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PubMed2001

Statins enhance arachidonic acid synthesis in hypercholesterolemic patients.

BACKGROUND AND AIM: It has been shown that statins enhance arachidonic acid biosynthesis from linoleic acid in vitro, and there is also evidence that statin-treated patients have high plasma and cellular arachidonic acid levels. The aim of this study was to investigate the possible effects of statins on the desaturating steps of arachidonic acid biosynthesis in patients. METHODS AND RESULTS: Plasma polyunsaturated fatty acids (percentages and concentrations), total cholesterol, LDL-cholesterol and triglycerides were measured in three groups of hypercholesterolemic patients before and after treatment with statins or fibrates for about three years, or before and after four months on a low-fat diet. As expected, there was a significant reduction in plasma total cholesterol (-23%) and LDL-cholesterol (-27%) levels in the statin group, and a significant reduction in triglycerides (-29%) and some decrease in total cholesterol (-12%) in the fibrate group; no change was observed in the control group. The selective increase in plasma arachidonic acid levels (in terms of absolute concentration and as a percentage of total fatty acids) was of the same order as the reduction in cholesterol, and the selective increase in the product/precursor ratios for delta 5 desaturation in the statin group indicated that this key step in arachidonic acid synthesis is affected. CONCLUSIONS: Our data show that an increase in arachidonic acid synthesis due to enhanced delta 5 desaturation is a major effect of statin treatment, and has the same order of magnitude as the reduction in plasma cholesterol levels.

Anticholesteremic Agents↗
PubMed2001

[Metabolic interactions with statins].

BACKGROUND: Isoenzymes of the cytochrome P450 (CYP) system play a prominent role in drug metabolism, including the HMG-CoA reductase inhibitors (statins). Alteration in metabolic activity is often the underlying mechanism of clinically relevant interactions, thus it is important to make a rational assessment of the risk for metabolic interactions with statins. MATERIAL AND METHODS: Articles covering the field of statin metabolism and related interactions were mainly searched for via PubMed. RESULT: More than 50% of the overall CYP metabolism is mediated through the isoenzyme CYP3A4, which is the main elimination route of simvastatin, lovastatin and atorvastatin. Interaction studies reveal that simvastatin and lovastatin have the highest potential for clinically relevant interactions related to this isoenzyme, most often leading to increased efficacy/toxicity of the statin. Interactions with agents that alter the activity of CYP3A4 can also be expected for atorvastatin. Other statins are to a lesser extent dependent on CYP3A4 in their elimination. Thus, pravastatin, cerivastatin and fluvastatin have a minor potential for interactions linked to this isoenzyme. Interactions associated with CYP2C9-interference may, however, be present for fluvastatin. INTERPRETATION: Since lipid-lowering therapy most often is life-long, the use of statins will frequently be accompanied by the use of multiple drugs, hence the importance of considering the risk for interactions when selecting statins.

Anti-Bacterial Agents↗
PubMed2001

[Role of statins in prevention of stroke and dementia].

There is accumulating evidence that statins reduce stroke risk, even though total cholesterol is not a risk factor for stroke. The explanation for this discrepancy is subject to discussion. It should be realised that the beneficial effects of statins on stroke risk have only been demonstrated in a select population, i.e. middle-aged men with ischaemic heart disease. Several clinical trials are underway to examine the effects of statins on stroke risk in more characteristic groups of patients who are at increased risk of developing stroke. The results of these studies should be awaited before statins are recommended for the prevention of stroke. Recently it has been reported that statins lower the risk of developing dementia. These conclusions were drawn from two cross-sectional studies. Because of the nature of the studies, only an association between the use of statins and a lower risk of developing dementia was shown, and not a causal relationship. Experimentally-controlled studies have to be designed to investigate the effect of statins on dementia.

Anticholesteremic Agents↗
PubMed2001

Managed care trends in statin usage.

