Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Statins”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 613 records · Page 34Linked to original sources
PubMed2004

Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis.

BACKGROUND AND PURPOSE: Previously published meta-analyses exploring the effect of statins on stroke incidence included 20,000 patients and found a 2% to 30% risk reduction. It is not clear whether this is attributable to low-density lipoprotein-cholesterol (LDL-C) reduction. Statin trials have now included >90,000 patients. We have determined the effect of statins and LDL-C reduction on stroke prevention. SUMMARY OF REVIEW: We performed a systematic review and meta-analysis of all randomized trials testing statin drugs published before August 2003. The trials were identified using a computerized PubMed search. We analyzed separately statin effect on incident strokes and on carotid intima-media thickness (IMT) according to LDL-C reduction. The relative risk reduction for stroke was 21% (odds ratio [OR], 0.79 [0.73 to 0.85]), with no heterogeneity between trials. Fatal strokes were reduced but not significantly: by 9% (OR, 0.91 [0.76 to 1.10]). There was no increase in hemorrhagic strokes (OR, 0.90 [0.65 to 1.22]). Statin size effect was closely associated with LDL-C reduction. Each 10% reduction in LDL-C was estimated to reduce the risk of all strokes by 15.6% (95% CI, 6.7 to 23.6) and carotid IMT by 0.73% per year (95% CI, 0.27 to 1.19). CONCLUSIONS: Statins may reduce the incidence of all strokes without any increase in hemorrhagic strokes, and this effect is mainly driven by the extent of between-group LDL-C reduction. Carotid IMT progression also strongly correlated with LDL-C reduction.

Carotid Artery Diseases↗
PubMed2006

Statins and the risk of lung, breast, and colorectal cancer in the elderly.

BACKGROUND: Although most randomized trials and meta-analyses suggest a slight or no increase in the risk of cancer in statin users, results from observational studies have been conflicting, and some have even suggested a large protective effect of statins on certain cancers. Long-term statin users tend to be healthier, less frail, and more adherent to therapy than nonusers, however. This could explain such apparent "protective" effects. METHODS AND RESULTS: We conducted the present cohort study by linking data from a large state drug benefit program with cancer registry data and Medicare healthcare utilization data. We identified all initiators of statins; initiators of glaucoma medications, another preventive drug, served as a comparison group. Outcomes included all registry-identified cases of colorectal, lung, and breast cancer. Multivariable Cox proportional models were used to adjust for confounding. Patient characteristics were similar in both groups, but statin initiators (n=24,439) were slightly younger and used some services more frequently than glaucoma drug initiators (n=7284). The mean follow-up was 2.9 years, with the longest follow-up being 8.4 years. Incidence rates of colorectal, lung, and breast cancers in both groups were very similar to rates in the general population. Adjusted hazard ratios were 0.96 (95% CI, 0.70 to 1.31) for colorectal cancer, 1.11 (95% CI, 0.77 to 1.60) for lung cancer, and 0.99 (95% CI, 0.74 to 1.33) for breast cancer. CONCLUSIONS: These data from a large population of typical older patients who began using statins indicate that it is unlikely that statins confer a clinically important decrease or increase in the risk of colorectal, lung, or breast cancer over the durations studied.

Aged↗
PubMed2002

Statins have biphasic effects on angiogenesis.

BACKGROUND: Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. METHODS AND RESULTS: Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model. CONCLUSIONS: HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.

Animals↗
PubMed2001

Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins.

3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase inhibitors or statins exert direct beneficial effects on the endothelium in part through an increase in nitric oxide (NO) production. Here, we examined whether posttranslational modifications of the endothelial NO synthase (eNOS) could account for the proangiogenic effects of statins. We used endothelial cells (ECs) isolated from cardiac microvasculature, aorta, and umbilical veins, as well as dissected microvessels and aortic rings, that were cultured on reconstituted basement membrane matrix (Matrigel). Tube or precapillary formation was evaluated after statin treatment, in parallel with immunoblotting and immunoprecipitation experiments. Atorvastatin stimulated NO-dependent angiogenesis from both isolated and outgrowing (vessel-derived) ECs, independently of changes in eNOS expression. We found that in macro- but not microvascular ECs, atorvastatin stabilized tube formation through a decrease in caveolin abundance and its inhibitory interaction with eNOS. We also identified the chaperone protein hsp90 as a key target for the proangiogenic effects of statins. Using geldanamycin, an inhibitor of hsp90 function, and overexpression of recombinant hsp90, we documented that the statin-induced phosphorylation of eNOS on Ser1177 was directly dependent on the ability of hsp90 to recruit Akt in the eNOS complex. Finally, we showed that statin promoted the tyrosine phosphorylation of hsp90 and the direct interaction of hsp90 with Akt, which further potentiated the NO-dependent angiogenic processes. Our study provides new mechanistic insights into the NO-mediated angiogenic effects of statins and underscores the potential of these drugs and other modulators of hsp90 and caveolin abundance to promote neovascularization in disease states associated or not with atherosclerosis.

