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PubMed2007

Statin therapy does not seem to benefit giant cell arteritis.

OBJECTIVE: Since statins interfere with a variety of immune-inflammatory pathways shared by atherosclerosis and giant cell arteritis (GCA), they might be potentially useful as adjunctive therapy to glucocorticosteroids in GCA. Our aim was to examine whether concomitant use of statins had any potential benefit in GCA. METHODS: Retrospective follow-up study of an unselected population of 121 patients with GCA. A comparative analysis between patients with and without statin therapy was performed. RESULTS: At the time of the GCA diagnosis, 30 patients (25%) had already been receiving statins and continued taking them during the corticosteroid treatment. No statistically significant reduction in the incidence of severe ischemic complications (including visual manifestations, jaw claudication, cerebrovascular accidents, ischemic heart disease, and limb claudication due to large artery stenosis) was observed in this group compared with the remaining patients. When we analyzed follow-up data, we found no significant differences between groups in terms of frequency of relapses, incidence of aortitis, and percentage of patients recovered from GCA. The duration of therapy and corticosteroids requirements among patients in permanent remission was similar in both groups. CONCLUSION: We did not observe a significant benefit derived from the use of statins at low to moderate doses in the incidence of severe ischemia or the disease outcome.

Aged↗
PubMed2004

Statins prevent oxidized low-density lipoprotein- and lysophosphatidylcholine-induced proliferation of human endothelial cells.

The proliferation of endothelial cells is induced by oxidized low-density lipoprotein (oxLDL) and its major component, lysophosphatidylcholine (LPC). The aim of this study was to investigate the effect of statins on the proliferation of endothelial cells derived from human umbilical cord veins (HUVEC). Cerivastatin, simvastatin and fluvastatin caused a dose-dependent inhibition of endothelial cell growth (n=12; P<.01) when using cell counts and [3H]-thymidine incorporation, respectively. The strongest inhibition of HUVEC proliferation was achieved at statin concentrations of 0.1 micromol/l (cerivastatin), 2.5 micromol/l (simvastatin) and 1 micromol/l (fluvastatin). Cell counts were significantly reduced from 22937+/-280.6 (control) to 7791+/-133.6 (cerivastatin), 7292+/-146.6 (simvastatin) and 6792+/-135.5 (fluvastatin) (n=12; P<.01). Interestingly, cell proliferation induced by oxLDL (10 microg/ml) and LPC (20 micromol/l) could be effectively prevented using statins at concentrations between 0.01 and 0.1 micromol/l (cerivastatin), 1 and 2.5 micromol/l (simvastatin) and 0.25 and 1 micromol/l (fluvastatin). This effect of the statins was abolished by preincubation with mevalonate (500 micromol/l). Our results demonstrate an interesting direct effect of statins on the proliferation of human endothelial cells induced by oxLDL and LPC, which may be beneficial to prevent vascular effects of these atherogenic lipids.

Cell Division↗
PubMed2006

Statins and the endothelium.

Statins have been shown to have pleiotropic effects apart from serum lipid-lowering effect in human. One of the major target organs for the effects of statins is the vascular endothelium, which plays an important role in the development of atherosclerosis and angiogenesis. Recent numerous studies have shown that the statins' cholesterol-independent vascular effects appear to involve directly restoring or improving endothelial function by increasing NO production, promoting re-endothelialization after arterial injury, and inhibiting inflammatory responses within the vessel wall that are thought to contribute to atherosclerosis. This review provides an update of the unique effects of statins on endothelial cells including endothelial progenitor cells as well as highlighting the therapeutic potential of statins beyond their established lipid-lowering effects.

Angiogenesis Inducing Agents↗
PubMed2001

Impact of preexisting statin use on adhesion molecule expression in patients presenting with acute coronary syndromes.

Of 147 patients admitted with acute coronary syndromes, 17 were taking statins at the time of presentation. These were matched with 17 subjects not taking statins. We found that statin therapy was associated with lower levels of sP-selectin, a marker of platelet and vascular endothelial activation. This provides further insight into the extralipid effect of statins in clinical practice and may help explain the greater-than-expected benefits of statin therapy in ischemic heart disease.

Angina, Unstable↗
PubMed2003

Effective strategies for long-term statin use.

