Pharmacogenomics of cholesterol-lowering therapy

The prevention of cardiovascular disease is critically dependent on lipid-lowering therapy, including 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), cholesterol absorption inhibitors, bile acid resins, fibrates, and nicotinic acid. Although these drugs are generally well tolerated, severe adverse effects can occur in a minority of patients. Furthermore, a subset of patients does not respond to cholesterol-lowering therapy with a reduction in coronary heart disease progression. Significant progress has been made in the identification of common DNA sequence variations in genes influencing the pharmacokinetics and pharmacodynamics of statins and in disease-modifying genes relevant for coronary heart disease (CHD). Among the most promising candidate genes for pharmacogenomic analysis of statin therapy are HMG-CoA reductase as a direct target gene and other genes modulating lipid and lipoprotein homeostasis. Based on data from pharmacogenetic trials, a combined analysis of multiple genetic variants in several genes is more likely to give significant results than single gene studies in small cohorts. In the future, pharmacogenomic testing may allow risk stratification of patients to avoid serious side effects and enable clinicians to select lipid-lowering drugs with the highest efficacy resulting in the best response to therapy.     

Statin Utilization Patterns for the Primary Prevention of Cardiovascular Events

BACKGROUND AND OBJECTIVE: In Hong Kong, about 10% of adults 25-74 years of age have diabetes mellitus. The management of dyslipidemia with lipid-lowering agents (LLAs), including HMG-CoA reductase inhibitors (statins) for the primary prevention of cardiovascular complications, has been found to be beneficial. This study examined statin utilization patterns for the primary prevention of cardiovascular events in patients with diabetes mellitus in two public hospitals in Kong Kong; clinical outcomes in patients who received statins for primary prevention were compared with those in patients not treated with any LLAs. METHODS: This was a retrospective study in patients who were diagnosed with diabetes mellitus. Only patients with no prior history of coronary artery disease were included in the study. Utilization patterns of LLAs and the incidences of cardiovascular complications were recorded from 1 January 2002 to 31 December 2003. RESULTS: A total of 222 patient records were reviewed. Only 75/222 (33.8%) of patients with diabetes mellitus received one or more LLAs for the primary prevention of cardiovascular events. Among these patients, only 21% of patients attained target lipid goals. Nearly half of the patients who were not treated with LLAs (n=147) had dyslipidemia problems. The overall incidence of cardiovascular complications in patients treated and not treated with LLAs was 12.2%. Absence of routine screening for cardiovascular risk and sub-optimal utilization and inadequate dosage titration of LLAs were identified as contributory factors towards cardiovascular events in this patient group. CONCLUSION: The current study failed to prove the benefits of LLAs in reducing the risk of first cardiovascular events in diabetic patients. This may have been due to the use of low doses of LLAs and a lack of laboratory monitoring of cholesterol levels. Development and implementation of guidelines may help promote the use of LLAs in primary prevention of cardiovascular complications.     

Statin therapy in the elderly: does it make good clinical and economic sense?

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.     

Managing hyperlipidemia: current and future roles of HMG-CoA reductase inhibitors.

The current and future roles of statins as antilipemic agents for the prevention and management of coronary artery disease (CAD) are reviewed. Therapy with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) substantially reduces total cholesterol and low-density-lipoprotein (LDL) cholesterol concentrations. Large clinical trials have documented the efficacy of statin therapy for both primary and secondary prevention of CAD. Nevertheless, many eligible patients are either untreated or inadequately treated with these agents. In one study, 61% of patients with documented CAD were not treated with a lipid-lowering agent. Large percentages of high-risk patients receiving such agents are not meeting cholesterol goals set by the National Cholesterol Education Program (NCEP). Populations at increased risk for coronary events include patients with diabetes, women, the elderly, and patients with established CAD. Comparative studies have not shown any one agent as clearly superior to the others. Future possibilities for statin use include early treatment of hypercholesterolemia and acute coronary syndromes consistent with guidelines established by NCEP. Many clinicians now believe that an aggressive approach to lowering LDL cholesterol may yield even greater reductions in coronary events. Treatment may reduce the risk of recurrent ischemic events when initiated within 96 hours of hospitalization for acute myocardial infarction or unstable angina and continued for up to four months. Another use may be the management of atherosclerotic cerebrovascular disease. Closer attention to potential adverse effects will be necessary before any expansion in statin use. Statins are highly effective for improving cardiovascular outcomes in high-risk patients but are frequently underused. Pharmacists can help extend the benefits of statins to more patients.     

