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PubMed2004

Statin treatment and the natural history of atherosclerotic-related diseases: pathogenic mechanisms and the risk-benefit profile.

Large-scale intervention trials demonstrate that treatment with statins, the most effective lipid lowering drug class, significantly reduces the risk of coronary heart disease events. Recent evidence suggests that more aggressive LDL cholesterol lowering with newly developed statins may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. There is increasing evidence that statins exert a myriad of other beneficial pleiotropic effects on the vascular wall, thus altering the course of atherosclerotic disease. In the long-term treatment, non-life-threatening side effects may occur in up to 15% of patients receiving one statin. Significant elevations in the activity of serum aminotransferase and creatine kinase alone or in combination with muscle pain in statin-treated patients should be taken seriously. The combination of the statins with gemfibrozil results in higher rates of drug toxicity. Reports show possible adverse effects of statins on nervous system function including mood alterations, however, statins have also been associated with improvement in central nervous system disorders. Special attention must be paid to the tolerability of the statins in children, elderly and transplant patients. Future clinical studies and surveillance information will warrant long term safety of each member of this class of lipid-lowering agents. New classes of patients with diabetes, metabolic syndrome and renal diseases may have clinical benefits from statins. New upcoming clinical trials will address the fundamental question of whether statin treatment can protect from the natural history of atherosclerotic-related diseases. This will require a more prolonged follow-up (i.e., 10 to 15 years). Finally, the basic understanding of newer pathogenic mechanisms involving the effects of statins on angiogenesis and the nitric oxide pathway should be explored in the clinical setting as well as the study of pathogenic mechanisms by which statins can affect plaque instability.

Animals↗

PubMed2004

Statin pleiotropy: fact or fiction?

Accumulating evidence from clinical trials and basic research indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of LDL cholesterol levels and effects independent of the lowering of LDL cholesterol levels. The latter effects are referred to as pleiotropic. The full potential of this exciting class of drugs in vascular and nonvascular protection is only just being realized. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, and stabilize unstable plaques. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. Ezetimibe, a recently approved medication, enhances the lipid-lowering effects of the statins by lowering LDL and increasing HDL levels through its property of inhibiting absorption of cholesterol in the small intestine. These salutary effects of ezetimibe on statin levels presumably enhance the beneficial effects attributed to statin pleiotropy. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. No other therapeutic agent can claim equally stellar results in such a wide variety of diseases. The common denominator in all of the diseases that have been shown to improve with statin pleiotropy could be arteriolar pathology due to hyperlipidemia, which improves in response to statins by a return of arteriolar function to normal rather than through statin pleiotropy. Recent reports indicate that higher doses of statins reverse atheromatous changes in the coronary artery when the LDL cholesterol level is lowered to well below 2.59 mmol/L (100 mg/dL). These results lend additional support to the probability that similar pathological changes that may be present in the small arteries and arterioles also can respond to adequate statin therapy. Statin pleiotropy: fact or fiction?

Arteriosclerosis↗

PubMed2003

Screening for statin-related toxicity: the yield of transaminase and creatine kinase measurements in a primary care setting.

BACKGROUND: Recommendations for monitoring levels of transaminases (alanine aminotransferase and aspartate aminotransferase) and of creatine kinase (CK) in patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) vary and are not based on data from clinical practice. We performed a study to determine the yield of routine screening of aminotransferase and CK levels among patients taking statins. METHODS: We performed a retrospective review of a primary care practice's computerized medical record. A computerized search identified all patients with a statin on their medication list and gave their alanine aminotransferase, aspartate aminotransferase, and CK values for 1998. We reviewed the records of all patients for whom these values were significantly or moderately abnormal to determine the values' relationship to statin therapy and outcomes. RESULTS: During the year of the study, 1014 (85%) of the 1194 patients who had a statin on their medication list had at least 1 monitoring test performed. Of these 1014 patients, 10 (1.0%) had a significant elevation and 5 (0.5%) a moderate elevation of transaminase levels, but none of these abnormalities appeared to be related to statin use. Moreover, 6 (0.9%) patients had at least 1 significantly abnormal CK value but it did not appear to be attributable to a statin; and of the 14 (2.1%) patients who had a moderate CK elevation, it was potentially due to a statin in only 2. There were no documented adverse sequelae associated with these abnormal results. CONCLUSIONS: In this study of statin use in a primary care practice, routine monitoring revealed no cases of significantly or moderately abnormal transaminase values attributable to statins. No significantly abnormal and only 2 moderately abnormal CK values were potentially attributable to statin use. This study questions the usefulness of routine measurement of transaminase and CK levels in all patients taking statins.

