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PubMed2000

Direct effects of statins on cells primarily involved in atherosclerosis.

Statins are lipid-lowering agents which 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) and macrophages, decrease interleukin-6 and inducible nitric oxide synthase expression in VSMCs, improve endothelial function and up-regulate endothelial nitric oxide synthase expression. The above effects of statins are independent of plasma cholesterol levels, and are completely blocked by exogenous mevalonate and some isoprenoids. These findings suggest that, in addition to their effects on plasma lipids, statins exert direct antiatherosclerotic effects on the cells primarily involved in atherosclerosis.

Animals↗
PubMed2000

Beneficial effects of statins in coronary artery disease--beyond lowering cholesterol.

OBJECTIVE: To review the benefits of statins in coronary artery disease management beyond their cholesterol-lowering effects. DATA SOURCES: A MEDLINE search (1966-May 2000) was conducted using the following terms: lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, endothelium, plaque stabilization, antithrombotic effects. STUDY SELECTION: English-language human studies and case reports. DATA EXTRACTION: Studies published demonstrating other mechanisms of statins' clinical beneficial effects were evaluated and reviewed. DATA SYNTHESIS: The understanding of the pharmacologic effects of statins has led to the realization that the benefits of these agents extend beyond simply lowering cholesterol. These properties include beneficial effects on vessel endothelial tissue; decreased low-density lipoprotein oxidation and inflammation; ability to stabilize atherosclerotic plaques and perhaps promote regression; proliferative effects on smooth-muscle growths, possibly strengthening atherosclerotic plaques; antithrombotic effects by inhibiting platelet aggregation and stimulation of fibrinolytic factors; and improvement of blood viscosity and flow. With these actions, statins may benefit the situation of long-term atherosclerotic plaque formation and the setting of acute coronary syndrome. CONCLUSIONS: Further large-scale studies are needed to determine the clinical importance and validity of these postulated beneficial effects of statins.

Blood Coagulation↗
PubMed2005

Differential association between statin exposure and elevated levels of creatine kinase.

BACKGROUND: Although hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are generally well tolerated, myopathy can be a serious adverse event. The association among different statins, doses, and related risk factors is not well understood. OBJECTIVE: To determine the prevalence of elevated creatine kinase (CK) levels in patients taking statins, specific doses of these drugs, and other factors. Simvastatin and lovastatin were the drugs of primary interest. METHODS: In a modified prevalence (cross-sectional) study, prescriptions and laboratory data for 215,191 patients exposed to a statin in 2002 were reviewed. A log-linear Poisson regression model was used to determine the statistical relationship of an elevated CK level to other independent variables. RESULTS: Prevalence of high elevation of CK levels (ie, n of cases/1000 pts. exposed to statins) was 1.6; prevalence of mild to moderate elevation of CK levels was 6.4. For high elevations, the prevalence ratios were lower for low doses of lovastatin than for high doses of simvastatin. A higher prevalence ratio was associated with elevated serum creatinine (SCr) levels (2.44), exposure to interacting drugs (1.62), male gender (1.48), and evidence of diabetes (1.34). For mild to moderate elevation, a higher prevalence ratio was associated with elevated SCr (1.45), exposure to interacting drugs (1.21), male gender (3.19), age < or =65 years (1.35), and evidence of diabetes (1.34). Lower prevalence ratios were associated with all doses of lovastatin compared with those of high doses of simvastatin. CONCLUSIONS: Compared with simvastatin, lovastatin was generally associated with a lower prevalence of high elevation and mild to moderate elevation of CK levels. An elevated SCr level, exposure to interacting drugs, male gender, evidence of diabetes, and age < or =65 years were associated with higher prevalence ratios.

Anticholesteremic Agents↗
PubMed2005

Determinants of the differences in LDL-cholesterol after initiation of statin treatment.

