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PubMed2005

Quantifying the use of the statin antilipemic drugs: comparisons and contrasts between Nova Scotia, Canada, and Queensland, Australia.

BACKGROUND: Jurisdictions are developing public drug insurance systems to improve access to pharmaceuticals, cost-effective prescribing, and patient health and well-being. We compared 2 jurisdictions with different pharmaceutical policies to determine prescribing patterns for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins). OBJECTIVE: The aim of this work was to investigate the feasibility of using available prescription administrative databases to compare the use of statins in Queensland, Australia, and in Nova Scotia, Canada. METHODS: Data from the Nova Scotia Pharmacare Program and the Health Insurance Commission in Australia were used to obtain dispensing data. Utilization was compared for the 5-year period from 1997 through 2001, using the World Health Organization anatomic therapeutic chemical/defined daily dose (DDD) system. RESULTS: In the year 2001, there were 177,000 beneficiaries in the public drug plan in Nova Scotia (62% aged > or = 65 years old) and 960,000 concession beneficiaries (pensioners and social security recipients, 61 aged > or = 65 years) in Queensland. These 2 groups were comparable. The overall utilization of statin medications increased steadily in both areas over the study period, from 50 to 205 DDD/1000 beneficiaries per day. Comparison of the 2 growth lines showed no statistically significant differences in overall statin use despite differences in brand availabilities and policies about prescribing. In the year 2001, atorvastatin was the most commonly prescribed statin in both areas, comprising 46% of statin use in Nova Scotia and 51% in Queensland. Mean doses of each statin prescribed were slightly above the DDDs. Expenditure on statins per 1000 beneficiaries and per DDD were similar in each jurisdiction, being slightly higher in Nova Scotia. CONCLUSIONS: Despite differences in pharmaceutical reimbursement systems, use of the statins was similar in Nova Scotia and Queensland. The feasibility of the methodology was demonstrated. Future studies, including comparisons of drug utilization for other classes of drugs for which drug policies may be divergent (eg, different pricing structures or prior authorization requirements), or for which less evidence for appropriate use is available, may be useful.

Aged↗
PubMed2005

Statin escape phenomenon: Does it really exist?

BACKGROUND: The normalization of blood lipid profile has become an accepted method of primary and secondary prevention of vascular disease, with statins being the most popular group of medicines prescribed to lower cholesterol and LDL cholesterol levels. The failure of statins, administered in an appropriate dose, to maintain the optimal level of LDL cholesterol is a rare phenomenon, and is still not well understood in patients compliant for both medication and diet. The entity of "statin escape phenomenon", proposed to explain the failure of statins in some of these patients, has not been studied or characterized extensively, and reports of its prevalence are scarce. METHODS: Patients with hyperlipidemia type 2a or 2b who had been treated with statins for at least 1 year and who were followed up in the lipid clinic on a regular basis every 3-4 months were included in this study. The charts of patients whose LDL cholesterol levels were elevated by 15% or more while receiving the same treatment were analyzed, and patients with putative statin escape phenomenon were included in the study and further characterized. RESULTS: Forty-five of 358 statin-treated patients demonstrated a 15% increase in LDL cholesterol levels, leading to suspicion of statin escape phenomenon. However, a strict exclusion analysis left only two patients without evident potential triggers for the observed elevation in LDL cholesterol. CONCLUSIONS: Whether a statin escape phenomenon really exists is still not certain, but if it does exist, it is probably an uncommon event with a low prevalence.

Journal Article↗
PubMed2005

Failure to achieve recommended LDL cholesterol levels by suboptimal statin therapy relates to elevated cardiac event rates.