Alanine Transaminase↗

PubMed2007

Statins induce differentiation and cell death in neurons and astroglia.

Statins are potent inhibitors of the hydroxy-methyl-glutaryl-coenzyme A reductase, the rate limiting enzyme for cholesterol biosynthesis. Experimental and clinical studies with statins suggest that they have beneficial effects on neurodegenerative disorders. Thus, it was of interest to characterize the direct effects of statins on CNS neurons and glial cells. We have treated defined cultures of neurons and astrocytes of newborn rats with two lipophilic statins, atorvastatin and simvastatin, and analyzed their effects on morphology and survival. Treatment of astrocytes with statins induced a time- and dose-dependent stellation, followed by apoptosis. Similarly, statins elicited programmed cell death of cerebellar granule neurons but with a higher sensitivity. Analysis of different signaling cascades revealed that statins fail to influence classical pathways such as Akt or MAP kinases, known to be activated in CNS cells. In addition, astrocyte stellation triggered by statins resembled dibutryl-cyclic AMP (db-cAMP) induced morphological differentiation. However, in contrast to db-cAMP, statins induced upregulation of low-density lipoprotein receptors, without affecting GFAP expression, indicating separate underlying mechanisms. Analysis of the cholesterol biosynthetic pathway revealed that lack of mevalonate and of its downstream metabolites, mainly geranylgeranyl-pyrophosphate (GGPP), is responsible for the statin-induced apoptosis of neurons and astrocytes. Moreover, astrocytic stellation triggered by statins was inhibited by mevalonate and GGPP. Interestingly, neuronal cell death was significantly reduced in astrocyte/neuron co-cultures treated with statins. We postulate that under these conditions signals provided by astrocytes, e.g., isoprenoids play a key role in neuronal survival.

Animals↗

PubMed2002

Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs.

Hypercholesterolemia is considered an important risk factor in coronary artery disease. Thus the possibility of controlling de novo synthesis of endogenous cholesterol, which is nearly two-thirds of total body cholesterol, represents an effective way of lowering plasma cholesterol levels. Statins, fungal secondary metabolites, selectively inhibit hydroxymethyl glutaryl-coenzyme A (HMG-CoA) reductase, the first enzyme in cholesterol biosynthesis. The mechanism involved in controlling plasma cholesterol levels is the reversible inhibition of HMG-CoA reductase by statins, related to the structural similarity of the acid form of the statins to HMG-CoA, the natural substrate of the enzymatic reaction. Currently there are five statins in clinical use. Lovastatin and pravastatin (mevastatin derived) are natural statins of fungal origin, while symvastatin is a semi-synthetic lovastatin derivative. Atorvastatin and fluvastatin are fully synthetic statins, derived from mevalonate and pyridine, respectively. In addition to the principal natural statins, several related compounds, monacolins and dihydromonacolins, isolated fungal intermediate metabolites, have also been characterized. All natural statins possess a common polyketide portion, a hydroxy-hexahydro naphthalene ring system, to which different side chains are linked. The biosynthetic pathway involved in statin production, starting from acetate units linked to each other in head-to-tail fashion to form polyketide chains, has been elucidated by both early biogenetic investigations and recent advances in gene studies. Natural statins can be obtained from different genera and species of filamentous fungi. Lovastatin is mainly produced by Aspergillus terreus strains, and mevastatin by Penicillium citrinum. Pravastatin can be obtained by the biotransformation of mevastatin by Streptomyces carbophilus and simvastatin by a semi-synthetic process, involving the chemical modification of the lovastatin side chain. The hypocholesterolemic effect of statins lies in the reduction of the very low-density lipoproteins (VLDL) and LDL involved in the translocation of cholesterol, and in the increase in the high-density lipoproteins (HDL), with a subsequent reduction of the LDL- to HDL-cholesterol ratio, the best predictor of atherogenic risk. The use of statins can lead to a reduction in coronary events related to hypercholesterolemia, but the relationship between benefit and risk, and any possible interaction with other drugs, must be taken into account.

