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At least 1,099 records · Page 61Linked to original sources
PubMed2006

Lower level of low-density lipoprotein cholesterol by statin prevents progression of coronary restenosis after successful stenting in acute myocardial infarction.

OBJECTIVE: It is unclear whether the reduction of coronary restenosis by statins is due to a decrease in low-density lipoprotein (LDL) cholesterol and/or pleiotropic effects. Therefore, we performed quantitative coronary angiography (QCA) and analyzed the lipid profile and changes in adhesion molecules and chemokines caused by statin in patients with acute myocardial infarction (AMI). METHODS: The subjects included AMI patients who had initial coronary angiograms and significant coronary stenosis and were implanted with a stent. After stent implantation, patients were treated either with (n = 36) or without (n = 14) statin. The primary end-point for this study was the absolute changes in the lipid profile, C-reactive protein (CRP), adhesion molecules, chemokines and stenosis measured by QCA between the post-stent and follow-up angiogram at 6 months after stenting. RESULTS: Treatment with statin reduced % coronary diameter stenosis (DS) and was associated with a greater reduction in LDL cholesterol at 6 months after stenting in patients with acute myocardial infarction (AMI), while there were no differences in adhesion molecules, chemokines, CC chemokine receptor or CXC chemokine receptor. Interestingly, changes in % DS between before and after statin treatment at 6 months (Delta%DS) were positively correlated with DeltaLDL cholesterol, and patients who had an LDL cholesterol level of less than 80 mg/dl had a significantly lower Delta%DS. In addition, Delta%DS was significantly related only to the reduction in LDL cholesterol as assessed by a stepwise multivariable regression analysis. CONCLUSION: These results suggest that the lower level of LDL cholesterol is the most critical factor in preventing coronary restenosis.

Aged↗
PubMed2001

Pleiotropic effects of statins on the vascular tissue.

The statins are lipid-lowering agents that act by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is responsible for the conversion of HMG-CoA to mevalonate. Products of mevalonate metabolism are critical for several cellular processes of eukaryotic cells, and inhibition of the mevalonate pathway by statins has pleiotropic effects. It has been reported that statins inhibit the migration and proliferation of vascular smooth cells (VSMCs), reduce interleukin-6 expression in VSMCs, improve endothelium-dependent vasomotion, and inhibit the expression of plasminogen activator inhibitor-1 and matrix metalloproteinases in endothelial cells. These effects of statins are independent of plasma cholesterol level, and are completely blocked by exogenous mevalonate and some isoprenoids. These findings suggest that statins exert direct antiatherosclerotic effects on the vascular wall beyond their effects on plasma lipids.

Animals↗
PubMed2005

Statins and thrombin.

L-Mevalonic acid is the distant precursor of cholesterol, in contrast to cholesterol, L-mevalonic acid, its distant precursor gives rise to farnesyl and geranylgeranyl pyrophosphates in relatively few metabolic steps. These isoprenyl pyrophophates covalently conjugate with specific G-proteins and serve as membrane anchors enabling them to carry out their function. Although farnesyl-proteins may participate in signal transduction, geranylgeranyl-proteins (e.g., Rho GTP binding proteins) are well known to downregulate signaling pathways by inhibiting L-mevalonic acid synthesis. Such inhibitors include 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, drugs (statins) and isoprenoids of dietary origins, where Rho protein activation appears to be necessary for cellular-mediated thrombin generation. Thrombin and other proteases (e.g., coagulation factor Xa, tryptase) upregulate protease-activated receptor (PAR) synthesis and PAR activation promotes synthesis and expression of other proteins [e.g., tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)]. With the PAR-1 activating peptide SSFLRNP, we found that either cerivastatin or atorvastatin mitigated platelet stimulation in a time- and dose-dependent manner, as predicted if a statin-mediated Rho pathway is required. We also found that simvastatin decreased prothrombin fragments F1+2 in plasma from type 2 diabetics, demonstrating that statins downregulate thrombin generation. Thus, independent of cholesterol, statins and dietary isoprenoids behave as inhibitors of TF-dependent thrombin generation. Because thrombin has multiple physiological functions, the 20 pleiotropic effects reported for statins may reflect a common mechanism for downregulation of thrombin-mediated events, in particular at the cellular level.