OBJECTIVES: The majority of patients with myocardial infarction (MI) and hypercholesterolaemia does not achieve guideline recommended low-density lipoprotein cholesterol (LDL) levels. Suboptimal dosages of statins explain this dilemma in most patients. DESIGN AND SETTING: We evaluated the relationship between statin treatment quality (optimal: LDL<115 mg/dl, suboptimal: LDL>/=115 mg/dl, no statin therapy despite hypercholesterolaemia) and the subsequent incidence of coronary events (coronary death, nonfatal MI, bypass surgery) over a 30 months follow-up in a large cohort of post MI patients with hypercholesterolaemia (n=2045). Analysis was performed in a nested case-control manner comparing 173 cases with a coronary event and 346 matched controls. RESULTS: Patients who developed a coronary event were treated optimally in 11.0%, suboptimally in 43.4% (p<0.05 vs. optimal treatment) and were untreated in 45.7% (p<0.001 vs. optimal treatment). Respective numbers in event-free patients were 21.4%, 47.7%, and 30.9%. After adjustment for most potential confounders, including all cardiovascular risk factors and medication, the relative risk of future non-fatal MI and coronary death associated with a suboptimal statin treatment was 2.02 (95% CI 1.04 to 4.18) compared to optimal statin treatment. Moreover, the statin equivalent dose in optimally treated individuals was significantly higher than in suboptimally treated individuals (0.85+/-0.03 vs. 0.78+/-0.02, p<0.05). CONCLUSION: In this community-based study, a lipid lowering therapy with statins into the recommended target range of LDL levels may be associated with decreased cardiovascular risk compared to a statin therapy without titrating the LDL level below 115 mg/dl. Thus, the quality of statin treatment was identified as an independent predictor of coronary events in post MI patients.

Aged↗
PubMed2006

Statin use and survival in patients with chronic heart failure--results from two observational studies with 5200 patients.

BACKGROUND: There is minimal evidence that HMG-CoA reductase inhibitors (statins) are beneficial in patients with chronic heart failure (CHF). Treatment with statins may lead to a lower mortality in CHF, independent of cholesterol levels, CHF etiology and clinical status. METHODS: In a first study, we included 3132 patients with CHF from the ELITE 2 study in whom information on body mass index (BMI) and statin use at baseline were available. In a second study, we pooled the databases of 5 tertiary referral centers with 2068 CHF patients. In this cohort 705 patients were on a statin (34%), 585 of 1202 (49%) patients with ischemic etiology, and 120 of 866 (14%) patients with non-ischemic etiology (established by coronary angiography). FINDINGS: Patients in ELITE 2 who received statin therapy at baseline (n=397, 13%) had lower mortality (hazard ratio [HR] 0.61, 95% CI 0.45-0.83; p=0.0007). In univariate analysis, increasing age, NYHA class, creatinine, and decreasing BMI, LVEF, and cholesterol, as well as lack of beta-blocker treatment and ischemic etiology (all p<0.002) related to higher mortality. In multivariable analysis, statin therapy related to lower mortality independently of all these variables (adjusted HR 0.66, 95% CI 0.47-0.93; p=0.017). In the second study CHF patients on statins had lower mortality (adjusted HR 0.58, 95% CI 0.44-0.77; p=0.0001). Both in patients with ischemic (p<0.0001) and non-ischemic etiology (p=0.028) statin treatment related to better survival. INTERPRETATION: In chronic heart failure, treatment with statins is related to lower mortality, independent of cholesterol levels, disease etiology and clinical status.

Aged↗
PubMed2004

Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure.

OBJECTIVES: This study aimed to investigate the impact of hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) therapy in patients with advanced heart failure (HF). BACKGROUND: Although statins are known to reduce mortality in coronary artery disease (CAD), the impact of statin therapy in patients with HF has not been well studied. Both the potential risks and benefits of statins in HF have been described. METHODS: We studied a cohort of 551 patients with systolic HF (left ventricular ejection fraction [EF] <or=40%) referred to a single university center for clinical management and/or transplant evaluation. Survival without the necessity of urgent heart transplantation was determined. RESULTS: The patients' mean age was 52 +/- 13 years; mean EF was 25 +/- 7%. Forty-five percent of the cohort had CAD, and 45% were receiving statin therapy, including 73% and 22% of CAD and non-CAD patients with HF, respectively. Patients receiving statins were significantly older and more likely to be male, with higher rates of hypertension, diabetes, and smoking. The EF and cholesterol levels were similar between treated and non-treated patients. Statin use was associated with improved survival without the necessity of urgent transplantation in both non-ischemic and ischemic HF patients (91% vs. 72%, p < 0.001 and 81% vs. 63%, p < 0.001 at one-year follow-up, respectively). After risk adjustment for age, gender, CAD, cholesterol, diabetes, medications, hemoglobin, creatinine, and New York Heart Association functional class, statin therapy remained an independent predictor of improved survival (hazard ratio 0.41 95% confidence interval 0.18 to 0.94). CONCLUSIONS: Statin therapy is associated with improved survival in patients with ischemic and non-ischemic HF. Randomized trials are needed for confirmation of a therapeutic benefit.