Biotechnology↗

PubMed2004

Early effects of statins in patients with coronary artery disease and high C-reactive protein.

Statins improve survival in patients with coronary artery disease, especially those with elevated C-reactive protein (CRP). Although some randomized studies have shown a delay in statin-related survival advantage of up to 2 years, recent studies demonstrated early (<2 months) survival benefit in certain patient groups. We hypothesized that this early benefit relates to baseline CRP concentration. Patients (n = 2,924) with significant, angiographically defined coronary artery disease (>/=70% stenosis in >/=1 coronary artery) were followed for an average of 2.4 years after discharged on a statin prescription. CRP was divided into tertiles (<1.2, 1.2 to 1.7, >1.7 mg/dl), and Kaplan-Meier methods were used to determine timing of statin benefit in both the overall population and a propensity score-matched subgroup. Cox regressions (multivariable and propensity score approaches) were used to predict mortality. Statins were prescribed for 28.4% of patients. In the first CRP tertile, no early statin benefit was observed (adjusted hazard ratio 0.69, 95% confidence interval [CI] 0.30 to 1.6, p = 0.39), and survival curves separated after >2 years. However, in the second and the third tertiles, statin survival curves separated much earlier ( approximately 3 months and 1 week, respectively) and statins predicted improved survival (second tertile: hazard ratio 0.63, 95% CI 0.32 to 1.2, p = 0.17; third tertile: hazard ratio 0.35, 95% CI 0.18 to 0.67, p = 0.002). Propensity score analysis confirmed both statin benefit and early timing. Thus, statin use in patients with high CRP provides not only a larger but also a significantly earlier absolute survival benefit than statin use in patients with lower CRP. This provides further evidence of an anti-inflammatory effect of statins.

Aged↗

PubMed2006

Statin use and breast cancer: prospective results from the Women's Health Initiative.

BACKGROUND: Despite experimental observations suggesting that 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have antitumor activity, clinical studies have reached mixed conclusions about the relationship between statin use and breast cancer risk. METHODS: To investigate associations between potency, duration of use, and type of statin used and risk of invasive breast cancer, we examined data for 156,351 postmenopausal women who were enrolled in the Women's Health Initiative. Information was collected on breast cancer risk factors and on the use of statins and other lipid-lowering drugs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical tests were two-sided. RESULTS: Over an average follow-up of 6.7 years, 4383 invasive breast cancers were confirmed by medical record and pathology report review. Statins were used by 11,710 (7.5%) of the cohort. Breast cancer incidence was 4.09 per 1000 person-years (PY) among statin users and 4.28 per 1000 PY among nonusers. In multivariable models, the hazard ratio of breast cancer among users of any statin, compared with nonusers, was 0.91 (95% CI = 0.80 to 1.05, P = .20). There was no trend in risk by duration of statin use, with HR = 0.80 (95% CI = 0.63 to 1.03) for < 1 year of use, HR = 0.99 (95% CI = 0.80 to 1.23) for 1- < 3 years of use, and HR = 0.94 (95% CI = 0.75 to 1.18) for > or = 3 years of use. Hydrophobic statins (i.e., simvastatin, lovastatin, and fluvastatin) were used by 8106 women, and their use was associated with an 18% lower breast cancer incidence (HR = 0.82, 95% CI = 0.70 to 0.97, P = .02). Use of other statins (i.e., pravastatin and atorvastatin) or nonstatin lipid-lowering agents was not associated with breast cancer incidence. CONCLUSIONS: Overall statin use was not associated with invasive breast cancer incidence. Our finding that use of hydrophobic statins may be associated with lower breast cancer incidence suggests possible within-class differences that warrant further evaluation.