Animals↗
PubMed2001

In vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products.

This study set out to clarify whether the inhibition of sterol or nonsterol derivatives arising from mevalonate biotransformation plays a major role in the in vivo anti-inflammatory action of statins. Hepatic synthesis of all these derivatives was inhibited in mice by administered statins, whereas squalestatin inhibited only sterol derivatives. Using a short-term treatment schedule, we found that statins reduced the hepatic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase without affecting blood cholesterol. This treatment inhibited lipopolysaccharide- and carrageenan-induced pouch leukocyte recruitment and the exudate production of interleukin-6, monocyte chemotactic protein-1, and RANTES. Coadministration of mevalonate reversed the effect of statin on leukocyte recruitment. The inhibition of sterol synthesis by squalestatin did not have any anti-inflammatory effect, indicating that the biosynthesis of nonsterol compounds arising from mevalonate is crucial for the in vivo regulation of cytokine and chemokine production by statins. Their inhibition by statins may account for the reported anti-inflammatory effects of these drugs and may provide a biochemical basis for the recently reported effects of statins in the prevention of cardiovascular disease and mortality.

Animals↗
PubMedDate not supplied

Heat shock protein antibody titers are reduced by statin therapy in dyslipidemic subjects: a pilot study.

Antibody titers to heat shock protein (Hsp)-60 and -65 are positively related to risk of vascular disease and cardiovascular endpoints. There are few data on the factors that regulate the levels of these antibodies. It is known that the statins have antiinflammatory and immunoregulatory properties. The authors examined the effects of 2 statins, simvastatin (Zocor) and atorvastatin (Lipitor) on antibody titers to Hsp-60, -65, and -70 in a group of dyslipidemic patients. Twenty patients attending a lipid clinic, and previously not receiving lipid-lowering treatment, were treated with 10 mg of simvastatin (n = 11) or atorvastatin (n = 9) for 4 months. An additional 14 patients were recruited from the same clinic at the same hospital as a control group. The medication of these latter patients was unaltered for 4 months and the same parameters were measured as for the statin group. Antibody titers to Hsp-60, -65, and -70 were measured by enzyme-linked immunosorbent assay and lipoprotein profile and highly sensitive serum C-reactive protein (CRP) were measured by routine methods before and after treatment. Pretreatment and posttreatment data were compared by paired t or Mann-Whitney tests. Overall statin treatment was associated with a significant reduction in median antibody titers to Hsp-60 (17.2%, p = 0.03), Hsp-65 (15.9%, p = 0.003) and Hsp-70 (8.3%, p = 0.006), but not in control patients. Both statins caused a reduction in median serum CRP concentrations (45% overall, p < 0.05), but significant changes were not observed in the control patients. The effects on Hsp antibody titers were not related to changes in serum CRP concentrations (p > 0.05). However, there was a significant correlation between changes in antibody titers to Hsp-60 vs Hsp-65 (p < 0.01), Hsp-60 vs Hsp-70 (p < 0.05), and Hsp-65 vs Hsp-70 (p < 0.001). Statin treatment was associated with a reduction in antibody titers to Hsp-60, -65, and -70. This reduction is not fully explained by the antiinflammatory effects of the statins but may be due to their other immunomodulatory properties.

Adult↗
PubMed2003

Anti-inflammatory effects of statins in patients with aortic stenosis.