Statin-associated peripheral neuropathy: review of the literature

Various pharmacologic agents are available for the treatment of hypercholesterolemia, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly referred to as statins, which offer favorable lipid-lowering effects and reductions in morbidity and mortality. Statins are usually better tolerated than other lipid-lowering agents and therefore have become a mainstay of treatment for hypercholesterolemia. However, recent case reports of peripheral neuropathy in patients treated with statins may have gone unnoticed by health care professionals. To evaluate the possible link between statins and peripheral neuropathy, literature searches using MEDLINE (January 1993--November 2003) and International Pharmaceutical Abstracts (January 1970--June 2002) were performed. Key search terms were statin, neuropathy, and HMG-CoA reductase inhibitors. Based on epidemiologic studies as well as case reports, a risk of peripheral neuropathy associated with statin use may exist; however, the risk appears to be minimal. On the other hand, the benefits of statins are firmly established. These findings should alert prescribers to a potential risk of peripheral neuropathy in patients receiving any of the statins; that is, statins should be considered the cause of peripheral neuropathy when other etiologies have been excluded.     

New drugs for the treatment of hypercholesterolaemia

Endogenous and exogenous pathways determine plasma levels of cholesterol and lipoproteins. Plasma cholesterol levels and coronary heart disease risk can be reduced pharmacologically by decreasing cholesterol synthesis, increasing its elimination and/or reducing its absorption from the intestine. The more profound knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin and pitavastatin), are being studied for their ability to improve lipid profiles. Rosuvastatin is a potent, hepato-selective and relatively hydrophilic statin with a low propensity for muscle toxicity and drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome p450-mediated drug interactions. Rosuvastatin seems to be more potent than other available statins while pitavastatin presents with a similar potency to that of atorvastatin. Another promising approach for lowering total and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity for inhibiting the intestinal cholesterol absorption is currently being investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both in monotherapy and in combination with other lipid-lowering drugs. Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal side effects, improving tolerability and patient compliance. Other lipid-lowering drugs with the ability to act at the enterocyte level, such as avasimibe and implitapide, are currently being investigated in humans.     

New drugs for the treatment of hypercholesterolaemia

Endogenous and exogenous pathways determine plasma levels of cholesterol and lipoproteins. Plasma cholesterol levels and coronary heart disease risk can be reduced pharmacologically by decreasing cholesterol synthesis, increasing its elimination and/or reducing its absorption from the intestine. The more profound knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin and pitavastatin), are being studied for their ability to improve lipid profiles. Rosuvastatin is a potent, hepato-selective and relatively hydrophilic statin with a low propensity for muscle toxicity and drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome P450-mediated drug interactions. Rosuvastatin seems to be more potent than other available statins while pitavastatin presents with a similar potency to that of atorvastatin. Another promising approach for lowering total and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity for inhibiting the intestinal cholesterol absorption is currently being investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both in monotherapy and in combination with other lipid-lowering drugs. Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal side effects, improving tolerability and patient compliance. Other lipid-lowering drugs with the ability to act at the enterocyte level, such as avasimibe and implitapide, are currently being investigated in humans.     

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.     

Who should receive HMG CoA reductase inhibitors?