Aged↗

PubMed1999

Statin prescribing in Nottingham general practices: a cross-sectional study.

BACKGROUND: The aim of the study was to determine the effect of deprivation on variations in statin prescribing in Nottingham general practices. Deprivation is used as a measure of population cardiovascular morbidity and need for statin treatment. The setting was all 118 general practices in contract with Nottingham Health Authority. METHODS: A cross-sectional study was undertaken. Statin prescribing in general practice during 1996 was related to indices of practice deprivation based on enumeration district (ED) level data from the 1991 Census. The relationship between statin prescribing per 1000 patients aged 35-69 and practice deprivation (measured both as Townsend score and as Jarman UPA(8) score) with additional adjustment for practice characteristics (number of partners, training status, total list size, fundholding status) cardiovascular prescribing costs net of lipid prescribing and hospital activity (total and medical admissions and new general practitioner total and medical out-patient referrals) for each practice. RESULTS: The prescription of statins during 1996 varied between nil and 14.1 'statin-years' of prescribing per 1000 patients aged 35-69. There was a significant inverse relationship between the rate of statin prescribing and the level of deprivation of that practice (p < 0.0001). Deprivation, as measured by Townsend index, accounted for 13 per cent of the total variability in statin prescribing, which rose to 19 per cent after adjustment. The prescribing of other lipid lowering agents of the fibrate class was positively associated with statin prescribing (p=0.001) and this association persisted after adjusting for deprivation. None of the other practice characteristics were found to be significantly associated with rates of statin prescribing. CONCLUSIONS: General practices with high deprivation indices serve more deprived populations with a higher prevalence of cardiovascular disease, and may be assumed to have a greater need for statins. Despite this, practices with higher deprivation indices prescribed fewer statins to their patients than less deprived practices. It was not possible to identify whether the more deprived general practices had successfully identified at risk individuals but it is likely that special efforts are needed to increase the uptake of effective health care in their patients.

Adult↗

PubMed2002

Safety considerations for statins.

PURPOSE OF REVIEW: The hydroxymethyl glutaryl coenzyme A reductase inhibitors or statins offer important benefits for the large populations of individuals at high risk for coronary heart disease. These drugs have a good safety profile. Nevertheless, differences in physicochemical and pharmacokinetic properties between statins may translate into significant differences in long-term safety. This review focuses on long-term adverse effects related to statin use, namely hepatotoxicity and myopathy. Moreover, the most common drugs used in combination with statins in long-term therapies are analyzed in terms of possible drug/drug interactions affecting the safety of statins. RECENT FINDINGS: The withdrawal of cerivastatin from the global market in 2001, because of severe cases of rhabdomyolysis, highlighted concerns regarding the safety of the entire class. Afterwards, the role of statins and their interactions with other drugs in precipitating this condition have been carefully reviewed. In approximately 60% of the total number of cases, statin-related rhabdomyolysis was found to be related to drug/drug interactions. Recently, all cases of fatal rhabdomyolysis associated with statin use have been reported to the US Food and Drug Administration. This has shown that fatal rhabdomyolysis among statin users is a rare event, the reporting rates being much less than one death per million prescriptions in the case of all statins except cerivastatin. SUMMARY: The safety and tolerability of the available statins support their use as the first-line treatment of patients at high risk for coronary heart disease, since the clinical benefits greatly outweigh the small risk of myopathy. Nevertheless, clinicians should be aware of the adverse effects possibly related to statin therapy, particularly in patients at high risk for coronary heart disease and requiring long-term multiple-drug therapies.

Anticholesteremic Agents↗

PubMed2004

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia.

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.