BACKGROUND: Aortic stenosis is an inflammatory process, as evidenced by increased tissue expression and serum levels of various endothelial cellular adhesion molecules. Aortic stenosis and atherosclerosis have many risk factors in common, including hypercholesterolemia. In atherosclerosis, statins lower cholesterol and display some anti-inflammatory activity. We hypothesized that statins might also have anti-inflammatory effects in patients with aortic stenosis. METHODS: This observational cross-sectional study measured levels of cellular adhesion molecules in 129 patients (88 male, mean age 68) with aortic stenosis (mean echo gradient 49 mm Hg, range 22 to 112) and compared levels in patients already on statin therapy for primary or secondary prevention of coronary artery disease, to those not on treatment. Concomitant conditions included hypertension (47%), diabetes (10%), and ischemic heart disease (54%). A comparison group consisted of 45 patients with stable ischemic heart disease. RESULTS: Patients on statins (35) were more likely to have hypertension (62% vs 42%, P =.05), but no significant differences existed in sex, age, concomitant ischemic heart disease, or diabetes. Statin-treated patients had a 20% lower vascular cellular adhesion molecule level than those without (484 +/- 143 ng/L vs 604 +/- 245 ng/L, P =.006). The reduction in cellular adhesion molecule levels was consistent in patients with aortic stenosis alone, aortic stenosis and ischemic heart disease, or ischemic heart disease alone. There were no differences in the levels of the other adhesion molecules between the three groups, or related to statin therapy. CONCLUSION: Statin therapy is associated with reduced serum levels of vascular cellular adhesion molecules in patients with aortic stenosis. Vascular cellular adhesion molecule levels are similar in patients who have aortic stenosis, ischemic heart disease, or both. A prospective study is required to confirm this finding and to determine whether this suppression of endothelial inflammation translates into a slowing of the progression of aortic stenosis.

Adult↗
PubMed2006

Statin-induced myopathy: the two faces of Janus.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have been shown to be effective at lowering low-density lipoprotein cholesterol and decreasing the risk of coronary heart disease. Although safe and well tolerated by most patients, statins have also been associated with muscle-related adverse events. This article reviews statin-associated myotoxicity to clarify the definitions of muscle-related adverse events and discusses their incidences in major statin trials, case reports, and review articles through January 2006. Milder complaints (ie, myalgia) are reported by approximately 5% to 7% of patients who take statins. More severe myotoxicity, namely rhabdomyolysis, is extremely rare for all statins save cerivastatin, and most recent estimates of its incidence are between 0.44 and 0.54 cases per 10 000 person-years. The mechanism of statin-associated myotoxicity has not been satisfactorily defined and is likely due to multiple factors, including membrane instability, mitochondrial dysfunction, and defects in myocyte duplication.

Biomarkers↗
PubMed2005

Underappreciated statin-induced myopathic weakness causes disability.

INTRODUCTION: Myopathic syndromes induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) include muscle complaints, myalgia, myositis, and rhabdomyolysis. No prospective study of statins, however, included tests of strength, so the incidence of weakness, with or without muscle symptoms and elevated enzymes, is unknown, and perhaps overlooked. METHODS: From a convenience sample of patients referred to an outpatient neurorehabilitation clinic over the course of 1 year, 8 patients with hemiparetic stroke and 10 patients with other presumed neurologic diseases presented with new difficulty walking by 3 to 12 months after starting one of 3 statins. They reported no myalgias, exercise-induced aches, or weakness. Examination revealed proximal paresis graded 4/5 on the unaffected side in the hemiparetic patients and symmetrical bilateral proximal limb and neck flexor weakness graded 4/5 in the others. They stood up with difficulty and walked with bilateral hip drop and imbalance on turns. RESULTS: Laboratory tests did not reveal myositis or other causes for paresis. No improvement in strength or mobility was found 6 weeks after initiating resistance exercises. The statin agent was stopped. By 3 months off statin, all recovered 5/5 proximal strength. Walking improved, and they arose from a chair without pushing off with their arms. DISCUSSION: Serial manual muscle testing after initiating a statin may detect a reversible cause of disability. A genetic predisposition to statin-induced myopathic proximal weakness with normal creatine kinase is consistent with a continuum of previously reported symptoms and signs but may be underappreciated.

Aged↗
PubMed2006

Effect of prior statin therapy on capillary permeability in the lungs after cardiac or vascular surgery.