During the last decade, the development of the HMG CoA reductase inhibitors, commonly referred to as 'statins', has contributed greatly to cholesterol lowering therapy and cardiovascular risk reduction. These agents are well tolerated and efficacious. Data on nearly 30,000 patients from five long-term randomised, placebo-controlled trials of statins have clearly demonstrated that a broad range of individuals can benefit from such therapy. These include men or women, younger or older individuals, those with elevated or normal cholesterol levels, with or without myocardial infarction or symptomatic coronary heart disease, with or without hypertension or diabetes mellitus, and those who are smokers or non-smokers. Benefits include reductions in the risks for myocardial infarction, and coronary, cardiovascular and all-cause mortality, stroke and the need for coronary revascularisation. Results of the recently completed Heart Protection Trial have clearly confirmed the results of the earlier trials and support the use of statin therapy in secondary prevention. The role of statins in acute coronary syndromes is being actively evaluated and appears promising. In primary prevention, the data are not as convincing and generalisations cannot be made as to whether, and in which subgroup, drug therapy to lower low density lipoprotein (LDL) cholesterol should be initiated. There are important cost implications to consider and the use of statin therapy has to be judged on an individual basis, particularly in those with high or very high LDL cholesterol levels and/or with multiple risk factors rendering them at high short- and long-term risk of coronary heart disease. There is evidence of a 'care gap' in translating trial data into practice, even in secondary prevention, and this needs closing in order to improve patient outcomes.     

Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins

Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.     

Role of Colesevelam in Combination Lipid-Lowering Therapy

Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug–drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.     

Ezetimibe: a selective cholesterol absorption inhibitor

Ezetimibe is the first agent of a novel class of selective cholesterol absorption inhibitors recently approved by the Food and Drug Administration for treatment in the United States. Ezetimibe inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids. Ezetimibe localizes at the brush border of the small intestine and decreases cholesterol uptake into the enterocytes. Preclinical studies demonstrated lipid-lowering properties of ezetimibe as monotherapy and showed a synergistic effect in combination with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). The efficacy and safety of ezetimibe 10 mg/day have been established in phase III clinical trials. In these trials, ezetimibe was investigated as monotherapy, as an add-on to ongoing statin therapy, and as combination therapy with statins in patients with primary hypercholesterolemia. In addition, ezetimibe has been evaluated in patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia. When given as monotherapy or in combination with statins or fenofibrate, ezetimibe reduces low-density lipoprotein cholesterol (LDL) by 15-20% while increasing high-density lipoprotein cholesterol by 2.5-5%. Unlike other intestinally acting lipid-lowering agents, ezetimibe does not adversely affect triglyceride levels and, due to its minimal systemic absorption, drug interactions are few. Ezetimibe's side-effect profile resembles that of placebo when given as monotherapy or in combination with statins. In clinical practice, ezetimibe has a role as monotherapy for patients who require modest LDL reductions or cannot tolerate other lipid-lowering agents. In combination therapy with a statin, ezetimibe is used in patients who cannot tolerate high statin doses or in those who need additional LDL reductions despite maximum statin doses.     

Have we forgotten the pivotal role of high-density lipoprotein cholesterol in atherosclerosis prevention?

The critical importance of high-density lipoprotein cholesterol (HDL-C) as an independent and predictive factor for coronary heart disease (CHD) has been increasingly recognised in treatment guidelines for prevention and treatment of cardiovascular disease. The association of low HDL-C with an increased incidence of CHD implies a critical role for raising HDL-C in protection against atherosclerotic disease. HDL-C appears to exert this effect via a number of mechanisms. HDL-C is involved in reverse cholesterol transport, prevents endothelial dysfunction and has anti-inflammatory, anti-oxidant and antithrombotic properties. Therapeutic interventions that increase HDL-C include statins, fibrates and nicotinic acid. Of these, nicotinic acid raises HDL-C more effectively than either statin or fibrate therapy and has been proven to reduce cardiovascular events in monotherapy studies. Preliminary clinical studies have shown that addition of nicotinic acid to primary statin therapy is safe, has proven beneficial effects on atherosclerosis and may also reduce the incidence of major coronary events. The available clinical evidence suggests that addition of nicotinic acid to primary lipid-lowering therapy has an important atheroprotective role in patients with or at risk of developing CHD.     