PURPOSE: HMG-CoA reductase inhibitors ("statins") have become the drug class of choice for the treatment of hyperlipidemia. Six product brands encompassing 20 dosage strengths have been available during the past two years. The objective of this review is to describe dosing trends for the six statin brands and to determine if and how these trends vary among managed care plans as a function of product market share. METHODOLOGY: Utilization of HMG-CoA reductase inhibitors was examined using the NDC Health Information Services (Phoenix, Ariz.) database for the two-year period ending December 2000. This database contains unit dispensing data at the dosage-strength level for 1,079 managed care plans. Trends in market share, mean daily dose, and dosage distribution of the six current statin brands were examined. The relationship of market share to mean dose was also examined for each brand. PRINCIPAL FINDINGS: Market share decreased for all statin brands during the two-year period, except for the two newest entries, atorvastatin (up 9.7 share points) and cerivastatin (up 4.6 share points). The mean dose of all statins increased during the two-year period. A statistically significant negative correlation between market share and mean dose was found for atorvastatin and a positive correlation was found for fluvastatin (P < 0.01). Furthermore, atorvastatin share was significantly correlated to lower mean doses of all other statin brands. That is, higher use of atorvastatin was associated with lower doses of all statin products. CONCLUSION: In developing a cost-management strategy, managed care organizations should take historical and anticipated market-share changes and dose-mix changes into account along with the product's clinical efficacy and total cost of care.

Anticholesteremic Agents↗
PubMed2001

[Myotoxicity and rhabdomyolisis due to statins].

Rhabdomyolysis is a rare but potentially fatal complication associated with the use of cholesterol synthesis inhibitors (statins). The complication can develop in susceptible patients and with the concomitant use of medications that impede the biodegradation of statins, for example, biotransformation via the cytochrome P450 system. This may result in the plasma and tissue concentrations of statins, and their active metabolites, increasing to levels that are toxic for striated muscle. Myopathy is present when plasma activity levels of creatinine kinase are raised to in excess of 10 times the upper limit of the normal value. Muscular complaints which may be indicative of myotoxicity and subsequent myopathy are present in 1-7% of statin users. Albeit to varying degrees, all statins can induce myotoxicity especially at high dosages. Rhabdomyolysis was clearly more prevalent under cerivastatin users than the users of other statins and was therefore recently withdrawn from the market. Statins should be withdrawn immediately if myopathy is suspected. Prompt withdrawal may prevent rhabdomyolysis.

Creatine Kinase↗
PubMed2003

Rapid increase in statins newly dispensed to Ontario seniors between 1994 and 2000.

BACKGROUND: The Ontario government spent approximately 10% (CDN $148 million) of the provincial medication budget on statins in 1998. This number can be expected to grow in light of new guidelines from the United States recommending that three times as many patients should be receiving antihyperlipidemic therapy. There is scant population-based information on the age and sex distributions of patients receiving these medications. OBJECTIVES: To estimate the rates of new use of statin medications among community-dwelling elderly adults in Ontario between 1994 and 2000. METHODS: Data from the Ontario Drug Benefit program were used on all medications dispensed to noninstitutionalized Ontarians over 65 years of age to estimate age- and sex-specific annual rates of patients newly dispensed a statin. Changes in rates were estimated using Poisson regression. RESULTS: The number of elderly Ontarians newly dispensed a statin increased rapidly between 1994 and 2000, with age-standardized rates rising from approximately 840 to 2600/100,000 women and from 810 to about 3100/100,000 men. The highest rates of new use were observed among patients of both sexes aged 65 to 74 years. However, the rate of change increased with advancing age so that the biggest increase was observed among those aged 85 years and above, among whom there was an 8.5-fold increase among women and a 12-fold increase among men. CONCLUSIONS: Statins have been shown to be safe, efficacious and cost effective in reducing the risk of sudden cardiac death and other acute coronary events among middle-aged patients with pre-existing cardiovascular disease. The present study showed that there was a rapid increase in the rate of statins newly dispensed to elderly patients in Ontario, among whom estimates of safety, efficacy and cost effectiveness are not well quantified. Better estimates of these parameters in the elderly are required because of the high costs and benefits and potential unintended beneficial and harmful effects of statins.