Cholesterol-lowering statins can ameliorate severe forms of vascular hyperpermeability in experimental studies, and may thereby ameliorate acute lung injury and sepsis. It is unknown whether this also applies to humans. This study aimed to define whether or not prior statin therapy reduces mild post-operative increases in pulmonary capillary protein permeability associated with acute lung injury after cardiac or major vascular surgery. A prospective observational study was performed in an intensive care unit of a university hospital on 64 patients, 37 after elective cardiac and 27 after major vascular surgery, of whom 68 and 44%, respectively, had received prior statin therapy. A mobile probe system was used to measure the pulmonary leak index (PLI), i.e. the transvascular transport rate of gallium-67-radiolabelled transferrin. For all of the patients together, the mean PLI did not differ between the statin and control groups (22.9 versus 24.4 x 10(-3) min(-1)). The prevalence of an elevated PLI was 57% in the statin and 59% in the control group. Subgroup analysis did not reveal significant differences caused by statins in the PLI of these patients. Prior statin therapy neither has an adverse effect on mildly increased pulmonary capillary permeability in patients after cardiac or major vascular surgery nor does it ameliorate this increased capillary permeability.

Adult↗
PubMed2003

Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation.

Statins such as simvastatin are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that inhibit cholesterol synthesis. We presently investigated statin effects on vascular endothelial growth factor (VEGF) expression in osteoblastic cells. Hydrophobic statins including simvastatin, atorvastatin, and cerivastatin-but not a hydrophilic statin, pravastatin-markedly increased VEGF mRNA abundance in nontransformed osteoblastic cells (MC3T3-E1). Simvastatin (10(-6) M) time-dependently augmented VEGF mRNA expression in MC3T3-E1 cells, mouse stromal cells (ST2), and rat osteosarcoma cells (UMR-106). According to heterogeneous nuclear RNA and Northern analyses, 10(-6) M simvastatin stimulated gene expression for VEGF in MC3T3-E1 cells without altering mRNA stability. Transcriptional activation of a VEGF promoter-luciferase construct (-1128 to +827), significantly increased by simvastatin administration. As demonstrated by gel mobility shift assay, simvastatin markedly enhanced the binding of hypoxia-responsive element-protein complexes. These results indicate that the stimulation of the VEGF gene by simvastatin in MC3T3-E1 cells is transcriptional in nature. VEGF secretion into medium was increased in MC3T3-E1 by 10(-6) M simvastatin. Pretreating MC3T3-E1 cells with mevalonate or geranylgeranyl pyrophosphate, a mevalonate metabolite, abolished simvastatin-induced VEGF mRNA expression; manumycin A, a protein prenylation inhibitor, mimicked statin effects on VEGF expression. The effect of simvastatin was blocked by pretreatment with wortmannin and LY294002, specific phosphatidylinositide-3 kinase inhibitors. Simvastatin enhanced mineralized nodule formation in culture, whereas coincubation with mevalonate, geranylgeranyl pyrophosphate, LY294002, or VEGF receptor 2 inhibitor (SU1498) abrogated statin-induced mineralization. Thus, statins stimulate VEGF expression in osteoblasts via reduced protein prenylation and the phosphatidylinositide-3 kinase pathway, promoting osteoblastic differentiation.

Animals↗
PubMed2005

REVIEW: Efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia.

CONTEXT: The Adult Treatment Panel III recommends 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, as first-line lipid-altering therapy for all adult patients with diabetes mellitus. This is based on the well-characterized efficacy and safety profiles of this class of agents as well as several clinical trials demonstrating that statin treatment reduces the risk of cardiovascular events. EVIDENCE ACQUISITION: This review provides an overview of the effectiveness and mechanisms of action of statins in patients with diabetes mellitus using small efficacy trials and large clinical outcomes trials as well as studies of the effects of statins on apolipoprotein B (apoB) metabolism. EVIDENCE SYNTHESIS: The major findings presented are a review of mechanistic studies of selected subjects with diabetes mellitus and dyslipidemia and a compilation of results from large-scale clinical trials of patients with diabetes. CONCLUSIONS: Statins are highly efficacious as low-density lipoprotein cholesterol-lowering agents and have more modest effects on very low-density lipoprotein triglyceride and high-density lipoprotein cholesterol levels. The effects of statins on plasma lipids and lipoproteins result from their ability to both increase the efficiency with which very low-density lipoprotein and low-density lipoprotein are cleared from the circulation and reduce the production of apoB-containing lipoproteins by the liver. Additional investigations are needed to clarify the mechanisms by which statins reduce apoB secretion from the liver.

Anticholesteremic Agents↗
PubMed2005

Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein.

