxidant enzyme system contribute to the development of side effects of statins.

O87 – 1771 Long-term simvastatin treatment for cognition and daily life in children with neurofibromatosis type 1: results from the NF1-SIMCODA trial

O87 – 1771 Long-term simvastatin treatment for cognition and daily life in children with neurofibromatosis type 1: results from the NF1-SIMCODA trial

Simvastatin influence on carotid atherosclerotic disease regression

The measurement of intima-media thickness (IMT) of carotid arteries has emerged as the method of choice for determining the anatomic extent of atherosclerosis and assessing cardiovascular progression. Statins are used in the primary and secondary prevention of cardiovascular and cerebrovascular disorders so as to reduce morbidity and mortality. To evaluate the effects of treatment with simvastatin in patients with elevated cholesterol levels and increased values of carotid arteries IMT. The study of 275 patients (155 male and 115 female, aged 37-79 years, mean 60.86 years) was performed from January 2008 - January 2010 at the Vascular and Endovascular Surgery Clinic of the Clinical Centre of Serbia. All patients were treated with simvastatin administered once a day for 6 months. Simvastatin treatment resulted in a statistically signuficant decrease of the IMT thickness of the right common carotid artery. There was no statistically significant reduction in the IMT of the left common carotid artery as well as in the IMT of the right and left internal carotid arteries. Long-term simvastatin treatment results in the regression or slowing down atherosclerosis in symptomatic, as well as in asymptomatic patients with a lower grade of carotid stenosis (IMT below 2.5 mm).

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

Statin Therapy Inhibits Remyelination in the Central Nervous System

Remyelination of lesions in the central nervous system contributes to neural repair following clinical relapses in multiple sclerosis. Remyelination is initiated by recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. Simvastatin, a blood-brain barrier-permeable statin in multiple sclerosis clinical trials, has been shown to impact the in vitro processes that have been implicated in remyelination. Animals were fed a cuprizone-supplemented diet for 6 weeks to induce localized demyelination in the corpus callosum; subsequent return to normal diet for 3 weeks stimulated remyelination. Simvastatin was injected intraperitoneally during the period of coincident demyelination and OPC maturation (weeks 4 to 6), throughout the entire period of OPC responses (weeks 4 to 9), or during the remyelination-only phase (weeks 7 to 9). Simvastatin treatment (weeks 4 to 6) caused a decrease in myelin load and both Olig2(strong) and Nkx2.2(strong) OPC numbers. Simvastatin treatment (weeks 4 to 9 and 7 to 9) caused a decrease in myelin load, which was correlated with a reduction in Nkx2.2(strong) OPCs and an increase in Olig2(strong) cells, suggesting that OPCs were maintained in an immature state (Olig2(strong)/Nkx2.2(weak)). NogoA+ oligodendrocyte numbers were decreased during all simvastatin treatment regimens. Our findings suggest that simvastatin inhibits central nervous system remyelination by blocking progenitor differentiation, indicating the need to monitor effects of systemic immunotherapies that can access the central nervous system on brain tissue-repair processes.

Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up

Our study investigated reactive oxygen species (ROS) generation and angiotensin II type 1 receptor (AT(1)-R) expression in primed polymorphonuclear leukocytes (PMNs) of dyslipidaemic subjects over prolonged statin treatment. Sixteen untreated dyslipidaemic subjects with moderately increased cardiovascular risk (National Cholesterol Education Program, Adult Treatment Panel III) were studied before and during long-term (1 year) simvastatin treatment. Neutrophils from dyslipidaemic subjects generated more ROS in comparison with cells from healthy control subjects. After 1 year of simvastatin treatment, ROS production (delta N-formyl-Met-Leu-Phe-induced generation and area under the curve) was significantly reduced. At baseline, AT1-R mRNA expression was also higher in dyslipidaemic subjects than in healthy controls and it was reduced after clinical treatment with simvastatin. In a subgroup of patients, a reduced angiotensin II-induced ROS generation was also observed upon clinical simvastatin treatment. Moreover, a direct effect of statin on the upregulated AT(1)-R expression was demonstrated in vitro in neutrophils of untreated dyslipidaemic subjects. A consistent reversion of pro-inflammatory oxidative functional response and reduction of AT(1)-R expression in primed PMNs was observed in patients during long-term statin treatment. The AT1-R reduction over treatment may contribute to the normalization of dysregulated neutrophil activation which occurs in the pre-clinical phase of atherosclerosis.

Effect of Simvastatin Use on Bone Mineral Density in Women with Type 2 Diabetes

To attempt to clarify the effect of simvastatin, a widely used statin, on the bone mineral density in women with type 2 diabetes. We performed a cross-sectional, controlled study of 37 women with type 2 diabetes who were taking simvastatin. Each woman was matched with 2 control subjects who were closest in age, years since menopause (if applicable), and duration of diabetes on the date on which the examination was performed. We measured bone mineral density at the spine and the hip with a dual-energy xray absorptiometry scanner and compared bone density in the 2 study groups. The mean bone mineral density values of patients in the simvastatin group were found to be slightly increased in comparison with those of the control group, both in the lumbar vertebrae and in the femoral neck, but these differences were not statistically significant (P>0.05). In this cross-sectional study, we could not demonstrate a positive effect of long-term simvastatin treatment on bone mineral density in women with type 2 diabetes and hypercholesterolemia.