Cohort Studies↗
PubMed2005

Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial.

OBJECTIVES: This study sought to evaluate what set of factors correlate with higher or lower C-reactive protein (CRP) levels in patients receiving standard and intensive statin therapy. BACKGROUND: C-reactive protein levels in blood are becoming recognized as a potential means of monitoring cardiovascular risk. Although statin therapy is known to reduce CRP levels, many patients have a high CRP level despite statin therapy. METHODS: This study was a cross-sectional study of 2,885 patients from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, which assessed the relationship between uncontrolled cardiovascular risk factors and CRP level at four months after enrollment. RESULTS: In a multivariate model, several risk factors were weakly but independently associated with higher CRP levels: age, gender (with or without hormone replacement therapy), body mass index >25 kg/m2, smoking, low-density lipoprotein > or =70 mg/dl, glucose >110 mg/dl, high-density lipoprotein <50 mg/dl, triglycerides >150 mg/dl, and the intensity of statin therapy. A direct relationship between the number of uncontrolled risk factors present and CRP levels (p < 0.0001) was observed for both statin regimens. Despite the presence of each uncontrolled risk factor, prior randomization to intensive statin therapy was associated with a lower CRP level (p < 0.0001). Across all strata, defined by the number of uncontrolled risk factors present, CRP levels were lower among those receiving intensive statin therapy. CONCLUSIONS: The use of intensive statin therapy lead to a lower CRP level independent of the presence of single or multiple cardiovascular risk factors. Even among patients receiving intensive statin therapy, a lower CRP level was observed in patients with the fewest coronary risk factors present, suggesting that control of multiple risk factors may be a means to further achieve lower CRP levels.

Acute Disease↗
PubMed2005

Evaluation of apoptosis and necrosis induced by statins using fluorescence-enhanced flow cytometry.

The purpose of this study was to evaluate the apoptosis and necrosis induced by five kinds of statins in IM-9 human lymphoblasts with fluorescence-enhanced flow cytometry using avidin-biotin complex. IM-9 human lymphoblasts (2 x 10(4) cells/cm2) were seeded into tissue culture plates and incubated with five kinds of statins. Statin-treated cells were first incubated with biotin-annexin V, followed by addition of avidin-FITC and propidium iodide, and then subjected to flow cytometry. The fluorescence intensity was enhanced using an avidin-biotin complex system, resulting in successful separate determination of the statin-induced apoptosis and necrosis by flow cytometry, which enabled us to quantitatively evaluate the statin-induced cell damage. Flow cytometric analysis results in the intensity of statin-induced apoptosis in IM-9 cells as follows: atorvastatin cerivastatin>fluvastatin simvastatin>pravastatin. The intensity of statin-induced necrosis in IM-9 cells was expressed as follows: atorvastatin cerivastatin>fluvastatin simvastatin>pravastatin. The total damage of IM-9 cells induced by five kinds of statins were expressed as the sum of both percentages of apoptosis and necrosis as follows: atorvastatin cerivastatin>fluvastatin simvastatin>pravastatin. Our studies show that fluorescence enhancement with avidin-biotin complex is useful for the identification and quantitation of annexin-positive apoptosis cells and thus, the fluorescence-enhanced flow cytometry was shown to be applicable for screening of statins as new anti-leukemia agents.

Apoptosis↗
PubMed2006

Rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy.

Inflammation has been recognized as having an important role in the development and progression of atherosclerosis. Statins reduce cardiovascular events mainly by cholesterol lowering. A large number of investigations have demonstrated that administration of statin could modify inflammatory response with a concurrent fall in cardiovascular events. Despite the known benefit of statin therapy, many cardiac patients abruptly discontinue therapy because of financial constraints, forgetfulness, or side effects. More recently, several studies have shown that abrupt cessation of statin therapy during treatment could increase the incidence of cardiac events in patients with atherosclerotic heart disease. However, the mechanisms of the increased incidence of cardiovascular events after abruptly stopping statin therapy are still unknown. A few data suggest that abrupt withdrawal of statin therapy deteriorates endothelial function, result in expression of pro-inflammatory gene involved in the development and progression of atherosclerosis. We hypothesis that rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy. Our very recent data showed that abrupt termination of statin therapy resulted in a rapid increased C-reactive protein (CRP) and interleukin-6 (IL-6) levels in patients with hypercholesterolemia. This finding may be of important interest in the connection between inflammatory response and abrupt withdrawal of statin therapy in patients with coronary artery disease.