Down-Regulation↗
PubMed2004

[Immunomodulatory activities of statins].

HMG-CoA (3-hydroxy-3-methyglutaryl coenzyme A) reductase inhibitors (statins) reduce cardiovascular morbidity and mortality. Although statins work in part via lipid modulation, several findings of statins indicate they have broader properties, including alteration of inflammatory pathways. Ex-vivo activities of statins include suppression of adhesion molecule expression, MHC class II expression, and effects on reactive oxygen and nitrogen intermediate production. Statins also modify apoptosis in smooth muscle and endothelial cells leading to altered vascular function and neovascularization. These properties offer the potential to modify the states of chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis with drugs that show minimal toxic effects in both the short and long term.

Animals↗
PubMed2005

Physiogenomic analysis links serum creatine kinase activities during statin therapy to vascular smooth muscle homeostasis.

Statins are highly effective at reducing coronary disease risk. The main side effects of these medications are a variety of skeletal muscle complaints ranging from mild myalgia to frank rhabdomyolysis. To search for physiologic factors possibly influencing statin muscle toxicity, we screened for genetic associations with serum creatine kinase (CK) levels in 102 patients receiving statin therapy for hypercholesteremia. A total of 19 single nucleotide polymorphism (SNPs) were selected from ten candidate genes involved in vascular homeostasis. Multiple linear regression was used to rank the SNPs according to probability of association, and the most significant associations were analyzed in greater detail. SNPs in the angiotensin II Type 1 receptor (AGTR1) and nitric oxide synthase 3 (NOS3) genes were significantly associated with CK activity. These results demonstrate a strong association between CK activity during statin treatment and variability in genes related to vascular function, and suggest that vascular smooth muscle function may contribute to the muscle side effects of statins.

Adult↗
PubMedDate not supplied

[Clinical trials of statins and fibrates --a meta-analysis].

INTRODUCTION: Several clinical trials of hypolipidemics showed a decrease in mortality by 30-40%, while others showed detrimental or no effects. The question remains: which trial should be the basis of clinical decision making in the choice of hypolipidemic therapy? MATERIAL AND METHODS: Meta-analysis is a method for combining research results of several studies. Effects of statins and fibrates with respect to placebo, were assessed by systematic literature review and meta-analysis. Medline and CENTRAL databases were searched using the following keywords: hyperlipoproteinemia, hypolipidemic agents and individual drug names. The main inclusion criteria were as follows: statin or fibrate, placebo controlled randomized trial, at least one year treatment on average, at least 100 patients per study arm and reported mortality. RESULTS: Fibrates showed almost complete absence of treatment effects on mortality with odds ratio of 0.99 and 95% confidence interval 0.80 - 1.11. The odds for statins were 0.87, 0.80 - 0.95. DISCUSSION: Despite the absence of treatment effects of fibrates, it is noteworthy that inclusion criteria of early fibrate trials focused mainly on cholesterol with recent identification of elevated triglycerides as an independent risk factor. As fibrates exert the most pronounced effect on triglycerides, they still may show effect in target populations. Effects of statins are confirmed, but they are noticeably lower than in individual trials which are given most publicity. CONCLUSION: Even after several decades of fibrate use, conclusive evidence of their beneficial effects still needs to be elucidated in appropriately designed trials. However, a beneficial effect of statins on mortality decrease has been proven. Meta-analysis has an important role in estimating true treatment effects and in the practice of evidence-based medicine.

Anticholesteremic Agents↗
PubMedDate not supplied

Statins and stroke.