Adolescent↗

PubMed2006

Statins and bone metabolism.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are potent inhibitors of cholesterol biosynthesis. Cholesterol-lowering therapy using statins significantly reduces the risk of coronary heart disease. However, extensive use of statins leads to increases of other undesirable as well as beneficial effects, so-called pleiotropic effects. With respect to these effects, statins augment the expression of bone morphogenetic protein-2, a potent simulator of osteoblast differentiation and its activity, and promote mineralization by cultured osteoblasts, indicating that statins have an anabolic effect on bone. Chronic administration of statins in ovariectomized (OVX) rats modestly increases bone mineral density (BMD) of cancellous bone but not of compact bone. In clinical studies, there are conflicting results regarding the clinical benefits of this therapy for the treatment of osteoporosis. Observational studies suggest an association between statin use and reduction in fracture risk. Clinical trials reported no effect of statin treatment on BMD in hip and spine, and on bone turnover. Statins also may influence oral osseous tissues. Administration of statins in combination with osteoporosis therapy appears to improve alveolar bone architecture in the mandibles of OVX rats with maxillary molar extraction. Statins continue to be considered as potential therapeutic agents for patients with osteoporosis and possibly with periodontal disease. Development of new statins that are more specific and potent for bone metabolism will greatly increase the usefulness of these drugs for the treatment of bone diseases.

Alveolar Process↗

PubMed2006

[Heterozygous family hypercholesterolemia: study of use of statins under clinical practice conditions].

OBJECTIVES: To compare the use profile of statins in patients with clinical diagnosis of heterozygous family hypercholesterolaemia (HFH) and the use profile of the general population treated with statins. DESIGN. Retrospective, observational study. SETTING: Galician Health Service, Spain. PARTICIPANTS: Patients under 65 years old treated with statins. MAIN MEASUREMENTS: In patients with HFH: number of patients, age, gender, statins used and defined daily dose per patient and day (DDD/patient/day). Variables in the rest of the population treated with statins: number of patients, statins used and DDD/patient/day. RESULTS: In a sample of 331 under-65 patients with HFH, 185 were men (55.86%) and 146 women (44.14%). Their average age was 44.56 years old (95% CI, 43.33-45.80), without statistically significant differences between men and women. Relevant differences in the daily mean consumption (DDD/patient/day) of statins between the studied sample and the rest of the under-65 population treated with statins were found (3.03 DDD/patient/day [95% CI, 2.70-3.36] vs 1.33 DDD/patient/day [95% CI, 1.16-1.40]; P< .001). These differences were caused by atorvastatin: 70% of HFH patients were being treated with atorvastatin (versus 37.6% of the rest of the population treated with statins). Differences in daily mean consumption of atorvastatin between HFH and the rest of the statin-treated population were also found (3.58 DDD/patient/day [95% CI, 3.15-4.02] vs 1.64 DDD/patient/day [95% CI, 1.37-1.90]; P< .001). CONCLUSIONS: The DDD/patient/day of statins in HFH patients is double that of the rest of the population treated with statins. The different pattern of use of atorvastatin in HFH is the main reason for these results.

Adolescent↗

PubMed2006

Statin use is associated with reduced mortality in COPD.

Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of ischaemic heart disease (IHD). Statins reduce mortality and morbidity in IHD. It has been hypothesised that statin treatment is associated with reduced long-term mortality in patients with COPD. Using a retrospective cohort design, 854 consecutive patients (mean age 70.8 yrs; 51.5% female) with a diagnosis of COPD exacerbation were included in the study at discharge from a Norwegian teaching hospital. Median follow-up was 1.9 yrs, during which 333 patients died. The crude mortality rate per 1,000 person-yrs was 110 in patients treated with statins, and 191 in patients not treated with statins. After adjustment for sex, age, smoking, pulmonary function and comorbidities, the hazard ratio (HR) for statin users versus statin nonusers was 0.57 (95% confidence interval 0.38-0.87). When subdividing statin users and statin nonusers into groups according to concomitant treatment with inhaled corticosteroids (ICS) the following HRs were found: 0.75 (0.58-0.98) for ICS only; 0.69 (0.36-1.3) for statins only; and 0.39 (0.22-0.67) for the combined treatment with statin and ICS compared with no such treatment. Treatment with statins was associated with improved survival after chronic obstructive pulmonary disease exacerbation, while inhaled corticosteroids appeared to increase the survival benefit associated with statin use.