Cardiovascular Diseases↗
PubMed2006

The under-use of statin in type 2 diabetic patients attending diabetic clinics in Italy.

BACKGROUND AND AIMS: The greatest decrease in mortality from cardiovascular disease (CAD) that can be achieved with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is seen in patients with the highest risk for CAD, such as diabetics. Yet, there is evidence for inadequate use of drug therapies to achieve lipid goals. Our aims were to: (1) assess the prevalence of statin use in patients attending diabetic clinics and (2) correlate the use of statins with their risk and clinical status. METHODS AND RESULTS: Of 9921 patients included, only 20.4% of them were receiving statin therapy. Statins were more progressively prescribed in those with risk factors additional to that of diabetes. Patients under statin treatment were older, mostly type 2 diabetics, more hypertensive and hyperlipidemic, had a higher prevalence of both macro- and microvascular disease. Among those with a total cholesterol concentration above 252 mg/dl, statin treatment was given only to 60% of diabetic patients with prior myocardial infarction, 56% of those with angina, 66% of those having had prior revascularization procedure, 54% of those with cerebrovascular disease and 51% of those with peripheral artery disease. CONCLUSIONS: At least in Italy, statins are not prescribed to the majority of diabetic patients, and a substantial proportion of patients not treated with statins present significant macro- and microvascular complications.

Adult↗
PubMed2005

Statins, especially atorvastatin, may favorably influence clinical presentation and biochemical progression-free survival after brachytherapy for clinically localized prostate cancer.

OBJECTIVES: To conduct a preliminary investigation on statin use and its impact on clinical presentation and biochemical progression-free survival after brachytherapy. METHODS: A total of 512 consecutive patients were treated with permanent brachytherapy for clinical Stage T1c-T3aNxM0 prostate cancer at least 3 years before analysis. Biochemical progression-free survival was defined by a prostate-specific antigen (PSA) level of 0.4 ng/mL or less after nadir. The median follow-up was 5.3 years. The clinical, treatment, and dosimetric parameters evaluated included use of any and specific statins, age, body mass index, PSA level, Gleason score, percentage of positive biopsies, perineural invasion, prostate volume, planning volume, dosimetric quality, supplemental external beam radiotherapy, tobacco use, hypertension, and diabetes. RESULTS: The actuarial 8-year biochemical progression-free survival rate for the entire group was 94.6%. On forward conditional Cox regression analysis, the pretreatment PSA level and percentage of positive biopsies were statistically significant predictors of biochemical outcome. However, a significantly lower pretreatment PSA level, percentage of positive biopsy cores, and PSA density and earlier clinical stage were found in the statin group. Almost every clinical presentation parameter comparison at least favored statin users. When stratified by any or specific statin use, 97.0% of patients taking statins compared with 94.3% not taking statins and 97.8% of patients taking atorvastatin compared with 94.7% taking other statins were free of biochemical progression. CONCLUSIONS: The results of this brachytherapy investigation with the longest reported follow-up period to date suggest that statins, especially atorvastatin, may improve most clinical presentations with a nonsignificant improvement in 8-year biochemical progression-free survival.

Aged↗
PubMed2003

Statin use is associated with enhanced collateralization of severely diseased coronary arteries.

BACKGROUND: The presence of coronary collateral vessels has been associated with improved clinical outcome in patients with coronary artery disease. Animal experiments have shown that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) can promote angiogenesis in ischemic tissues in a cholesterol-independent manner. We hypothesized that statin therapy is associated with increased coronary collateral formation in patients with severe coronary artery disease. METHODS AND RESULTS: Patients undergoing clinically indicated coronary angiography at the Tufts-New England Medical Center from September 2000 to April 2001 who had at least 1 major coronary artery occlusion, or a stenosis of > or =95% with Thrombolysis In Myocardial Infarction (TIMI) trial grade < or =1 anterograde flow on their angiograms, were included. Fifty-one patients were taking statins before admission, and 43 patients were not. Their angiograms were reviewed and coronary collaterals were graded from 0 to 3 according to the Cohen-Rentrop method. The statin-treated group had a significantly higher mean collateral score compared with the patients not taking statins (2.05 vs 1.52, P =.005). Multivariate analysis supported the significance of the effect of statin therapy on the collateral score. There was no relation between collateral score and low-density lipoprotein levels (r = -0.06, P =.64). The statin-treated group also had a significantly higher left ventricular ejection fraction compared to the patients not taking statins (51% vs 44%, P <.05). CONCLUSIONS: Statin therapy is associated with enhanced coronary collateral formation in patients with severely diseased coronary arteries.