An important issue for stroke prevention is the identification and treatment of risk factors such as hypercholesterolaemia. The 4 reasons to test if the statins have a role in stroke prevention are: (i) a statistical link between elevated low density lipoprotein-cholesterol or decreased high density lipoprotein-cholesterol and ischaemic stroke; (ii) a reduction in vascular risk with statins in randomised trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins; and (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e. with statins in secondary prevention trials). The question of whether statins also have a neuroprotective effect in humans and reduce the risk of post-stroke dementia remains unsettled.

Animals↗
PubMedDate not supplied

[A case of interstitial lung disease with atorvastatin (Tahor) and a review of the literature about these effects observed under statins].

The 3-Hydroxy-3-methyl-glutaryl coenzyme A (HGM-CoA) reductase inhibitors, or statins, are competitive inhibitors of the rate-limiting enzyme in cholesterol synthesis. Generally, statins have an excellent safety profile. Elevations of liver transaminases and creatine phosphokinase with myalgia have been associated with the use of HGM-Co A reductase inhibitors, case reports of rhabdomyolysis are rare, most occurring with concomitant use with other drugs such as cyclosporin, fusidic acid and gemfibrozil. We describe here the clinical case of a patient who developed interstitial lung disease as probably a result of the use of statins which particularly increased with long-term atorvastatin treatment. The present review details some case-reports of interstitial lung disease reported under statins in the literature. Few systemic adverse effects such as lupus-like-syndromes and polymyositis have been reported. Recent experimentations have demonstrated that cholesterol is not the only intracellular target of statins but that they also have a potential role in atherosclerosis and in organ transplantation as immunosuppressor agents.

Atorvastatin↗
PubMed2000

Associations between change in C-reactive protein and serum lipids during statin treatment.

Hypolipidaemic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment reduces cardiovascular risk and is also associated with the reduction of C-reactive protein (CRP) concentrations. However, there is scant data concerning the relationship between CRP and lipid changes during statin treatment. We studied 60 hypercholesterolaemic coronary patients who participated in the Treat to Target (3T) study comparing atorvastatin and simvastatin. Serum lipids and CRP (with a sensitive method) were measured before treatment at baseline and after 12 months of statin treatment. Low-density lipoprotein (LDL) cholesterol was substantially decreased and high-density lipoprotein (HDL) cholesterol increased during statin treatment. CRP decreased significantly (sign test P = 0.03) during treatment, and the changes of CRP were significantly associated with changes in HDL cholesterol (r = -0.45; P < 0.001) and apolipoprotein A1 (r = -0.40; P < 0.001) but not with changes in LDL cholesterol or triglycerides. The change in HDL cholesterol explained 20% of the change in CRP during statin treatment. The results are in line with previous suggestions that HDL has anti-inflammatory properties.

Anticholesteremic Agents↗
PubMed2006

Rosiglitazone increases LDL particle size and buoyancy and decreases C-reactive protein in patients with type 2 diabetes on statin therapy.

A substantial number of individuals with type 2 diabetes mellitus (T2DM) demonstrate a predominance of small dense low-density lipoprotein (sdLDL), which is associated with an increased risk of cardiovascular disease (CVD). In some cases, sdLDL persists after treatment with a statin to reduce levels of LDL. The effect of the addition of a thiazolidinedione, rosiglitazone (RSG) (4 mg/day or 8 mg/day) to statin therapy on LDL phenotype and C reactive protein (CRP) levels was investigated in a 12- week, placebo-controlled study of 72 T2DM patients who were well controlled and on a statin, but who had persistently predominant sdLDL. Addition of RSG 8 mg to statin therapy significantly increased LDL buoyancy (relative flotation +0.014, p = 0.003) and LDL particle size (+4.2A, p = 0.001) from baseline and relative to the change with placebo (+0.014 and +3.8A; p = 0.03 and p = 0.04, respectively), and was associated with a non-significant decrease in sdLDL. RSG 8 mg moderately, but significantly, increased total cholesterol (by 12.2%, p = 0.004), LDL-cholesterol (11.2%, p = 0.02) and intermediate-density lipoprotein (IDL)-cholesterol from baseline but did not increase total or LDL apolipoprotein B. RSG 4 mg and 8 mg significantly reduced CRP compared with placebo (-44.9% and -48.0%; p = 0.008 and p = 0.004, respectively), and significantly reduced insulin resistance and fasting plasma glucose from baseline. Addition of RSG to statin therapy may further reduce cardiovascular risk by improving the LDL phenotype, as well as reducing insulin resistance and CRP levels. However, the increase in IDL may be proatherogenic and must be considered when assessing the benefits of rosiglitazone.