Aged↗
PubMed2003

Role of statin pleiotropism in acute coronary syndromes and stroke.

Several landmark clinical trials have demonstrated the benefit of lipid-lowering with statins for the primary and secondary prevention of coronary heart disease. The clinical data in support of lowering cholesterol by statins are unequivocal. The established mechanism of action is via sterol regulatory element binding protein (SREBP) activation due to reduced hepatic cholesterol synthesis and secondary upregulation of the low-density lipoprotein (LDL)-receptor, leading to enhanced clearance of circulating cholesterol and lipids. Although it is widely accepted that most clinical benefit obtained with statins is a direct result of their lipid-lowering properties, there is still some debate as to whether the so-called 'pleiotropic effects' of statins contribute to the clinical outcome in vascular disease, or whether all the beneficial effects of statins are simply due to lipid-lowering. For example, these agents appear to display additional cholesterol-independent effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Thus, further studies are needed to understand the full impact of statin therapy on each of these processes and whether these effects contribute to the clinical benefits of statins in acute coronary syndromes and stroke.

Cholesterol↗
PubMed2003

[Prevention of coronary heart disease with statins. Which patients profit?].

Statins are generally considered as safe drugs with a very favorable cost-efficacy-ratio. Calculation of health expenses limits the prescription of statins in primary prevention to persons on high risk (i.e. 20% risk of a coronary infarction within the next 10 years). Prescription of statins in secondary prevention of atherosclerosis is mandatory. Advanced age, impairment of renal function or polypharmacotherapy increase the incidence of severe side-effects, especially myopathy and rhabdomyolysis. These patients should be given statins with lesser risk of these side-effects. Combination of statins with fibrates has attracted public concern, but may be indicated in persons with otherwise not treatable hyperlipidemia. These patients need intensive monitoring, just as patients on other drugs that are metabolized via the enzyme CYP3A4. Patients on statins should get dietary counseling, as an appropriate diet increases the effect of statins.

Anticholesteremic Agents↗
PubMed2003

Emerging non-statin LDL-lowering therapies for dyslipidemia and atherosclerosis.

Elevated low-density lipoprotein cholesterol is an important risk factor for atherothrombotic arterial disease. HMG-CoA reductase inhibitors, or statins, are very effective in lowering cholesterol levels, and several trials using statins have shown reductions in mortality and cardiovascular events, leading to the recent recommendations that all patients with known vascular disease, or who are at high risk for vascular disease, should be considered candidates for statin therapy. Yet statins reduce cardiovascular events by only about 20%-40%. Nonstatin therapies (either as monotherapy or in addition to statins) to reduce LDL cholesterol by mechanisms that do not involve inhibition of HMG-CoA reductase are likely to be useful for patients in need of LDL reduction; particularly those who either cannot take statins or respond only partially or not at all to statins alone. These therapies include cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, farnesoid X receptor antagonists, sterol-regulating binding protein cleavage activating protein, and microsomal triglyceride transfer protein.

Arteriosclerosis↗
PubMed2003

Early statin therapy in acute coronary syndromes.

Patients who survive an acute coronary syndrome are at much higher risk of a recurrent event within the following year than patients with stable coronary syndromes. Risk factor modification, including statin therapy, lowers the risk of recurrent events over many years, but also to reduces the high risk of an another event within the weeks to months following the initial acute coronary syndrome. The mechanisms that contribute to this benefit are likely related to improvements in endothelial function, a decrease in vascular inflammation, and reduced prothrombotic factors. The effects of statins may be mediated by cholesterol reduction, cholesterol-independent effects (particularly by decreasing isoprenoids), and mechanisms that are independent of inhibiting HMG CoA reductase. Observational studies show an early reduction in mortality with statin therapy started before discharge from hospital after an acute coronary syndrome. Several randomized controlled trials also support a rapid reduction in the risk of recurrent events after starting statins during the hospital admission for an acute coronary syndrome. Early statin therapy is also related to improved compliance and use of statins several years after a coronary event. Thus early statin therapy may improve both early and long-term secondary prevention efforts.