Aged↗
PubMed2003

Prevention of stroke and dementia with statins: Effects beyond lipid lowering.

Stroke is a major cause of mortality and morbidity. The epidemiologic association between elevated serum cholesterol and stroke risk is controversial. However, recent secondary prevention studies with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke without an increase in hemorrhagic stroke. Statins probably reduce stroke by a variety of mechanisms, including modulation of precerebral atherothrombosis in the aorta and the carotid artery, thus preventing plaque disruption and artery-to-artery thromboembolism. Statins also improve endothelial homeostasis by increasing the bioavailability of nitric oxide, which orchestrates the paracrine antiatherosclerotic functions of the endothelium. Studies in experimental models of ischemic stroke show that statin therapy reduces brain infarct size and improves neurologic outcome by directly upregulating brain endothelial nitric oxide synthase. Putative anti-inflammatory actions of statins may also contribute to neuroprotection and stroke prevention. Although the clinical benefit of statins largely depends on lowering low-density lipoprotein cholesterol, accumulating data indicate that many of the pleiotropic effects of statins are attributable to the cellular consequences of depletion of intermediates in the cholesterol biosynthetic pathway (isoprenoids). These molecules play fundamental roles in cell growth, signal transduction, and mitogenesis. In addition to reducing stroke risk, emerging data suggest that statins may reduce dementia. Further studies are needed to fully address the role of statins in the prevention of stroke in patients without established vascular disease and the role of cholesterol modulation in the treatment of dementia.

Anticholesteremic Agents↗
PubMed1998

Comparison of statins in hypertriglyceridemia.

In 1996, the first 2 studies using 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin") therapy in hypertriglyceridemic subjects were published. In subjects with isolated triglyceride elevations who were treated with atorvastatin 5, 20, and 80 mg/day, large and dose-related reductions were noted. In subjects with combined hyperlipidemia treated with 10 mg simvastatin, triglyceride reduction similar to that reported for the 5 mg atorvastatin dose was seen. In response to these findings, we conducted comparative assessments to determine whether all statins are effective in lowering triglyceride levels and whether their effect on triglycerides is related to factors such as drug, dose, and baseline triglyceride levels. To standardize these assessments, we devised a ratio that related changes in triglyceride levels to the known predictable response of low-density lipoprotein (LDL) cholesterol to statins. This triglyceride/LDL cholesterol ratio was obtained by dividing the percent change from baseline in the triglyceride level by the percent change from baseline in the LDL cholesterol level. The triglyceride/LDL cholesterol ratio was initially applied to several published studies, and found to be approximately 1.0 and 0.5 in hypertriglyceridemic and nonhypertriglyceridemic populations, respectively. We then assessed the effect of various statins on triglycerides using a pooled laboratory database of 2,689 subjects who had participated in 7 separate studies with similar designs. All of the studies had a placebo run-in followed by a randomized, double-blind, active treatment phase of at least 4 weeks with a statin. Entry into these studies required a triglyceride level of <400 mg/dL. In subjects with baseline triglyceride >250 mg/dL, significant and dose-dependent reductions in triglyceride of 22-45% were seen with all statins. When baseline triglyceride was <150 mg/dL, no significant or dose-dependent effect on triglyceride was seen. The triglyceride/LDL cholesterol ratio was evaluated using a linear model that included baseline triglyceride level, drug, and dose. Only the baseline triglyceride level was significantly (p <0.001) related to this ratio. Moreover, the triglyceride/LDL cholesterol ratio was fairly constant across all statins and doses for patients with baseline triglyceride levels of <150 mg/dL, 150-250 mg/dL, and >250 mg/dL, at 0.0+/-0.3, 0.5+/-0.2, and 1.2+/-0.3, respectively. We conclude that all statins are effective in decreasing triglyceride levels, but only in hypertriglyceridemic patients. Due to the relatively constant triglyceride/LDL cholesterol ratio, our analysis indicates that the more effective the statin is in decreasing LDL cholesterol, the more effective it will also be in decreasing triglyceride levels in patients with hypertriglyceridemia.