Long-term statin use achieves a significant reduction in mortality (24% to 42%) for patients with coronary artery disease (CAD) that is equal to or greater than that seen with other secondary prevention medications, including aspirin, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors. In patients with diabetes, the reduction in mortality exceeds that seen with tight glycemic control or any other treatment for diabetes. Several studies have found that almost all patients with atherosclerosis are considered candidates for statin treatment. The scientific evidence needed to revise the national guidelines has been provided by showing that initiation of statins before hospital discharge results in (1). a marked increase in long-term treatment rates, (2). improved long-term patient compliance, (3). more patients reaching levels of low-density lipoprotein (LDL) cholesterol <100 mg/dL, and (4). improved clinical outcome. Nonetheless, many studies in a variety of clinical settings have demonstrated that, regardless of the health care delivery system, an unacceptable number of patients with atherosclerosis are left untreated or undertreated with statin therapy. Applying hospital-based systems has been demonstrated to address the problems of underuse. The national guidelines now recommend that, in addition to diet and exercise counseling, lipid-lowering medications be initiated before hospital discharge for patients diagnosed with cardiovascular disease. Optimal use of statins and other cardioprotective medications in high-risk patients could save >83000 lives per year in the United States.

Cardiovascular Diseases↗
PubMed1998

Cost-effectiveness of statins.

Currently, 6 hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are marketed in the United States (US). Given the wide variation in the prices and efficacy of statins, formal cost-effectiveness analysis may improve drug selection decisions. To assess the cost-effectiveness of statin therapy in primary and secondary prevention of coronary heart disease, we developed a model of the costs and consequences of lipid-regulating therapy and estimated the incremental cost-effectiveness of 5 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) at usual starting doses versus no therapy. Drug effects on serum lipids were assessed using data approved by the US Food and Drug Administration for product labeling. Annual risks of coronary event occurrence were estimated using Framingham Heart Study coronary risk equations developed for use in this model. Current estimates of direct medical costs of coronary heart disease were used to assign costs to health states and acute coronary events. Main outcome measurements were net cost (statin therapy minus savings in coronary heart disease treatment), gain in life expectancy, and cost per life-year saved. The maximum gain in life expectancy was achieved with atorvastatin, which also had a lower net cost than lovastatin, pravastatin, and simvastatin. Compared with fluvastatin, atorvastatin's greater effectiveness is attained at a lower cost per life-year saved. The cost-effectiveness of HMG-CoA reductase inhibition in primary and secondary prevention of coronary heart disease has been improved with the introduction of atorvastatin.

Aged↗
PubMed2001

Clinically relevant differences between the statins: implications for therapeutic selection.

Although the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, share a common lipid-lowering effect, there are differences within this class of drugs. The low-density lipoprotein (LDL) cholesterol-lowering efficacy, pharmacokinetic properties, drug-food interactions, and cost can vary widely, thus influencing the selection of a particular statin as a treatment option. The statins that produce the greatest percentage change in LDL cholesterol levels are atorvastatin and simvastatin. Atorvastatin and fluvastatin are least affected by alterations in renal function. Fewer pharmacokinetic drug interactions are likely to occur with pravastatin and fluvastatin, because they are not metabolized through the cytochrome P450 (3A4) system. The most cost-effective statins, based on cost per percentage change in LDL cholesterol levels, are fluvastatin, cerivastatin, and atorvastatin. Awareness of these differences may assist in the selection or substitution of an appropriate statin for a particular patient.

Decision Making↗
PubMed2003

Statin effects on cholesterol micro-domains in brain plasma membranes.

Recent epidemiological studies revealed inhibitors of the hydroxymethylglutaryl-coenzyme A reductase, so-called statins, to be effective in lowering the prevalence of Alzheimer's disease (AD). In vitro, statins strongly reduced the cellular amyloid beta-protein load by modulating the processing of the amyloid beta precursor protein. Both observations are probably linked to cellular cholesterol homeostasis in brain. So far, little is known about brain effects of statins. Recently, we could demonstrate that treatment of mice with the lipophilic compound lovastatin resulted in a discrete reduction of brain membrane cholesterol levels. To follow up these findings, we subsequently carried out a further in vivo study including lovastatin and simvastatin as lipophilic agents, as well as pravastatin as a hydrophilic compound, focussing on their efficiency to affect subcellular membrane cholesterol pools in synaptosomal plasma membranes of mice. In contrast to the hydrophilic pravastatin, the lipophilic lovastatin and simvastatin strongly reduced the levels of free cholesterol in SPM. Interestingly, lovastatin and pravastatin but not simvastatin significantly reduced cholesterol levels in the exofacial membrane leaflet. These changes were accompanied by modified membrane bulk fluidity. All three statins reduced the expression of the raft marker protein flotillin. Alterations in transbilayer cholesterol distribution have been suggested as the underlying mechanism that forces amyloidogenic processing of APP in AD. Thus, our data give some first insight in the mode of action of statins to reduce the prevalence of AD in clinical trials.