Acute Disease↗
PubMed2003

The cost-effectiveness of a new statin (rosuvastatin) in the UK NHS.

Statins are central to the government's National Service Framework (NSF) for coronary heart disease (CHD). NHS spending on statins is currently about pounds sterling 500 million per annum and rising at an annual rate of 30%. Although generally considered to be a cost-effective treatment for hyperlipidaemia and cardiovascular disease, given the high and rising expenditure on statins in the UK, there is a pressing need to ensure that the choice between available statins reflects cost-effectiveness considerations. A decision model was developed to establish the cost-effectiveness of treating new hypercholesterolaemic patients to UK and European target levels of blood total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C), using rosuvastatin, atorvastatin, simvastatin, pravastatin or fluvastatin. The model was used to estimate the proportion of patients reaching target and the associated costs over a one-year period from the perspective of the NHS. The effectiveness of the alternative statins were modelled using data from the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. Monte Carlo simulation was used to reflect uncertainty in the parameter estimates applied in the model. Rosuvastatin is demonstrated to dominate (i.e. lower costs and a higher number of patients treated to target) atorvastatin, simvastatin and pravastatin. Compared with fluvastatin, the incremental cost per additional patient to target (PTT) for rosuvastatin was pounds sterling 24 using LDL-C and pounds sterling 83 using TC. The probability that rosuvastatin is cost-effective exceeds 95%, provided the NHS is prepared to pay at least pounds sterling 35 per PTT to achieve target LDL-C cholesterol levels (pounds sterling 160 for TC). The analysis demonstrates rosuvastatin is more cost-effective than the other statins in achieving UK and European cholesterol targets.

Coronary Disease↗
PubMed2003

Do Singapore patients require lower doses of statins? The SGH Lipid Clinic experience.

A substantial number of physicians in Asian countries believe that Asian patients need lower doses of statins to achieve therapeutic lipid target because of the smaller size of patients. This belief is deep rooted and we looked at the SGH Lipid Clinic to determine if our experience bears out this belief. Between 1996 and August 2000, the Lipid Unit treated a total of 841 patients, of which 548 patients (77.5% Chinese, 12.1% Malays, 7.6% Asian Indians; 49.6% males, 50.4% females; 54.7% diabetics, 45.3% non-diabetic) were on statins alone. These patients had > or =2 coronary risk factors, diabetes mellitus or documented coronary heart disease. The pre-treatment lipid levels or the worst lipid levels available were entered as the baseline lipid values (mean LDL-C: 5.38+1.5 mmol/l). Duration of therapy ranged from six months to five years. The choice and titration of statins were determined by attending physicians. The median statin dose (Simvastatin equivalent) was 20.0 mg with 52.5% requiring 20 mg or more. Statin dose did not differ between diabetic and non-diabetic subjects. The median statin dose was 15 mg for the lower two tertiles and 20 mg for the upper tertile; this difference did not achieve statistical significance. The reduction in LDL cholesterol was 41.5% (40.1-42.8) and total cholesterol was 33.0% (32.9-34.1). Only 25% of our patients achieved LDL cholesterol of less than 2.6 mmol/l whilst 77.5% had LDL cholesterol less than 3.4 mmol/l. Our experience at the Lipid Clinic suggests that the Asian patients require similar statin doses to achieve target cholesterol levels.

Adult↗
PubMed2004

Rosuvastatin: new preparation. Opt for statins with evidence of efficacy on clinical outcome.