Rhabdomyolysis is a severe adverse effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin-induced apoptosis by the detection of membrane flip-flop using flow cytometric analysis. L6 rat myoblasts were treated with various statins (atorvastatin (3 microM), cerivastatin (3 microM), fluvastatin (3 microM), pravastatin (3 mM), or simvastatin (3 microM)) for 2, 4 or 6 h followed by reacting with FITC-conjugated annexin V for the detection of initial apoptosis signal (flip-flop). Various statin-treated myoblasts were significantly stained with FITC-annexin V at 6 h, whereas they were not detected at 2 h. Moreover, immunoblot analysis indicated that when the cells were treated with cerivastatin (3 microM), membrane-associated Ras protein was activated and detached until 6 h, resulting in cell death through the consequent activation of caspase-8. On the other hand, since cytosolic Ras activation did not activate, there is still an unknown mechanism in statin-related Ras depletion. In conclusion, statin-induced apoptosis in muscular tissue was directly initiated by the farnesyl-anchored Ras protein depletion from cell membrane with subsequent apoptosis.

Animals↗
PubMed2005

Statins and cognitive function in the elderly: the Cardiovascular Health Study.

OBJECTIVE: To examine the association of statin drug use on cognitive and MRI change in older adults. METHODS: Participants in the Cardiovascular Health Study, a longitudinal study of people age 65 or older, were classified into three groups determined by whether they were taking statin drugs on a continuous basis, intermittently, or not at all. The untreated group was further divided into categories based on National Cholesterol Education Program recommendations for lipid-lowering treatment. Participants with prevalent or incident clinical TIA or stroke or with baseline Modified Mini-Mental State Examination (3MS) scores at or below 80 were excluded. Outcomes examined included rate of change on the 3MS over an average observational period of 7 years, along with changes in MRI white matter grade and measures of atrophy. RESULTS: Three thousand three hundred thirty-four participants had adequate data for analysis. At baseline, the untreated group in which lipid-lowering drug treatment was recommended were slightly older, less likely to be on estrogen replacement, and had higher serum cholesterol and lower 3MS scores than the statin-treated group. The rate of decline on the 3MS was 0.48 point/year less in those taking statins compared with the untreated group for which treatment was recommended (p = 0.069) and 0.49 point/year less in statin users compared with the group in which lipid-lowering treatment was not recommended (p = 0.009). This effect remained after controlling for serum cholesterol levels. One thousand seven hundred thirty participants with baseline 3MS scores of > 80 underwent cranial MRI scans on two occasions separated by 5 years. There was no significant difference in white matter grade change or atrophy measures between groups. CONCLUSION: Statin drug use was associated with a slight reduction in cognitive decline in an elderly population. This relationship could not be completely explained by the effect of statins on lowering of serum cholesterol.

Aged↗
PubMedDate not supplied

Statin-fibrate combination therapy.

BACKGROUND: Precautionary warnings for severe myopathy and rhabdomyolysis from the coadministration of statins and fibrates have been well publicized. However, a recent cerivastatin labeling change made the combined use with fibric acid derivatives a contraindication. Practical recommendations for clinicians who care for patients with refractory mixed hyperlipidemia are needed. OBJECTIVE: To provide recommendations for clinicians in the treatment of refractory mixed hyperlipidemia. DATA SOURCES: A comprehensive MEDLINE (1966-July 2000) and bibliographic search was performed. DATA SYNTHESIS: Thirty-six published clinical trials and 29 case reports involving combination therapy with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and fibric acid derivatives regarding the occurrence of rhabdomyolysis or myopathy were reviewed. The literature review demonstrated that combination therapy with a statin and fibrate increases the risk of muscle damage, with an incidence of 0.12%. Risk factors that predispose patients to myopathy caused by combination statin-fibrate therapy include increased age, female gender, renal or liver disease, diabetes, hypothyroidism, debilitated status, surgery, trauma, excessive alcohol intake, and heavy exercise. CONCLUSIONS: Combination therapy with a statin and fibrate offers significant therapeutic advantage for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination does increase the risk of myopathy, with an incidence of approximately 0.12%, this small risk of myopathy rarely outweighs the established morbidity and mortality benefits of achieving lipid goals. Nevertheless, a higher incidence of myopathy has been reported with statin monotherapy. When monotherapy with a statin fails to control mixed hyperlipidemia, combination therapy may be considered. Niacin may be added before a fibrate is considered, as it appears to have less risk of myopathy. Statin-fibrate combination therapy must be undertaken cautiously and only after careful risk-benefit analysis. Patient counseling on the risks and warning signs of myopathy is extremely important.