Blood Glucose↗
PubMed2004

Inhibitory effect of statins on the proliferation of human breast cancer cells.

OBJECTIVE: Long-term hormone therapy in the postmenopause is associated with a moderate increase in cardiovascular and breast cancer risk. Of great concern, therefore, is the question of how women with menopausal symptoms and enhanced cardiovascular risk can be treated. Evidence is growing that an estrogen/statin combination may be a good choice, since this combination seems to elicit additive beneficial effects on the lipid profile and on the vasculature. METHODS: In the present study, the effect of two statins on the proliferation of breast cancer cells in the presence and absence of estradiol was investigated. RESULTS: Atorvastatin and fluvastatin were able to inhibit the proliferation of MCF-7 cells in the absence of estradiol. This effect seems to depend on an apoptotic statin effect which may be mediated by the down-regulation of the anti-apoptotic protein Bcl-2 rather than up-regulation of Fas-L or p53. However, in the presence of estradiol the inhibitory effect of the statins was less pronounced. CONCLUSIONS: The present data indicate that statins may possess anticancerogenic properties concerning the development of breast cancer in postmenopausal women. Clinical trials are necessary to prove a beneficial statin effect on breast cancer risk when combined with long-term hormone therapy.

Anticholesteremic Agents↗
PubMed2006

Meta-analysis: the effect of statins on albuminuria.

BACKGROUND: Albuminuria is an independent risk factor for cardiovascular and renal disease with limited therapeutic options. Data on the effects of statins on albuminuria are conflicting. PURPOSE: To determine whether and to what degree statins affect albuminuria. DATA SOURCES: English-language and non-English-language studies found in PubMed, MEDLINE, EMBASE, BIOSIS, SciSearch, PASCAL, and International Pharmaceutical Abstracts (IPA) databases and the Cochrane Central Register of Controlled Trials that were published between January 1974 and November 2005. STUDY SELECTION: Randomized, placebo-controlled trials of statins reporting baseline and follow-up measurements of albuminuria or proteinuria measured by 24-hour urine collection or the urinary albumin-to-creatinine ratio. DATA EXTRACTION: Two investigators independently abstracted study quality, characteristics, and outcomes. DATA SYNTHESIS: Fifteen studies involving a total of 1384 patients and averaging 24 weeks in duration were included. Meta-analysis of the proportional reduction in proteinuria showed that statins reduced albuminuria (11 studies) and proteinuria (4 studies) in 13 of 15 studies. The reduction in excretion was greater among studies with greater baseline albuminuria or proteinuria: change of 2% (95% CI, -32% to 35%) for those with excretion less than 30 mg/d, -48% (CI, -71% to -25%) for those with excretion of 30 to 300 mg/d, and -47% (CI, -67% to -26%) for those with excretion more than 300 mg/d. Statistical heterogeneity was evident only in the group with excretion greater than 300 mg/d (excretion < 30 mg/d, I2 = 23% [P = 0.27]; excretion of 30 to 299 mg/d, I2 = 0% [P = 0.64]; excretion > or = 300 mg/d, I2 = 63% [P = 0.020]). LIMITATIONS: Published studies were not of high quality on average and varied markedly in effect size, as well as in characteristics of the cohorts. Unpublished studies showing no effect could impact these results. CONCLUSION: Statins may have a beneficial effect on pathologic albuminuria. The validity of this finding, and whether this effect translates into reduction of cardiovascular or end-stage renal disease, requires larger studies.