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.     

他汀类药物对糖尿病的非降脂作用及机制

他汀类药物是胆固醇合成的限速酶3羟基-3甲基戊二酰辅酶A的抑制剂。由于胆固醇堆积与动脉粥样硬化等心血管疾病紧密相关,而2型糖尿病患者也常伴有高胆固醇血症,因此他汀类药物被作为冠心病二级预防和改善糖尿病脂质紊乱的一线用药。近年的临床和基础研究证明,他汀类药物除了降脂作用外,还有改善胰岛素敏感性、胰岛β细胞功能和糖代谢,减轻糖尿病并发症和炎症的作用。也有不少相关不良反应的报道,但作用机制尚不明了。研究和探讨他汀类药物在糖尿病防治中的降脂外作用和机制,将有利于这类药物的合理应用。文中主要介绍他汀类药物对糖尿病的非降脂作用及可能机制。     

Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes

Recent large clinical trials have demonstrated that HMG-CoA reductase inhibitors, or statins, markedly reduce morbidity and mortality when used in the primary and secondary prevention of cardiovascular disease. It has been established that the benefits of statin therapy in cardiovascular disease can be explained not only by the lipid-lowering potential of statins but also by nonlipid-related mechanisms (so-called "pleiotropic effects") that contribute to the positive effect of statins on the incidence of cardiovascular events.The coagulation and fibrinolytic systems are two separate but reciprocally linked enzyme cascades that regulate the formation and breakdown of fibrin. Numerous studies have demonstrated that disturbances of coagulation and fibrinolysis contribute to the development and progression of atherosclerosis, and that they affect the incidence of atherosclerosis-related clinical events. High plasma levels or activities of fibrinogen, factor VII, factor VIII, von Willebrand factor (vWF), soluble thrombomodulin, tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are thought to be associated with increased morbidity and mortality related to cardiovascular disease.Experimental studies and many clinical studies have recently shown that statins produce favourable effects on haemostatic parameters, including those that are risk factors for cardiovascular disease. Statins diminish procoagulant activity, which is observed at different stages of the coagulation cascade, including tissue factor (TF) activity, conversion of prothrombin to thrombin and thrombin activity. In some studies, statins also reduced fibrinogen levels. By altering the levels and activities of tPA and PAI-1, statins seem to stimulate fibrinolysis. The data on the effects of combined treatment with statins and other drugs on haemostasis are rather limited. They suggest that statins combined with fibric acid derivatives, omega-3 fatty acids and 17beta-estradiol are superior to statins alone. The only two clinical studies performed in patients with acute coronary syndromes showed a relatively weak effect of statins on haemostasis in those patients. Although various statins may produce different effects on individual variables, there are no convincing data showing that differences in their physicochemical and pharmacokinetic properties significantly alter their net effect on excessive procoagulant activity. Apart from the lipid-lowering effect, statins suppress the synthesis of several important nonsterol isoprenoids derived from the mevalonate pathway, especially farnesyl and geranylgeranyl pyrophosphates, which via enhanced protein prenylation, are involved in the regulation of many cellular processes. It is presumed that the inhibitory effect of statins on the mevalonate pathway is involved in the regulation of some key steps of coagulation and fibrinolysis processes. In this way they probably regulate the synthesis of TF, tPA and PAI-1, and perhaps they also control the generation and activity of thrombin.The beneficial effects of statins on coagulation and fibrinolysis may be responsible for their ability to decrease the number of cardiovascular events. The lipid-independent effects of statins on haemostasis may contribute to the marked decrease in the incidence rates of mortality, hospitalisation and revascularisation in patients treated with these drugs.     

Is combination therapy an effective way of reaching lipid goals in type 2 diabetes mellitus?