Adult↗
PubMed2002

Early statin therapy for acute coronary syndromes.

OBJECTIVE: To review the clinical benefit of statins in the early management of acute coronary syndromes (ACSs) and their possible mechanisms of benefit. DATA SOURCES: A MEDLINE search (1966-September 2001) was conducted using the following terms: pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, statins, hydroxymethylglutaryl coenzyme A reductase inhibitor, acute coronary syndromes, unstable angina, and myocardial infarction. Pertinent articles referenced in these publications were also reviewed. STUDY SELECTION AND DATA EXTRACTION: French- and English-language human and animal studies were selected and analyzed. DATA SYNTHESIS: In addition to their lipid-lowering properties, statins produce several nonlipid-related properties. These pleiotropic properties include improved endothelial function, reduction of inflammation at the site of the atherosclerotic plaque, inhibition of platelet aggregation, and anticoagulant effects, all of which may result in clinical benefit during ACSs. Preliminary studies and retrospective analyses of large clinical trials support the hypothesis that statins may be of benefit in ACSs. A recently published randomized, double-blind, multicenter trial evaluated the clinical impact of high-dose atorvastatin in patients with ACSs. Use of atorvastatin resulted in a decrease in a combined endpoint of cardiovascular events. Furthermore, initiation of statin therapy during hospitalization improves long-term compliance and may significantly improve clinical outcome. CONCLUSIONS: Early use of statins in ACSs appears to decrease cardiovascular events. We believe statin therapy should be initiated early (at the latest before hospital discharge) in all patients who have been hospitalized for ACSs. Ongoing studies will clarify the benefit of these agents in ACSs, the importance of their nonlipid-lowering properties, and the optimal cholesterol-target concentrations.

Animals↗
PubMed2005

Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK.

BACKGROUND: Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate alpha-secretase-type shedding of the alpha-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPP(alpha)). Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases-Rho A, B, and C-as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs). Several cell-surface molecules are substrates for activated alpha-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved. METHODS AND FINDINGS: We found that both atorvastatin and simvastatin stimulated sAPP(alpha) shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPP(alpha) shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPP(alpha) shedding. CONCLUSION: Together, these data suggest that statins exert their effects on shedding of sAPP(alpha) from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1.

Alzheimer Disease↗
PubMed2006

A case of simvastatin-associated pancreatitis and review of statin-associated pancreatitis.

Reduction of low-density lipoprotein cholesterol (LDL) concentration has become the primary goal and a standard of care in the practice of cholesterol management. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most frequently prescribed lipid lowering agents on the market. As more information is learned through the results of clinical trials, LDL goals become more stringent and difficult to attain. Large doses of high-potency statins, sometimes given in combination with other lipid-lowering agents, are frequently necessary to achieve these goals. As a result, the frequency of adverse effects from statin therapy may be expected to increase, and less common adverse effects may occur more often. As statins are used more aggressively, rare and possibly dangerous adverse effects must be identified, especially those that are becoming more frequently encountered. Increased awareness may lead to earlier diagnosis and management of diseases that may be caused by the statins. We describe a 58-year-old man who was hospitalized with idiopathic pancreatitis 4 months after starting simvastatin therapy. His oral drug therapy was withheld, and he was treated with bowel rest. The patient was discharged on hospital day 5, and his oral drug regimen, including simvastatin, was resumed. He was admitted again 16 months later with a second diagnosis of acute pancreatitis and was discharged after 3 days of bowel rest with no oral drug therapy. Simvastatin was restarted on discharge, but the patient stopped taking it after experiencing muscle soreness and weakness in his arms. He recalled having similar arm pain that preceded the previous episode of acute pancreatitis. All other causes of the pancreatitis had been ruled out; thus, the correlation between simvastatin-induced myalgia and onset of acute pancreatitis on two separate occasions made simvastatin the suspected instigating agent. Pancreatitis is a rare adverse effect of statin therapy, but it has been documented in several case reports involving most of the statins. Continued reporting is necessary to increase awareness of this rare adverse effect of simvastatin so that it may be promptly managed or avoided in the future.

Humans↗