BACKGROUND: Randomized clinical trials may not accurately predict drug benefit in clinical practice because the patients and conditions of therapy almost always differ between those settings. OBJECTIVE: To determine whether differences in low-density lipoprotein cholesterol (LDL-C) time curves between clinical trial results and usual care experience after initiation of statin therapy could be explained fully in terms of observable characteristics of patients and practice in usual care. METHODS: We compared LDL-C measurements for 3 years after initiation of statin treatment in individuals enrolled in a health maintenance organization (HMO), with enrollees in the active treatment arm of the CARE (Cholesterol and Recurrent Events) trial. Analysis of the determinants of variation in LDL-C in the HMO cohort was used to adjust the crude results to the distribution of patient and treatment characteristics in the trial. RESULTS: The mean percent decrease in LDL-C was lower in the HMO cohort (n = 1245) than in the clinical trial at the end of each 6-month period, with the difference diminishing over time. Adjustment of the HMO time curve to the baseline characteristics of the clinical trial cohort did not significantly change the mean estimates at any time point. Assuming optimal adherence in the HMO cohort raised the curve over time, with 95% confidence intervals including the means observed in CARE after 18 months. Fixing treatment to pravastatin 40 mg/day, as in CARE, brought the estimates in the HMO cohort very close to those of the clinical trial, with 95% confidence intervals including the means observed in CARE at all time points. CONCLUSIONS: Treatment selection, dosing, and adherence under usual care were the primary reasons for which improvements in LDL-C in practice fell short of expectations that are based on clinical trial findings for statin therapy. Beginning with a low dose of statins and titrating to a satisfactory response can delay effective treatment by 18 months or more. Poor adherence accounts for a further substantial shortfall from maximal effect. Differences between trial populations and the general population of statin users with respect to age, gender, and baseline LDL-C have no measurable impact on discrepancies between predicted and observed LDL-C improvement in usual practice.

Adult↗
PubMed2006

Considerations for supplementing with coenzyme Q10 during statin therapy.

OBJECTIVE: To review the literature concerning the effects of statin use on coenzyme (Co) Q10 concentrations and explain the rationale behind considering CoQ10 supplementation. DATA SOURCES: A MEDLINE search was conducted through January 2006. Search terms included ubiquinone, coenzyme Q10, HMG-CoA reductase inhibitors, statins, myotoxicity, and clinical trials. DATA SYNTHESIS: Statin therapy reduces blood CoQ10 concentrations. Studies exploring how this affects the development of myotoxicity have been small and dissimilar, thus limiting the ability to draw strong conclusions. Isolated studies suggested that statins induce mitochondrial dysfunction, but the clinical implications of this effect are limited. Limited data suggest that patients with familial hypercholesterolemia, heart failure, or who are over 65 years of age might represent at-risk populations who would benefit from CoQ10 supplementation. CONCLUSIONS: Routine CoQ10 supplementation for all patients taking statins to prevent myotoxicity is not recommended. However, certain subpopulations might be at risk and warrant further study.

Animals↗
PubMed2005

Statins and their roles in cancer.

The association of long-term statin use with cancer risk has recently become an interesting topic because of rather conflicting clinical evidence. On the one hand, early animal toxicology studies suggested the carcinogenicity of statins. On the other hand, although several large-scale, randomized clinical trials with secondary endpoints assessing associated cancer risk confirmed the safety of long-term statin use, results concerning the risk of specific cancer types remain inconclusive. To further complicate matters, retrospective studies concluded that the use of statins can actually reduce cancer risk. In addition, several small-scale cancer trials have shown evidence supporting the use of statins as therapeutic anticancer agents. In this review, we will discuss the results of the clinical studies, emphasize their strengths and weaknesses, and evaluate their potential impact on clinical practice.

Anticarcinogenic Agents↗
PubMed2003

The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity.

Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.

Animals↗
PubMed2005

Familial hypercholesterolemia and response to statin therapy according to LDLR genetic background.

Familial hypercholesterolemia is an autosomal dominant disease defined at the molecular level mainly by the presence of mutations in the low-density lipoprotein receptor gene and is characterized by elevated low-density lipoprotein cholesterol, tendon xanthomas and increased risk of early cardiovascular disease. The type of mutation in the low-density lipoprotein receptor gene has been associated with different phenotype expression and response to statins. Several studies have been undertaken to assess the efficacy of statins and evaluate the influence of mutations on the response to treatment with statins. Not all patients respond to statin therapy with a reduction in cardiovascular disease. In this review paper, we will discuss the results available to date that correlate the low-density lipoprotein receptor genotype to the response to statins, and the interest in developing diagnostic systems which will allow identification of patients at increased risk of adverse drug reactions or patients in which a therapeutic effect is lacking.