Anticholesteremic Agents↗
PubMed2000

Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability.

Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statin therapy demonstrate an improvement in cardiovascular end points and coronary stenosis. However, an improvement in cardiovascular end points and coronary stenosis is incompletely explained by the baseline or treated LDL cholesterol level. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify endothelial function, smooth muscle cells, and monocyte-macrophage: vasomotor function, inflammatory responses, and plaque stability. Augmented bioactivity of NO by statin therapy either indirectly by its effect on lipoprotein levels and protection of LDL from oxidation, or directly by effects on NO synthesis and release, might account for enhancement of endothelium-dependent vasodilation. Recent experimental and animal studies have demonstrated that statins dose-dependently decrease smooth muscle cells migration and proliferation, independently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages and expression of matrix metalloproteinase, resulting in plaque stability. These effects of statins were completely prevented by the addition of mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites, probably through prenylated proteins, in regulating these cellular events. Statins have been shown to prevent the activation of monocytes into macrophages, inhibit the production of pro-inflammatory cytokines, C-reactive protein, and cellular adhesion molecules. Statins decrease the adhesion of monocyte to endothelial cells. Accordingly, statins exert their cardiovascular benefits through a direct antiatherogenic properties in the arterial wall, beyond their effects on plasma lipids.

Animals↗
PubMed2002

Statin enhances cytokine-mediated induction of nitric oxide synthesis in vascular smooth muscle cells.

OBJECTIVE: We investigated the effects of the statins, cerivastatin and fluvastatin, on the induction of nitric oxide (NO) production in vascular smooth muscle cells (VSMC) stimulated by interleukin-1beta (IL-1) or in combination with interferon-gamma (IFN). METHODS: We measured NO release, inducible NO synthase (iNOS) mRNA and protein levels, iNOS gene transcription rates, and iNOS mRNA stabilities in cytokine-activated VSMC. We also evaluated nuclear factor (NF)-kappaB activity and tetrahydrobiopterin (BH4) synthesis. RESULTS: NO production induced by cytokines was dose-dependently enhanced by both statins. Incubating VSMC with IL-1/IFN stimulated iNOS mRNA and protein expression. Both statins significantly upregulated IL-1/IFN-stimulated iNOS mRNA and protein expression, and enhanced iNOS gene transcription as shown by nuclear run-on assays. However, they did not alter the stability of iNOS mRNA. Both statins slightly modulated IL-1/IFN-induced NF-kappaB activation, which was not associated with their effect on NO production. Cytokines induce the de novo synthesis of BH4 in VSMC. This event is essential for the induction of NO synthesis, which requires transcriptional induction of the genes that encode not only iNOS but also guanosine triphosphate cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in de novo BH4 synthesis. The synthesis of BH4 and GTPCH mRNA induced by IL-1/IFN were enhanced by both statins. Exogenous mevalonate significantly prevented and geranylgeranylpyrophosphate reversed the stimulatory effect of both statins. Furthermore, the geranylgeranyltransferase I inhibitor GGTI-298 significantly increased IL-1/IFN-induced NO production. CONCLUSION: Our data demonstrated that statins enhance immunostimulants-induced NO production by increasing iNOS gene expression at the transcriptional level via an NF-kappaB-independent pathway. The effect of statins on NO production is due at least partly through blocking the biosynthesis of mevalonate, which prevents isoprenoid biosynthesis. In addition to augmenting iNOS expression, statins potentiate GTPCH gene expression and BH4 synthesis, thereby preventing a relative shortage of BH4 which may shift the balance between NOS-catalyzed generation of protective NO and deleterious reactive oxygen species.

Animals↗
PubMed2003

Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells.