Animals↗
PubMed2002

Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressed by statins.

Apolipoprotein E (ApoE) genotype modulates the risk of Alzheimer's disease. ApoE has been shown essential for amyloid beta-peptide fibrillogenesis and deposition, a defining pathological feature of this disease. Because astrocytes and microglia represent the major source of extracellular apoE in brain, we investigated apoE secretion by glia. We determined that protein prenylation is required for apoE release from a continuous microglial cell line, primary mixed glia, and from organotypic hippocampal cultures. Using selective protein prenylation inhibitors, apoE secretion was found to require protein geranylgeranylation. This prenylation involved a protein critical to apoE secretion, not apoE proper. ApoE secretion could also be suppressed by inhibiting synthesis of mevalonate, the precursor to both types of protein prenylation, using hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins). Recent reports have described the beneficial effects of statins on the risk of dementia. Our finding that protein geranylgeranylation is required for apoE secretion in the brain parenchyma provides another contributing mechanism to explain the effective properties of statins against the development of dementia. In this model, statin-mediated inhibition of mevalonate synthesis, an essential reaction in forming geranylgeranyl lipid, would lower extracellular levels of parenchymal apoE. Because apoE has been found necessary for plaque development in transgenic models of Alzheimer's disease, suppressing apoE secretion by statins could reduce plaques and, in turn, improve cognitive function.

Alkyl and Aryl Transferases↗
PubMed2003

Statins inhibit high glucose-mediated neutrophil-endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide.

Neutrophil-endothelial adhesion is a crucial step in vascular inflammation, which is recognized as the direct cause of atherosclerosis-mediated serious diseases. We demonstrated previously that high glucose increased adhesion in a protein kinase C (PKC)-dependent manner within 48 h through increasing surface expression of endothelial adhesion molecules. On the other hand, statins, used for patients with hypercholesterolemia, have been shown to decrease the incidence of atherosclerosis-mediated diseases, but direct effects of statins on endothelial cells remain unclear. In this study, we examined the effects of these compounds on high glucose-mediated neutrophil-endothelial adhesion with respect to the participation of PKC and nitric oxide (NO). After human endothelial cells were cultured for 48 h in high glucose medium, neutrophils from healthy volunteers were added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring their myeloperoxidase activities, and surface expression of endothelial adhesion molecules was determined with an enzyme immunoassay. Both pravastatin (0.05 microM) and fluvastatin (0.5 microM) significantly attenuated the adhesion mediated by 27.8 mM glucose for 48 h through decreasing surface expression of endothelial adhesion molecules (intercellular adhesion molecule-1, P-selectin, and E-selectin). NO synthase inhibitors reduced the inhibitory effects of statins, whereas statins did not affect the adhesion mediated by a PKC activator. These data suggest that statins act directly on endothelial cells to inhibit expression of adhesion molecules and neutrophil adhesion mediated by high glucose through increasing endothelial NO production, but not by inhibiting PKC.

Cell Adhesion↗
PubMed2006

[Statin induced neuropathy: myth or reality?].

BACKGROUND: Statins are lipid-lowering drugs widely used in the world. They are effective and safe in the treatment and in the primary and secondary prevention of cerebrovascular and cardiovascular diseases. Besides they are known for their muscular side-effects. It has been suggested that they also have a toxic effect on the peripheral nervous system. STATE OF ART: Case reports and retrospective studies emphasize the possibility that statins can induce peripheral nerves side-effects. A single prospective study contradicts this hypothesis. Statins are hydroxymethyl glutaryl coenzyme A reductase (HMGCoA reductase) inhibitors, this action is responsible for the lipid-lowering effect but can also explain the nervous toxicity. Statins interfere with cholesterol synthesis that may alter myelin and nerve membrane function and they prevent mitochondrial respiratory chain enzyme synthesis which may disturb neuron energy use. CONCLUSIONS: It can be considered that statins have an insignificant toxicity on peripheral nerves. The relevance of their prescription must be however well evaluated and treated patients must be closely followed.