Genotype↗
PubMed2001

Statins in the 21st century: end of the simple story?

The development of the HMG-CoA reductase inhibitors (the statins) has lead to important advances in the management of cardiovascular disease. There have several landmark mortality and morbidity clinical trials with the statins. The 4S (Scandinavian Simvastatin Survival Study) was the first large-scale randomised cholesterol-lowering trial to show a decrease in mortality. In patients with coronary heart disease and relatively high cholesterol, simvastatin decreased mortality, hospital stays, the risk of undergoing myocardial re-vascularisation, stroke and transient ischaemic attack. The CARE (Cholesterol and Recurrent Events) trial showed that lowering average cholesterol levels after myocardial infarction with pravastatin reduced a composite primary end point of coronary mortality and myocardial infarction, coronary bypass surgery, angioplasty and strokes. The LIPID (Long-term Intervention with Pravastatin in Ischaaemic Disease) study showed that lowering average cholesterol levels after previous myocardial infarction or unstable angina reduced mortality. WOSCOPS (The West of Scotland Coronary Prevention Study) was the first trial to demonstrate the benefit of pravastatin, as primary prevention for cardiovascular disease, in men with high cholesterol levels. AFCAPS/Tex CAPS (The Air Force/Texas Coronary Atherosclerosis Prevention Study) showed that the benefits of lowering cholesterol levels were also evident in healthy men and women who initially had average cholesterol levels. Rather surprisingly the reductions in mortality and morbidity with statins are only associated with small improvements in coronary angiographic findings. A preliminary study indicated than lovastatin prevented restenosis, but larger and better-controlled studies indicate that the statins do not have beneficial effects in restenosis. Effects other than lipid-lowering or as a consequence of their lipid-lowering may contribute to the beneficial effects of statins. These effects include improvement in vascular endothelial function, cardiac remodelling, changes in blood rheology, anti-oxidant, anti-inflammatory and anti-hypertensive actions.

Clinical Trials as Topic↗
PubMed2003

Combination lipid-lowering therapy with statins: safety issues in the postcerivastatin era.

Combination lipid-altering regimens represent an emerging clinical paradigm to meet increasingly stringent consensus lipoprotein targets for coronary prevention. This practice, together with escalating prevalences of coronary artery disease in certain ageing (western industrial) populations, polypharmacy in the elderly and the recent voluntary market withdrawal of cerivastatin, warrants a re-examination of the safety profiles of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (i.e., statins). These agents are exceedingly well-tolerated in the vast majority of patients, very infrequently precipitating musculoskeletal symptoms and/or signs. Statins vary in their pharmacological profiles, leading to distinct levels of systemic exposure and capacities to penetrate skeletal myocytes. Pharmacokinetic interactions with certain agents increase the likelihood of statin-induced myopathy and, in exceedingly rare instances, potentially fatal rhabdomyolysis with myoglobinuria and renal failure. As with other medical decisions, the anticipated benefits of long-term statin therapy, with or without other lipid-altering agents, need to be weighed against the prospects of clinically significant drug interactions. In clinical trials and postmarketing surveillance, the two statins that are not metabolised by the cytochrome P450 3A4 system (fluvastatin and pravastatin) have exhibited very low propensities to elicit myopathy when combined with other agents. These agents should be considered initially when contemplating combination lipid-lowering regimens for coronary prevention.

Cytochrome P-450 Enzyme System↗
PubMed2004

Statins and liver toxicity: a meta-analysis.

STUDY OBJECTIVE: To assess the risk of liver function test (LFT) abnormalities with the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) for the treatment of hyperlipidemia. DESIGN: Meta-analysis of randomized, placebo-controlled trials of statins used for the treatment of hyperlipidemia or for primary or secondary prevention of cardiovascular disease. SETTING: University research center. PATIENTS: A total of 49,275 patients from 13 trials. INTERVENTION: A literature search of published clinical trials was performed in MEDLINE (January 1966-March 2003) and the Cochrane Controlled Trials Registry (first quarter 2003). Studies also were identified from the references of the trials and of published systematic reviews. MEASUREMENTS AND MAIN RESULTS: For a trial to be included in the meta-analysis, its duration of follow-up had to be at least 48 weeks and the trial had to include at least 400 patients, with at least 200 treated with a statin. Trials conducted in transplant recipients were excluded. The proportion of patients having LFT abnormalities was low in both groups (statins 1.14% vs placebo 1.05%, odds ratio [OR] 1.26, 95% confidence interval [CI] 0.99-1.62, p=0.07). Only fluvastatin was associated with a significant increase in the odds of having LFT abnormalities (fluvastatin 1.13% vs placebo 0.29%, OR 3.54, 95% CI 1.1-11.6, p=0.04) compared with placebo, although this finding was based on only two trials. CONCLUSIONS: Our results support previous observations that pravastatin, lovastatin, and simvastatin at low-to-moderate doses are not associated with a significant risk of LFT abnormalities. Additional data are required to determine whether other statins have a similar safety profile.