OBJECTIVES: HMG-CoA reductase inhibitors (statins) can modulate the formation of new blood vessels, but the reports on their contribution to angiogenesis are contradictory. Therefore, we investigated whether the effect of statins is dependent either on the concentration of the drug or on the cell type. METHODS AND RESULTS: Under basal conditions human vascular smooth muscle cells (HVSMC) and microvascular endothelial cells (HMEC-1) constitutively generate and release vascular endothelial growth factor (VEGF). In contrast, primary macrovascular endothelial cells (HUVEC) produce minute amounts of VEGF. Different statins (atorvastatin, simvastatin and lovastatin, 1-10 micromol/l) significantly reduced basal and cytokine-, nitric oxide- or lysophosphatidylcholine (LPC)-induced VEGF synthesis in HMEC-1 and HVSMC. Interestingly, at the same concentrations statins upregulated VEGF generation in HUVEC. Furthermore, statins exerted dual, concentration-dependent influence on angiogenic activities of HUVEC as determined by tube formation assay. At low concentrations (0.03-1 micromol/l) the pro-angiogenic activity of statins is prevalent, whereas at higher concentrations statins inhibit angiogenesis, despite increasing VEGF synthesis. CONCLUSION: Our data show that statins exert concentration- and cell type-dependent effects on angiogenic activity of endothelial cells and on VEGF synthesis. The data are of relevance for elucidating the differential activity of statins on angiogenesis in cardiovascular diseases and cancer.

Atorvastatin↗
PubMed2006

Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis.

BACKGROUND: Atherosclerosis and sepsis share several pathophysiological similarities, including immune dysregulation, increased thrombogenesis, and systemic inflammation. The relation between statins and risk of sepsis in patients with atherosclerosis is unknown. METHODS: We did a population-based cohort analysis through linked administrative databases in Ontario, Canada, with accrual from 1997 to 2002. We identified 141,487 patients older than 65 years who had been hospitalised for an acute coronary syndrome, ischaemic stroke, or revascularisation, who survived for at least 3 months after discharge. 46,662 (33%) were prescribed a statin within 90 days of discharge, 94,825 (67%) were not. Propensity-based matching, which accounted for each individual's likelihood of receiving a statin, yielded a cohort of 69,168 patients, of whom half (34,584) received a statin and half (34,584) did not. FINDINGS: Incidence of sepsis was lower in patients receiving statins than in controls (71.2 vs 88.0 events per 10,000 person-years; hazard ratio [HR] 0.81; 95% CI 0.72-0.91). Adjustment for demographic characteristics, sepsis risk factors, comorbidities, and health-care use gave similar results (HR 0.81; 95% CI 0.72-0.90). The protective association between statins and sepsis persisted in high-risk subgroups, including patients with diabetes mellitus, chronic renal failure, or a history of infections. Significant reductions in severe sepsis (HR 0.83; 95% CI 0.70-0.97) and fatal sepsis (0.75; 0.61-0.93) were also observed. No benefit was noted with non-statin lipid-lowering agents (0.95; 0.75-1.22). IMPLICATIONS: Use of statins in patients with atherosclerosis is associated with a reduced risk of subsequent sepsis. Randomised trials of statins for prevention of sepsis are warranted.

Aged↗
PubMed2003

[Pharmacological interactions of statins].

OBJECTIVE: To determine in primary care the frequency of pharmacological interactions of statins. DESIGN: Transversal observational study.Setting. Urban health centre.Participants. 384 patients taking statins who were chosen by systematic sampling based on long-treatment cards (95% CI, accuracy 5% and expected proportion of possible interactions unknown). MAIN MEASUREMENTS: Consumption of statins, the accompanying medication taken, presence of interactions according to the technical details of statins (Spanish Medication Agency, Ministry of Health and Consumption) and social and demographic variables. RESULTS: In 55 patients (14.3%) (95% CI, 10.8%-17.8%) one of the statin interactions with the other drugs was checked, especially with acenocoumarol, digoxin and anti-acid drugs. In patients with some interaction, the mean number of other drugs was significantly higher (4.51.5 vs 3.31.9 SD; P<.001). 19.1% of men and 10.8% of women showed interactions, the difference being statistically significant (P=.02). By means of logistic regression, both masculine gender (OR=1.8) and taking of other medication in quantities of 5 or more (OR=2.7) appeared as variables associated with the presence of interactions. CONCLUSIONS: The potential pharmacological interactions of statins reach 14.3% of patients with hypercholesterolaemia who take medication long-term. The possibility of reaching high plasma concentrations of statins and/or of modifying the therapeutic effect of various drugs enables a more appropriate use of statins to be recommended, with prescription of those statins that metabolise less through the P450 cytochrome.

Adult↗