Humans↗
PubMed2002

HMG CoA reductase inhibitor (statin) and aortic valve calcium.

There is no known pharmacological therapy for calcific aortic valvular sclerosis or stenosis. Because leaflet calcification occurs in areas of lipoprotein deposition, we hypothesised that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG COA) reductase inhibitors (statins) might slow aortic valve calcium (AVC) accumulation. We retrospectively identified 65 patients who had undergone two electron-beam computed tomography scans at a mean (SD) interval of 2.5 (1.6) years. 28 (43%) patients were receiving statins. Patients who were treated with statins had a 62-63% lower median rate of AVC accumulation (p=0.006) and 44-49% fewer statin patients had definite AVC progression (p=0.043). These findings suggest that statins may decrease AVC accumulation.

Aortic Valve↗
PubMed2004

Selenoprotein synthesis and side-effects of statins.

Statins are possibly the most effective drugs for the prevention and treatment of hypercholesterolaemia and coronary heart disease. They are generally well tolerated, however, they do cause some unusual side-effects with potentially severe consequences, most prominently myopathy or rhabdomyolysis and polyneuropathy. We noted that the pattern of side-effects associated with statins resembles the pathology of selenium deficiency, and postulated that the mechanism lay in a well established, but often overlooked, biochemical pathway--the isopentenylation of selenocysteine-tRNA([Ser]Sec). A negative effect of statins on selenoprotein synthesis does seem to explain many of the enigmatic effects and side-effects of statins, in particular, statin-induced myopathy.

Coronary Disease↗
PubMed2002

Beyond lipid lowering: the role of statins in vascular protection.

The introduction of the hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in 1987 was a major advance in the prevention and treatment of cardiovascular disease. Several landmark clinical trials have demonstrated the benefit of lipid lowering with statins for the primary and secondary prevention of coronary heart disease (CHD), namely The Scandinavian Simvastatin Survival Study (4S), Cholesterol And Recurrent Events (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), West of Scotland Coronary Prevention Study (WOSCOPS) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Although it is widely accepted that the majority of clinical benefit obtained with statins is a direct result of their lipid-lowering properties, these agents appear to display additional cholesterol-independent or pleiotropic effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Although the full impact of statin therapy on each of these processes is not fully understood, ongoing studies with current and new statins are likely to shed further light on the potential cholesterol-independent benefits of these agents.

Animals↗
PubMed2003

The effect of statin therapy on ventricular late potentials in acute myocardial infarction.

AIMS: To determine whether early statin therapy in acute myocardial infarction has any effect on ventricular late potentials which are considered as a noninvasive tool for evaluation of arrhythmogenic substrate. METHODS AND RESULTS: Study population consisted of prospectively enrolled 72 patients presenting with acute myocardial infarction (<6 h). Thirty-four of the patients were randomized to pravastatin (40 mg/day) on admission irrespective of lipid levels. All patients received thrombolytic therapy. Signal-averaged ECG recordings were obtained serially prior to thrombolytic therapy, 48 h after and 10 days later. Late potentials were defined as positive if signal-averaged ECG met at least two of Gomes criteria: filtered total QRS duration >114 ms, root mean square voltage of the last 40 ms of the QRS <20 mV, or the duration of the terminal low (<40 mV) amplitude signals >38 ms. Changes observed in signal-averaged ECG recordings after thrombolysis were evaluated statistically with regard to statin usage. There were no significant differences between the clinical characteristics of the two randomized groups. There was a significant decrease in the rates of late potentials between the first and third signal-averaged ECG recordings after thrombolytic therapy in pravastatin group. Pravastatin group also had lower incidence of ventricular arrhythmias compared with control group (26 vs. 63%, P=0.021). The in-hospital cardiovascular event rates were also lower in statin group. CONCLUSION: Early use of pravastatin reduces the incidence of late potentials following thrombolytic therapy in acute myocardial infarction. Statin therapy also seems to be reducing the incidence of in-hospital ventricular arrhythmias. These beneficial effects of statins might be explained through prevention of new myocardial ischemic episodes due to early plaque stabilization or regulation of endothelial and platelet functions.