Albuminuria↗
PubMed1999

[Statins consumption in autonomous communities in Spain: opportunities for savings].

OBJECTIVE: To identify opportunities for reducing the costs of the treatment of hypercholesterolaemia, using cost-effectiveness criteria for selecting statins. DESIGN: Modelling the costs of prescription guided by cost-effectiveness criteria. The most cost-effective statin was determined by reviewing the cost-effectiveness literature. The frequency with which different ways of reducing LDL-c are required was calculated from epidemiological data. From data on consumption (units) and cost (pesetas) of statin prescription in Spain in 1997, the potential saving to be gained through cost-effective prescription was calculated. MEASUREMENTS AND MAIN RESULTS: Possible savings in 1997 if statins had been prescribed according to cost-effectiveness criteria were calculated at between 5435 and 7027 million pesetas. CONCLUSION: There is a chance of optimising resource allocation in treating hypercholesterolaemia by selecting the most cost-effective statin on the basis of the need for LDL-c reduction.

Adolescent↗
PubMed2000

[Cholesterol and stroke risk: a role for statins?].

Atherosclerosis is the most common cause of vascular diseases, but the relevance of cholesterol has only been definitely associated with coronary artery disease and peripheral vascular disease. In comparison, the role of cholesterol in stroke is, while a tempting assumption, subject to controversy in the literature. The crucial question--is cholesterol a risk factor for stroke?--remains open. Recent trials with statin drugs, such as 4 S, CARE, LIPID and WOSCOP, have created a new wave of enthusiasm by showing decreased risk of stroke in the statin-treated patients. However, these trials are most often designed for patients with a known history of coronary artery disease. In contrast, studies investigating the impact of statins in the secondary prevention of stroke are still lacking. Moreover, the beneficial effects of statins on clinical events may involve non-cholesterol mechanisms. In regard to stroke prevention, there is no absolute evidence to recommend the use of statin drug therapy.

Anticholesteremic Agents↗
PubMed2000

[Effects of the statins in kidney transplantation].

A retrospective analysis was performed to assess the immunosuppressive activity of statins in kidney transplantation, determining their effects on serum cholesterol and triglyceride levels post-transplantation, on the incidence of acute rejection episodes and on renal function. A total of 97 patients who underwent a kidney transplant in a three-year period, had more than one-month graft survival, and a minimum of one year of follow-up, were included. Group A consisted of 38 patients who received statins; this group was subsequently divided into four subgroups, according to the time post-transplant when statins were prescribed. Group B consisted of 59 patients (control Group). Initial and final serum total cholesterol levels in Group A were not different (218 +/- 7.8 mg/dl vs 222 +/- 7.5 mg/dl); however, final levels were higher than initial values in Group B (216 +/- 6.0 mg/dl vs 189 +/- 6.4 mg/dl, P = 0.0021). Initial serum triglyceride levels were higher than final levels in Group A (305 +/- 25.5 mg/dl vs 188 +/- 10.6 mg/dl, P < 0.0001). Group A showed a better allograft survival (P = 0.0350), a reduction in the incidence of acute rejection episodes (1 vs 38 events, P < 0.0001) and a lower serum creatinine level (1.96 +/- 0.21 mg/dl vs 2.77 +/- 0.27 mg/dl, P = 0.0374). In Group A subgroups, kidney function was significantly better in patients who received statins early after transplantation. These data suggest that in kidney transplantation statins exert additional immunosuppressive effects, reduce the number of acute rejection episodes, improve allograft survival and kidney function and are effective in preventing serum cholesterol from rising; these effects correlate with a significant decrease in serum triglyceride but are independent of a hypocholesterolemic action.

Adult↗
PubMed2001

[Does statin therapy reduce the risk of stroke? A meta-analysis].