Aged↗

PubMed2003

Modulation of the inflammatory process by statins.

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.

Animals↗

PubMed2006

Statins and myotoxicity: a therapeutic limitation.

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors represent the most successful class of drugs for the treatment of hypercholesterolaemia and dyslipidaemia implicated in the pathogenesis of coronary heart disease and atherosclerosis. However, the popular profile of statins in terms of efficacy has been maligned by its adverse events. The myotoxicity, ranging from mild myopathy to serious rhabdomyolysis, associated with HMG-CoA reductase inhibitors, during treatment of hypercholesterolaemia is of paramount importance. Rhabdomyolysis is a rare but idiosyncratic muscle wasting disorder of different etiologies. Statin-associated rhabdomyolysis causes skeletal muscle injury by self-perpetuating events leading to fatal irreversible renal damage through a series of biochemical reactions. Preferential distribution and action of statins in liver could be the key to minimise myotoxicity concerns. Hepato-specific distribution of statins is governed by various factors such as physicochemical properties, pharmacokinetic properties and selective transporter-mediated uptake in liver rather in extrahepatic cells. The interactions of statins with concomitant drugs of different classes merit attention for their safety profile. Although pharmacokinetic as well as pharmacodynamic interactions have been implicated in pathophysiology of statin-induced muscle wasting, the underlying mechanism is not clearly understood. Besides, pharmacokinetic and phramcodynamic factors, statin-associated myotoxcity may also implicate pharmacogenomic factors. The pharmacogenomics characterised by CYP polymorphism and other genetic factors is responsible for inter-individual variations to efficacy and tolerability of statins. The pathophysiological mechanisms may include statin-induced differences in cholesterol:phospholipid ratio, isoprenoid levels, small GTP binding proteins and apoptosis. However, the present understanding of pathophysiological mechanisms, does not offer a reliable approach to address the same at preclinical level. Although statin-associated myotoxicity affects compliance, quality of life of patient and discontinuation rate, yet the low incidence of myotoxicty including rhabdomyolysis and less severity of commonly occurring myopathy and myalgia do not raise doubts about the clinical efficacy and tolerability of statins. Medical management of myotoxicity seems to be pivotal for the proper compliance of patients with statin treatment. The appropriate and judicious use of drugs would substantially reduce the likelihood of developing clinically important myopathy.

Biological Availability↗

PubMed2002

Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same?

The 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase inhibitors or statins, specifically inhibit the enzyme HMG-CoA in the liver, thereby inhibiting the rate limiting step in cholesterol biosynthesis and so reducing plasma cholesterol levels. Numerous studies have consistently demonstrated that cholesterol lowering with statin therapy reduces morbidity and mortality from coronary heart disease, whilst recent evidence has demonstrated that benefits of statin therapy may also extend into stroke prevention. Since hypercholesterolaemia is a chronic condition, the long-term safety and tolerability of these agents is an important issue. Numerous large-scale clinical trials have consistently demonstrated a positive safety and tolerability profile for statins. Hepatic, renal and muscular systems are rarely affected during statin therapy, with adverse reactions involving skeletal muscle being the most common, ranging from mild myopathy to myositis and occasionally to rhabdomyolysis and death. Postmarketing data supports the positive safety and tolerability profile of statins, with an overall adverse event frequency of less than 0.5% and a myotoxicity event rate of less than 0.1%. The recent withdrawal of cerivastatin from the world market due to deaths from rhabdomyolysis has, however, focused attention on the risk of adverse events and in particular myotoxicity associated with statins. Indeed, initial clinical trial data supports postmarketing data, demonstrating a higher incidence of myotoxicity associated with cerivastatin, particularly when used in combination with fibrates. The potential mechanisms underlying statin-induced myotoxicity are complex with no clear consensus of opinion. Candidate mechanisms include intracellular depletion of essential metabolites and destabilisation of cell membranes, resulting in increased cytotoxicity. Cytochrome P450 3A4 is the main isoenzyme involved in statin metabolism. Reduced activity of this enzyme due to either reduced expression or inhibition by other drugs prescribed concomitantly such as cyclosporin or itraconazole may increase drug bioavailability and the risk of myotoxicity. Such factors may partly account for the interindividual variability in susceptibility to statin-induced myotoxicity, although other as of yet unclarified, genetic factors may also be involved. The risk of rhabdomyolysis is increased with combination fibrate-statin therapy, with initial evidence suggesting that gemfibrozil-statin combination may particularly increase the risk of myotoxicity, with pharmacodynamic as well as pharmacokinetic mechanisms being involved.