Type 2 diabetes mellitus is associated with a specific pattern of plasma lipid and lipoprotein abnormalities. Lipid goals are often not attained with statins alone, and combination lipid-lowering strategies may need to be considered in an attempt to further reduce the residual cardiovascular risk. Combination therapy utilizes various classes of lipid-lowering medications with different mechanisms of action and different effects on lipid levels. Clinical trial data support the efficacy of combining statins with fibrates, niacin, ezetimibe (cholesterol absorption inhibitor) and colesevelam (bile acid sequestrant) with the caveat that there are insufficient clinical trial data to show a further robust benefit on cardiovascular outcomes. Of the different combination therapy options to potentiate low-density lipoprotein cholesterol lowering in combination with a statin, colesevelam provides additional beneficial effects by further reducing hemoglobin A1c levels in Type 2 diabetes mellitus.     

Rosuvastatin

The HMG-CoA reductase inhibitor (statin) rosuvastatin (Crestor) is widely available for use in the management of dyslipidemia, and was recently approved in the US to slow the progression of atherosclerosis as part of a strategy to lower low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) to target levels. Rosuvastatin has greater lipid-lowering efficacy than any of the other currently available statins, and significantly more patients receiving rosuvastatin than other statins achieve LDL-C goals. Rosuvastatin delayed the progression of carotid atherosclerosis in patients with subclinical carotid atherosclerosis, moderately elevated cholesterol levels, and a low risk of cardiovascular disease in a primary prevention trial (METEOR). The results of METEOR suggest a possible role for the earlier use of rosuvastatin in primary prevention, although more data are needed from trials examining the effects of the drug on cardiovascular endpoints. Significant regression of atherosclerosis was seen with rosuvastatin 40 mg/day in patients with established coronary heart disease (CHD) in the ASTEROID trial, supporting the use of intensive lipid lowering in secondary prevention patients (although it should be noted that it has not yet been established that atherosclerotic regression translates into improved cardiovascular outcomes). Rosuvastatin is generally well tolerated, with a similar tolerability profile to that of other currently available statins. Thus, rosuvastatin is an important lipid-lowering treatment option that has been shown to cause regression of atherosclerosis in secondary prevention patients, and has a potential future role in delaying atherosclerosis in primary prevention patients.     

Statins and coronary artery bypass graft surgery: preoperative and postoperative efficacy and safety

Background: In patients with native coronary artery disease, strong evidence supports the use of statins to reduce the risk of recurrent cardiovascular events and improve survival. However, for patients undergoing coronary artery bypass graft surgery (CABG), statins appear to be underutilized, and concerns have been raised regarding their perioperative safety. Objective: The goal of this systematic review is to evaluate the safety and efficacy of statin therapy before and after coronary surgical revascularization. Methods: A systematic review was performed to retrieve relevant articles from the Medline database published between 1987 and January 2009. Results: Administered before CABG, statins have been demonstrated to reduce perioperative mortality, stroke and atrial fibrillation. Preoperative statin therapy also reduces the systemic inflammatory response associated with cardiopulmonary bypass. Following CABG, statins inhibit saphenous vein graft disease and the progression of atherosclerosis in native coronary arteries. In addition, postoperative statins reduce the recurrence of cardiovascular events and improve all-cause mortality. High-intensity lipid reduction to achieve low-density lipoprotein levels to 70 mg/dl may benefit post-CABG patients, but this has yet to be evaluated prospectively. Adverse effects related to perioperative statin therapy seem to be extremely rare, and little data are available to support the practice of withholding statin therapy before or after surgery. Conclusion: Numerous studies have demonstrated that statins improve the outcomes of patients undergoing CABG. The benefits seem to outweigh the risks associated with their use, both in the preoperative and postoperative period. In the absence of contraindications, essentially all CABG patients are candidates for life-long statin therapy that ideally should be started before surgery. The optimal postoperative statin regimen remains unknown and should be the subject of future study.