Aged↗
PubMedDate not supplied

Quantifying the effect of applying the NCEP ATP III criteria in a managed care population treated with statin therapy.

OBJECTIVE: Revised treatment goals suggested by the third report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) represent a challenge to both physicians and the health care industry. We sought to quantify the impact of these changes in a large managed care population being treated with statin therapy. METHODS: Using data collected from a retrospective chart review of 1,962 managed care enrollees who received statin drug therapy between February 2001 and August 2001, we quantified the low-density lipoprotein cholesterol (LDL-C) goals and goal attainment of this population according to both the NCEP ATP II and ATP III criteria and further identified independent predictors of ATP III goal attainment using multivariable logistic regression modeling. RESULTS: Overall, 21.1% (n = 414) of statin patients moved to a more stringent LDL-C goal when ATP III criteria were applied over ATP II. Substituting ATP III criteria for ATP II criteria resulted in a 6.8% decrease in the percentage of participants who had their most recent LDL-C value below the suggested goal, from 59.8% under ATP II to 53.0% under ATP III. Persons with existing coronary heart disease, diabetes, obesity, and stroke or transient ischemic attack were all less likely to meet the suggested NCEP ATP III LDL-C goal. CONCLUSION: Taking into account the revised risk stratification of the ATP III guidelines and the lack of LDL-C goal attainment in patients currently taking statins, there will be an increase in the number of statin patients who require dose or agent adjustment, combination therapy, or compliance counseling to achieve their lower LDL-C goal.

Adult↗
PubMed2001

Current thinking in statin therapy.

The HMG-CoA reductase inhibitors (statins) are now considered the most potent lipid-lowering drugs. Treatment with statins reduces both morbidity and mortality rates due to coronary artery disease. There is now increasing evidence that the clinical benefits obtained with statins cannot be solely attributed to a decrease in low-density lipoprotein (LDL) level. These drugs may also have beneficial effects on endothelial dysfunction, LDL oxidation, rheological and thrombogenic factors, cellular inflammation and plaque formation and stability. Further, there are differences among the various statins on these non-lipid variables. The biochemical effects of statins, as well as their clinical benefits, should be taken into consideration.

Cholesterol, LDL↗
PubMed2004

Role of statins in acute coronary syndromes.

Statins reduce major coronary events and all-cause mortality in patients with coronary artery disease. Statin therapy has a proven track record for the secondary prevention of coronary artery disease. The extension of the benefit to patients with acute coronary syndromes can be expected. Apart from their lipid-lowering effects, statins significantly and favourably alter the natural history of acute coronary syndromes. Promotion of plaque stability, improvement of endothelial dysfunction and reversal of coagulation and platelet abnormalities are only some of the effects which are beneficial in the management of these patients. Early potential clinical benefits further strengthen the rationale for starting statin treatment as soon as possible after acute coronary events particularly in patients in whom invasive intervention is planned. This review examines their role in acute coronary syndromes and emphasizes the benefits of early statin therapy.

Acute Disease↗
PubMed2006

Overcoming 'ageism' bias in the treatment of hypercholesterolaemia : a review of safety issues with statins in the elderly.

Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.

Aged↗
PubMed1998

Are there potential non-lipid-lowering uses of statins?