(1) Simvastatin and pravastatin are the two reference statins for type IIA and type IIB hypercholesterolaemia because they have the best-documented protective effect against cardiovascular events. Simvastatin and pravastatin are also the reference statins for familial heterozygous hypercholesterolaemia, though there is no evidence that they prevent cardiovascular events in this group. Statins are not very effective in familial homozygous hypercholesterolaemia. (2) Rosuvastatin is the sixth statin to arrive on the French market. The fifth, cerivastatin, was withdrawn from the market in 2001 because of serious adverse effects. (3) Rosuvastatin has not been assessed in terms of morbidity or mortality. The results of comparative trials in type IIA and type IIB hypercholesterolaemia suggest that rosuvastatin is slightly more active than simvastatin, pravastatin and atorvastatin on some lipid parameters after a few weeks of treatment. (4) Rosuvastatin has not been compared with simvastatin or pravastatin in familial heterozygous hypercholesterolaemia. One trial showed it to be slightly more effective than atorvastatin on cholesterol levels. According to one trial, rosuvastatin does not appear to be more effective than atorvastatin in homozygous forms. (5) In clinical trials the adverse effects of rosuvastatin were similar to those of other statins, with the exception of renal adverse effects. We don't know whether rosuvastatin is more or less likely than other statins to cause rhabdomyolysis. (6) Clinical trials reported some cases of proteinuria and renal failure suggesting there is a need for more thorough assessment in long-term trials. (7) In practice, statins with the best-documented benefits (simvastatin and pravastatin) should be used first for cardiovascular prevention in patients with hypercholesterolaemia.

Anticholesteremic Agents↗
PubMed2005

Evaluation of the male reproductive organs after treatment with continuous sustained delivery of statin for fracture healing.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for the treatment of hyperlipidemia, and recent in vitro and animal data suggest that statins promote bone formation and increase bone strength. We examined the relationship between sustained continuous delivery of statin and fracture healing rates in adult male animals with femoral segmental fractures. Because statin affects the production of cholesterol we also evaluated the influence of statin, on adrenal and testicular steroidogenesis and the morphology of the reproductive tract tissues in animals receiving statin for a period of 12 weeks post surgery. Simvastatin significantly increased fracture healing and without significant influence on the body weights and the weights of the reproductive organs. Basal plasma LH, FSH and testosterone levels were not affected by active treatment with simvastatin. Reproductive tissue morphology was unchanged by local sustained release of statin. In conclusion, long-term simvastatin treatment delivered at a fracture target site did not influence testicular reproductive and endocrine function, but was able to effectively heal complicated segmental fracture.

Animals↗
PubMed2005

[Influence of prolonged statin therapy on the arterial distensibility in stable ischemic heart disease].

BACKGROUND: Hypercholesterolemia and atherosclerosis are known to influence the mechanical properties of the arterial tree. Statins may alter the arterial distensibility because they decrease plasma cholesterol level and inhibit the progression of atherosclerosis. Pulse wave velocity (PWV) provides an indirect, non-invasive measurement of the mechanical properties of the arteries. AIM: The evaluation of the influence of statin therapy on arterial elasticity in patients with stable coronary artery disease. MATERIAL AND METHODS: The study group consisted of 46 patients with angiographically documented, clinically stable coronary heart disease and with high normal plasma cholesterol level. They were randomized into Group I--23 patients who received placebo and Group II--23 patients who received statin therapy. Before and following 6 months of treatment PWV was evaluated using a computer system--COMPLIOR. In each patient carotid-femoral PWV was measured. For automatic measurement of PWV pressure waveforms were digitized at rate 500Hz for carotid-femoral distance. RESULTS: After 6-month therapy with statin a significant decrease of PWV was observed. (from 12.28 +/- 2.81 m/s to 8.84 +/- 1.79 m/s, p < 0.01). This result may be explained by beneficial effect of statins on the degree of plaque growth. The alternative explanation may be the influence of statins on vascular remodelling. CONCLUSION: Statin therapy may improve arterial distensibility in patients with high normal plasma cholesterol and stable coronary artery disease.