Humans↗

PubMed2003

Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review.

BACKGROUND: Statins reduce cardiovascular events to a greater extent than can be explained by their effect on lipids. Several studies have attempted to elucidate mechanisms by which statins reduce cardiovascular risk. PURPOSE: To summarize the effects of statins on nonlipid serum markers and to correlate statins' effect on serum markers with lipid levels and cardiovascular outcomes. DATA SOURCES: MEDLINE (1980 to 2003) search limited to English-language articles. STUDY SELECTION: Studies reporting original data in at least 10 participants on the effect of statins on outcomes of interest, excluding studies of cerivastatin, drug combinations, and patients with organ transplants. DATA EXTRACTION: Study design, sample size, treatment, and outcome data extracted on the basis of preestablished criteria. When appropriate, meta-analysis was performed by using a random-effects model. DATA SYNTHESIS: All statins are effective at lowering C-reactive protein levels, and the effect is not dose-dependent. Studies do not demonstrate a correlation between statins' effects on C-reactive protein levels and on lipids or cardiovascular outcomes. Statins do not affect fibrinogen levels, and limited data suggest little effect on lipid oxidation, tissue plasminogen activator, or plasminogen activator inhibitor. Platelet aggregation data are inconclusive. CONCLUSIONS: Among nonlipid serum markers examined, only C-reactive protein levels are statistically significantly affected by statins. These findings suggest that statin-mediated anti-inflammatory effects may contribute to the ability of statins to reduce risk for cardiovascular disease. Overall, however, available data are insufficient to support recommendations for using nonlipid serum markers in decisions regarding statin therapy for individual patients.

Biomarkers↗

PubMed2004

Association of statin therapy with outcomes of acute coronary syndromes: the GRACE study.

BACKGROUND: Statins administered early in patients with acute coronary syndromes may lead to modest reductions in recurrent ischemic events. OBJECTIVE: To examine the association between previous and early in-hospital statin therapy and the presentation and outcomes of an acute coronary syndrome. DESIGN: Cohort study. SETTING: 94 hospitals in 14 countries participating in the Global Registry of Acute Coronary Events (GRACE). PATIENTS: 19,537 patients with an acute coronary syndrome who were enrolled from April 1999 to September 2002. MEASUREMENTS: Statin use before and after presentation with an acute coronary syndrome and associated rates of myocardial infarction, hospital complications, and hospital mortality. The composite end point included death, in-hospital myocardial infarction, and stroke. RESULTS: Patients who were already taking statins when they presented to the hospital were less likely to have ST-segment elevation (odds ratio [OR], 0.79 [95% CI, 0.71 to 0.88]) or myocardial infarction (OR, 0.78 [CI, 0.70 to 0.86]). Patients who continued to take statins in the hospital were less likely to experience complications or die than patients who never received statins (OR, 0.66 [CI, 0.56 to 0.77]). Patients not previously taking statins who began statin therapy in the hospital were less likely to die than patients who never received statin therapy (OR, 0.38 [CI, 0.30 to 0.48]). However, adjustment for the hospital of admission attenuated the association between initiation of statin therapy and the composite end point (OR, 0.84 [CI, 0.65 to 1.10]). LIMITATIONS: This observational study cannot exclude confounding by clinical and hospital factors. CONCLUSIONS: These data support the hypothesis that statin therapy can modulate early pathophysiologic processes in patients with acute coronary syndromes. A randomized trial of statin therapy in acute myocardial infarction is warranted.

Age Factors↗