Plant sterol or stanol esters retard lesion formation in LDL receptor-deficient mice independent of changes in serum plant sterols

Statins do not always decrease coronary heart disease mortality, which was speculated based on increased serum plant sterols observed during statin treatment. To evaluate plant sterol atherogenicity, we fed low density lipoprotein-receptor deficient (LDLr(+/-)) mice for 35 weeks with Western diets (control) alone or enriched with atorvastatin or atorvastatin plus plant sterols or stanols. Atorvastatin decreased serum cholesterol by 22% and lesion area by 57%. Adding plant sterols or stanols to atorvastatin decreased serum cholesterol by 39% and 41%. Cholesterol-standardized serum plant sterol concentrations increased by 4- to 11-fold during sterol plus atorvastatin treatment versus stanol plus atorvastatin treatment. However, lesion size decreased similarly in the sterol plus atorvastatin (-99% vs. control) and the stanol plus atorvastatin (-98%) groups, with comparable serum cholesterol levels, suggesting that increased plant sterol concentrations are not atherogenic. Our second study confirms this conclusion. Compared with lesions after a 33 week atherogenic period, lesion size further increased in controls (+97%) during 12 more weeks on the diet, whereas 12 weeks with the addition of plant sterols or stanols decreased lesion size (66% and 64%). These findings indicate that in LDLr(+/-) mice 1) increased cholesterol-standardized serum plant sterol concentrations are not atherogenic, 2) adding plant sterols/stanols to atorvastatin further inhibits lesion formation, and 3) plant sterols/stanols inhibit the progression or even induce the regression of existing lesions.

Protective Effects of Statins Involving Both eNOS and tPA in Focal Cerebral Ischemia

Previous studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect the brain against ischemic injury by upregulating endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that statins provide additional beneficial effects by also upregulating endogenous tissue plasminogen activator (tPA) and enhancing clot lysis in a mouse model of embolic focal ischemia. Heterologous blood clots (0.2 mm) were injected into the distal internal carotid artery to occlude blood flow in the middle cerebral artery territory after long-term (14 days) simvastatin, atorvastatin or vehicle treatment. Ischemic lesion volume, neurologic deficits, as well as residual blood clots were measured at 22 h. Reverse transcription-polymerase chain reaction assessed mRNA levels of eNOS, tPA, and the endogenous plasminogen activator inhibitor PAI-1. Ischemic lesion volumes and neurologic deficits were significantly reduced in wild-type mice by both simvastatin and atorvastatin. Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1. In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In contrast, statins did not have protective effects in tPA knockout mice after embolic focal ischemia, but only in a filament model where focal ischemia was achieved via mechanical occlusion. These results suggest that statins protect against stroke by multiple mechanisms involving both eNOS and tPA. The involvement of each pathway may be revealed depending on the choice of experimental stroke model.

Common sequence variations in ABCG8 are related to plant sterol metabolism in healthy volunteers

Polymorphisms in the ATP binding cassette (ABC) transporters ABCG5 and ABCG8 are related to plasma plant sterol concentrations. It is not known whether these polymorphisms are also associated with variations in serum plant sterol concentrations during interventions affecting plant sterol metabolism. We therefore decided to study changes in serum plant sterol concentrations with ABCG5/G8 polymorphisms after consumption of plant stanol esters, which decrease plasma plant sterol concentrations. Cholesterol-standardized serum campesterol and sitosterol concentrations were significantly associated with the ABCG8 T400K genotype, as were changes in serum plant sterol concentrations after consumption of plant stanols. The reduction of -57.1 +/- 38.3 10(2) x micromol/mmol cholesterol for sitosterol in TT subjects was significantly greater compared with the -36.0 +/- 18.7 reduction in subjects with the TK genotype (P = 0.021) and the -16.9 +/- 13.0 reduction in subjects with the KK genotype (P = 0.047). Changes in serum campesterol concentrations showed a comparable association. No association with serum LDL cholesterol was found. Genetic variation in ABCG8 not only explains cross-sectional differences in serum plant sterol concentrations but also determines a subject's responsiveness to changes in serum plant sterols during interventions known to affect plant sterol metabolism.

Long-term simvastatin treatment not associated with cancer risk

Long-term simvastatin treatment not associated with cancer risk

Increased soluble CD40L levels are reduced by long-term simvastatin treatment in peritoneally dialyzed patients.