Aged↗
PubMed2006

Effects of sustained release of statin by means of tricalcium phosphate lysine delivery system in defect and segmental femoral injuries on certain biochemical markers in vivo.

Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely used for the treatment of hyperlipidemia, and recent studies and animal data suggest that statins promote osteogenesis and increase bone strength. However, little is known about the effects of statins delivered by sustained delivery system to a target site of a defect and segmental bone fractures on certain biochemical markers including reproductive hormones. The purpose of this study was to develop a targeted statin delivery system using Tricalcium Phosphate Lysine (TCPL) for defect and segmental femoral injuries and evaluate the effects on alkaline phosphatase, total protein, malinodialdehyde, glutathione, total cholesterol, testosterone, luteinizing hormone, statins, and follicle-stimulating hormone. Because of the influence oral intake of statins might have on certain body organs, we also examine the histomorphology of the vital and reproductive organs of the animals receiving statins for a period of 30 days and 12 weeks post surgery. Simvastatin used in this study significantly increased fracture healing and without significant influence on the body weights and the weights and morphology of the vital and reproductive organs. There was a significant reduction in the cholesterol levels on the 3rd week in both phases of the study and at the conclusion of the study the difference in the cholesterol levels was no more significant in both phases. Other biochemical markers including plasma LH, FSH and testosterone levels were not affected by active treatment with simvastatin. In conclusion, short and long-term simvastatin treatment delivered at a fracture target site did not influence vital and reproductive organs, the systemic levels of the biochemical markers studied, but was able to effectively stimulate bone formation in simple and complicated segmental fractures.

Animals↗
PubMed2006

Update for primary healthcare providers: recent statin trials and revised National Cholesterol Education Program III guidelines.

Statins produce large, clinically important beneficial effects on total low-density lipoprotein (LDL) cholesterol and triglycerides while raising high-density lipoprotein (HDL) cholesterol--each of which increases the risks for cardiovascular disease (CVD). In randomized trials of secondary and primary prevention, and their meta-analyses, statins confer statistically significant, clinically important reductions in myocardial infarction, stroke, and CVD death. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III included LDL as the primary target, recommending optional goals of < 100 mg/dL for high-risk patients, < 130 mg/dL for moderate-risk patients, and < 160 mg/dL for low-risk patients. We conducted a search of randomized trials of statins whose results were published since May 15, 2001. We extracted overall trial results and data on adverse events, when available. We reviewed 7 published trials of statins, some of which contributed to the recent addendum to the NCEP ATP III guidelines that recommend reducing LDL goals to < 70 for very high-risk and < 100 for moderately high-risk patients via statins. Data from these trials demonstrate that greater LDL reductions produce larger CVD benefits in various categories of high- and moderate-risk patients, including a large number of primary prevention patients with metabolic syndrome who should be treated as aggressively as patients who have survived a myocardial infarction or stroke. Together, these recent statin trials and the NCEP ATP III revised guidelines, if implemented by primary healthcare providers, would result in many more patients receiving statins of proven benefit and reassuring adverse event profile.

Cardiovascular Diseases↗
PubMed2006

Statins, especially atorvastatin, may improve survival following brachytherapy for clinically localized prostate cancer.

This is the largest and longest clinical study to date to examine statin usage and overall patient survival following clinically localized prostate cancer. In a retrospective examination of 938 consecutive patients with early-stage prostate cancer treated with brachytherapy, 191 patients were documented to be taking statin medications. The patients taking statin medications had significantly lower prostate-specific antigen values, percent positive biopsies, and prostate volume than those patients not taking statin medications. Statin usage resulted in a nonstatistical improvement in all survival parameters with the results most pronounced for atorvastatin. Improving prostate cancer survival with statins could have important treatment implications and could potentially limit or even improve the role of supplemental therapies. A prospective trial of statin medications in conjunction with definitive local treatment for prostate cancer is recommended.

Aged↗