Recent clinical trials have demonstrated beyond doubt that statins are effective in the prevention of acute coronary events. Critical analysis of these studies suggests that the benefits of statin therapy cannot be fully explained on the basis of reductions in plasma cholesterol levels. Accumulating knowledge of the actions of these drugs shows that they may prevent several processes that eventually lead to plaque rupture and the development of occlusive thrombosis, the basis of acute coronary events. Hence, statins may correct endothelial dysfunction (thus protecting against ischaemic injury), stabilise existing plaques and modify the coagulation pathway, thereby reducing the likelihood of a sudden vascular event. At a cellular level, these drugs inhibit the synthesis not just of cholesterol, but of other compounds important in cell proliferation. Antiproliferative effects have been demonstrated in vitro and may broaden the applications of statins to the treatment of noncardiovascular diseases. Finally, preliminary clinical studies indicate that as a result of immunosuppressive actions, statins may reduce the incidence of rejection following organ transplantation.

Animals↗
PubMed2004

Cost-effectiveness of ezetimibe coadministration in statin-treated patients not at cholesterol goal: application to Germany, Spain and Norway.

BACKGROUND: Despite the growing use of statins, many hypercholesterolaemic patients fail to reach their lipid goal and remain at elevated risk of coronary heart disease (CHD). Alternative treatment strategies, such as ezetimibe coadministration and statin titration, can help patients achieve greater lipid control, and thereby lower their CHD risk. But is it cost effective to more aggressively lower cholesterol levels across a broad range of current statin users? METHODS: Using a decision-analytic model based on epidemiological and clinical trials data, we project the lifetime benefit and cost of alternative lipid-lowering treatment strategies for CHD and non-CHD diabetic patients in Germany, Spain and Norway. RESULTS: It is projected that from 40% to 76% of these patients who have failed to reach their lipid goal with their current statin treatment will be able to reach their goal with ezetimibe coadministration; this represents a gain of up to an additional absolute 14% who will be able to reach their goal compared with a 'titrate to goal' strategy where patients are titrated in order to reach their lipid goal (up to the maximum approved dose). For CHD patients, the estimated incremental cost-effectiveness ratio for ezetimibe coadministration is under Euro 18 000 per life-year gained (Euro/LYG) and 26 000 Euro/LYG compared with strategies based on the observed titration rates and the aggressive 'titrate to goal' strategy, respectively; for non-CHD diabetic patients, these ratios are under 26 000 Euro/LYG and 48 000 Euro/LYG for ezetimibe coadministration compared with the two titration strategies. CONCLUSION: Compared with statin titration, ezetimibe coadministration is projected to be cost effective in the populations and countries studied.

Anticholesteremic Agents↗
PubMed2005

Pharmacoeconomic impact of non-compliance with statins.

There are numerous studies examining the pharmacoeconomic impact of HMG-CoA reductase inhibitor (statin) therapy on healthcare costs and outcomes. A recently published review demonstrated that the cost-benefit of these agents depends primarily on the risk of developing a coronary event. That is, as the risk of a coronary event increases, the cost-effectiveness ratio decreases. The typical cost per life-year saved (LYS) ranged from USD 1800 to USD 40,000 in patients with pre-existing coronary artery disease (CAD) and from USD 15,000 to > USD 1 million per LYS in patients without pre-existing CAD. The literature is sparse on the pharmacoeconomics of medication non-compliance in patients taking statin medications. Data from two studies suggest that >75% compliance results in decreased coronary events such as myocardial infarction. However, retrospective database analyses indicate that the average compliance rate hovers around the 65% mark. Many of the studies discuss medication non-compliance as a factor, but do not independently analyse compliance pharmacoeconomically. We examined the pharmacoeconomic impact of non-compliance using published studies that contained pharmacoeconomic data and/or compliance data. In general, we used the placebo arm of these published studies as the surrogate marker for complete non-compliance. The results suggest that for almost 100% compliance versus initial non-compliance, the cost effectiveness of statin medications ranges from USD 4500 to over USD 250,000 per LYS depending on patient age, presence or absence of risk factors and whether the statin is being used for primary or secondary prevention. Alternate-day or weekly dosing studies were also used to examine the impact of compliance on cost and health outcomes. Alternate-day dosing represented 50% compliance and weekly dosing 29% compliance. Less than full compliance had the expected effect of worse health outcomes and lower drug costs. However, the studies were small and not designed as true pharmacoeconomic studies looking at the relationship between medication compliance and cost. The results of this review suggest that there needs to be further examination of the relationship between compliance with statins and cost effectiveness, and studies need to include compliance in their data collection and analysis.

Cost-Benefit Analysis↗