Large scale clinical trials have clearly demonstrated that the HMG-CoA reductase inhibitors (statins) reduce cardiovascular mortality by about 30%. The specific benefit on stroke prevention remains however to be determined. We reviewed all controlled clinical trials comparing statins versus placebo in primary and secondary prevention of cardiovascular disease. We identified 13 studies including 4S, CARE, WOSCOPS and LIPID. More than 32000 patients were randomized. The meta-analysis was performed using relative risk as treatment effect parameter. Statin treatment induced a significant relative risk reduction (RRR) of 24% (95% CI [12%-34%]) for stroke (2.1% vs 2.8%). RRR achieved 25% (95% CI [17%-32%]) for cardiovascular mortality and 34% (95% CI [30%-38%]) for myocardial infarction, without heterogeneity between trials. Stroke was reduced by 25% in secondary prevention, and by 15% in primary prevention, without significant heterogeneity between them. RRR of stroke was similar with pravastatin (RRR=0.79, p=0.0038) and with simvastatin (RRR=0.71, p=0.049). The effect model analysis (relationship between annual incidence of events in treated group versus placebo group in each trial) showed that RRR was constant whatever the baseline risk. These results are in favor of a preventive efficacy of statin treatment against stroke in middle aged patients with coronary heart disease. Complementary information will be needed to clarify the mechanism of this beneficial effect and to demonstrate statin efficacy in a population with a higher risk of stroke such as the elderly.

Age Distribution↗
PubMed2001

[Therapeutic and pleiotropic effects of statins in primary and secondary prevention of atherosclerosis].

Strategy for management of patients displaying hyperlipidemia has changed since the first statin has been launched in France more than ten years ago. Following the first primary and secondary prevention studies conducted with hyperlipidemic subjects, results have been extended to patients with cholesterol levels within normal range both in primary (AFCAPS/TexCAPS) and secondary (CARE) prevention. Drug therapy has been simplified with targets tailored to the patient's risk. Despite these important results from intervention studies with statins, other crucial questions remain. Among these questions the first one concerns the possibility that cardiovascular benefits demonstrated with statins are also partly due to other (pleiotropic) effects. This was first hypothesised when statins were proven to be efficacious after short term treatments (one year in the regression studies). The second question is whether we can extend the benefit observed in populations included in published trials to primary prevention of stroke and to the groups less well represented in previous trials including women, elderly patients. The current trends and economic strains of every health care systems have focused on evidence-based medicine and cost-efficacy studies. Beyond LDL-cholesterol there is clear emergence of a role of triglyceride in cardiovascular disease as well as new data on pathophysiology of the so-called reverse cholesterol transport. Recent trials including patients with hypertriglyceridemia as well as a decline of the benefit observed in hypertriglyceridemic patients strongly suggest that the use of statins may have its own limitation. Finally, translating results of recent trials in clinical practice remains a challenge for treating physicians who face poor compliance and difficulties in implementing diet in patients.

Anticholesteremic Agents↗
PubMed2001

[Novel actions of HMG-CoA reductase inhibitors(statins)--vascular and cerebral protection through inhibition of small GTPase Rho].

Clinical trials have demonstrated the beneficial effect of HMG-CoA reductase inhibitors(statins) for stroke prevention, independent of their lipid-lowering effects. Recent experimental progress indicated the effects of statins for brain protection on both vascular walls(endothelium, smooth muscle, inflammatory cells and platelets) and extra-vascular tissues(brain parenchyma). These pleiotropic effects of statins have been, at least in part, ascribed to inhibition of small GTPases Rho and Ras, which require isoprenoids (intermediates of the cholesterol biosynthesis pathway) for activation. Importantly, statin inhibition of Rho (1) attenuates the infarct size in a rat model of brain ischemia via the elevation of eNOS expression, and (2) suppresses vascular smooth muscle proliferation through up-regulation of CDK inhibitor p27kip1. The novel action of statin, as inhibitor of small GTPase family, should expand its potential toward integrative organ protection, beyond its conventional lipid-lowering and anti-atherogenic effects.

Animals↗