Adult↗
PubMed2003

A comparative study of the in vitro antioxidant activity of statins.

BACKGROUND: Treatment of hypercholesterolemia with statins is remarkably effective in cardiovascular prevention. This has led to the hypothesis that these drugs may act on the atherosclerotic plaque by mechanism(s) independent of the reduction of serum cholesterol levels. The aim of this study was to assess the total antioxidant activity of the most prescribed statins: fluvastatin, atorvastatin, pravastatin and simvastatin. METHODS: We measured the in vitro antioxidant activity of statins as their ability to antagonize the oxidation of alpha-keto-gamma-methiolbutyric acid by both hydroxyl and peroxyl radicals. The results are expressed as Total Oxyradical Scavenging Capacity (TOSC) units. Uric acid and Trolox were used as the reference antioxidants. RESULTS: The scavenging capacity towards hydroxyl radicals was highest for simvastatin (3375+/-112 U/mg), a value 270.2% higher (P<0.0001) compared to uric acid (reference antioxidant vs. hydroxyl radicals, 1249+/-71 U/mg). Among the tested statins, fluvastatin exhibited the highest anti-peroxyl radical antioxidant capacity (8755+/-187 U/mg) which appeared 50% lower (P<0.0001) compared to Trolox (reference antioxidant vs. peroxyl radicals, 17460+/-379 U/mg). CONCLUSIONS: All the statins tested have intrinsic antioxidant activity with both anti-hydroxyl and peroxyl radical activity. Simvastatin was the most effective as an anti-hydroxyl radical antioxidant and fluvastatin as an anti-peroxyl radical antioxidant.

Analysis of Variance↗
PubMed2002

Statins as immunomodulators.

HMG-CoA reductase inhibitors, or statins, are effective lipid lowering agents, extensively used in medical practice. Statins have never been shown to be involved in the immune response, although few clinical reports have suggested a better outcome of cardiac transplantation in patients under pravastatin therapy. Major histocompatibility complex class II (MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon gamma (IFN-gamma). We and others recently demonstrated that statins act as direct inhibitors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T cell activation. This effect was observed in several cell types, including primary human endothelial cells and macrophages. Interestingly, this inhibition is specific for inducible MHC-II expression and does not concern either constitutive expression of MHC-II or expression of MHC-I. In repressing induction of MHC-II, and subsequent T lymphocyte activation, statins therefore behave as a novel type of immunomodulator. This unexpected effect provides a scientific rationale for suggesting the use of statins as novel immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.

Animals↗
PubMed2001

Four cases of tendinopathy in patients on statin therapy.

During the last decade, statins have been widely prescribed as lipid-lowering drugs. Their overall safety profile is good. The main musculoskeletal side effects have consisted of muscle pain and weakness, peripheral neuropathy, and a few cases of drug-induced lupus. We report the first four cases of tendinopathy in patients receiving statin therapy. There were three men and one woman. The diagnoses were extensortenosynovitis at the hands (case 1), tenosynovitis of the tibialis anterior tendon (case 2), and Achilles tendinopathy (cases 3 and 4). Two patients were on simvastatin and two on atorvastatin. The tendinopathy developed 1 to 2 months after treatment initiation. The outcome was consistently favorable within 1 to 2 months after discontinuation of the drug. Similar cases have been reported to French pharmacovigilance centers. This report of four cases of tendinopathy draws attention to a possible and heretofore unrecognized side effect of a drug class that is becoming increasingly popular. Statins are effective in lowering high cholesterol levels in patients with type IIa or IIb hypercholesterolemia. They have been widely used for the last decade, particularly in the secondary and primary prevention of major coronary events. Statins act by inhibiting the enzyme hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Although most patients tolerate statins extremely well, a few experience side effects requiring treatment discontinuation. Reported musculoskeletal side effects include myalgia and a few cases of rhabdomyolysis and polymyositis. Induced lupus and peripheral neuropathy are exceedingly rare.

Acute Disease↗