Dyslipidemia and increased mortality due to cardiovascular events are common in peritoneally dialyzed patients [continuous ambulatory peritoneal dialysis (CAPD)]. Statins show beneficial effects on serum lipids and reduce cardiovascular mortality. The CD40-CD40 ligand (CD40L) system has proved critical for the activation of tissue structural cells that include endothelial cells, epithelial cells and fibroblasts. It has been reported that enhanced CD40L-CD40 interaction in familial hypercholesterolemia may be downregulated by statins, but prospective studies on CAPD patients are lacking. To determine the effects of 6 months treatment with simvastatin on platelet aggregation, markers of endothelial cell injury, and sCD40L in 15 hyperlipidemic CAPD patients. Simvastatin (Zocor, Merck Sharp & Dohme) was given in a dose of 10 mg at bedtime. CD40L decreased significantly after 6 months of the therapy. Thrombomodulin decreased significantly after 3 months of the therapy, whereas von Willebrand factor, E-selectin and P-selectin did not change significantly during the study. Simvastatin reduced enhanced sCD40L levels together with amelioration of endothelial dysfunction. Treatment with simvastatin might downregulate enhanced CD40L-CD40 interactions in CAPD patients.

Evidence for an Independent and Cumulative Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Endothelial Dysfunction and Oxidative Stress Generation

Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction through oxidative stress; however, the distinct role of these two factors is a matter of debate. Thirty type 2 diabetic patients and 20 normal subjects ate 3 different meals: a high-fat meal; 75 g glucose alone; and high-fat meal plus glucose. Glycemia, triglyceridemia, nitrotyrosine, and endothelial function were assayed during the tests. Subsequently, diabetics took 40 mg/d simvastatin or placebo for 12 weeks. The 3 tests were performed again at baseline, between 3 to 6 days after the start, and at the end of each study. High-fat load and glucose alone produced a decrease of endothelial function and an increase of nitrotyrosine in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters but reduced the effect on endothelial function and nitrotyrosine observed during each different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations of endothelial function and nitrotyrosine during the tests. This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect. Simvastatin shows a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as the lipid-lowering action of the drug.

Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients

Baseline cholesterol metabolism was hypothesized to regulate responses of cholesterol synthesis and absorption, and serum cholesterol lowering to hypolipidaemic treatment. Thus, serum cholesterol and non-cholesterol sterols were measured before and during long-term simvastatin treatment (inhibition of cholesterol synthesis) and subsequent combination of statin with plant stanol ester margarine (inhibition of cholesterol absorption) consumption in subjects with low ( n=15) and high ( n=15) absorption of cholesterol, defined by respective low and high baseline ratios of serum cholestanol to cholesterol. Cholesterol synthesis (defined by precursors of cholesterol) was markedly reduced by the long-term statin treatment in both groups, but more extensively in the low than high absorption group ( P<0.05), yet the respective serum cholesterol reductions were similar. From among the absorption markers, sitosterol and cholestanol ratios were correspondingly increased more in the low than in the high absorption group. Plant stanol ester margarine consumption, combined with chronic statin treatment, further lowered the serum cholesterol level ( P<0.001) only in the high absorption group. The sum of cholesterol absorption markers was reduced more ( P<0.05) in the high than in the low absorption group, while the non-significant serum cholesterol reduction of the low absorption group was associated with relatively high increase of cholesterol synthesis. Thus, stanol ester margarine combined with chronic simvastatin treatment reduces cholesterol absorption and serum cholesterol more consistently in subjects with high than low baseline absorption of cholesterol. The profile of baseline cholesterol metabolism determines the changes in synthesis and absorption of cholesterol to hypolipidaemic treatments, but affects less differently serum cholesterol level.

Adrenocorticotrophic hormone exerts marked lipid-lowering effects in simvastatin-treated patients.

Recently, it was reported that treatment with adrenocorticotrophic hormone (ACTH) has a strong lipid-lowering effect in healthy individuals. The mechanism behind this has not been established. The aim of the present investigation was to study the effect of ACTH on the plasma lipoprotein pattern in patients treated with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor. The ACTH treatment was given to 10 patients who were on long-term treatment with simvastatin 40 mg daily. ACTHI-24 was administered at the dose of 1 mg daily for four consecutive days. Blood samples for analyses of lipids, lipoproteins and apolipoproteins were collected before and after treatment. Second baseline was obtained 2 weeks after the end of treatment. The serum concentrations of cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein(a) fell significantly by 16, 23, 23, 10 and 38%, respectively. The serum apolipoprotein E concentration increased significantly by 39%; the fraction that was not associated with apolipoprotein B increased by 47% whereas the fraction that was did not change significantly. There were no changes in the serum concentrations of high density lipoprotein (HDL) cholesterol and apolipoprotein AI. At the second baseline, the lipid variables had generally returned to previous levels. In patients on long-term simvastatin treatment, ACTH had marked lowering effects on the lipoproteins that contain apolipoprotein B. Moreover, the serum apolipoprotein E concentration increased significantly in response to ACTH treatment.

Sitostanol Ester Added to Long-term Simvastatin Treatment of Coronary Patients With Low and High Basal Cholesterol Absorption

Sitostanol Ester Added to Long-term Simvastatin Treatment of Coronary Patients With Low and High Basal Cholesterol Absorption