Chronic kidney disease and statins: Improving cardiovascular outcomes

The burden of chronic kidney disease (CKD) continues to increase worldwide. Patients with CKD are at greater risk of mortality from cardiovascular events than end-stage renal disease. This review describes the pathogenesis of dyslipidemia in CKD patients and the role of statins in reducing coronary heart disease morbidity and mortality. The major clinical trials with statins in CKD patients are reviewed along with a discussion of statin safety. Although statin dosing and safety in patients with early CKD (Stage I or II) are similar to those of the general population, dose adjustments are required in advanced CKD (Stages III–V) due to differences in statin pharmacokinetics and renal excretion. Although the use of statins to reduce cardiovascular events in patients with mild to moderate CKD is strongly supported by existing clinical trials, no clinical benefit has been demonstrated in two large clinical trials involving hemodialysis patients.     

Statin Pharmacogenomics: Lipid Response and Cardiovascular Outcomes

Use of lipid-lowering agents, mainly statins, is a proven strategy to prevent cardiovascular disease events. Because most of the beneficial effect of statins is accounted for by the improved lipid profile, more than 40 genes have been studied to ascertain whether variation therein modulates lipid response or prevention of cardiovascular disease during statin therapy. In addition, recent studies have also shown that genetic variation may stratify pleiotropic statin effects. Although this review briefly covers the pharmacogenetic implications on biochemical markers such as low-density lipoprotein cholesterol, it mainly focuses on recent findings (after 2005) on cardiovascular disease outcomes during statin therapy. Pharmacogenomic analysis of large trials of statin treatment is becoming a predominant trend. Another future direction is genome-wide analysis, which will reveal additional candidate genes to be further tested in prospective trials. The results so far are preliminary, and successful replication of the findings is needed in large unrelated populations before the evidence for any polymorphism is solid enough for clinical applications.     

慢性肾脏疾病的最新调脂进展

血脂异常是慢性肾脏疾病的常见并发症,也是导致动脉粥样硬化性心血管疾病的独立危险因素.慢性肾脏病患者心血管疾病的发病率及病死率明显增加.尽管许多研究证实他汀降脂药物可以明显降低心血管疾病的发病率及死亡率,但是对于慢性肾脏疾病患者的调脂治疗能否降低心血管疾病的发病率及死亡率仍存在争议.现主要针对慢性肾脏疾病患者采取药物调脂治疗,降低心血管事件及保护肾脏的有效性及药物的安全性等问题的最新临床研究现状进行综述.     

Managing dyslipidemia in chronic kidney disease

The incidence of chronic kidney disease (CKD) in the U.S. continues to increase, and now over 10% of the U.S. population has some form of CKD. Although some patients with CKD will ultimately develop renal failure, most patients with CKD will die of cardiovascular disease before dialysis becomes necessary. Patients with CKD have major proatherogenic lipid abnormalities that are treatable with readily available therapies. The severe derangements seen in lipoprotein metabolism in patients with CKD typically results in high triglycerides and low high-density lipoprotein (HDL) cholesterol. Because of the prevalence of triglyceride disorders in patients with CKD, after treating patients to a low-density lipoprotein goal, non-HDL should be calculated and used as the secondary goal of treatment. A review of the evidence from subgroup analysis of several landmark lipid-lowering trials supports treating dyslipidemia in mild to moderate CKD patients with HMG-CoA reductase inhibitors. The evidence to support treating dyslipidemia in hemodialysis patients, however, has been mixed, with several outcome trials pending. Patients with CKD frequently have mixed dyslipidemia and often require treatment with multiple lipid-lowering drugs. Although statins are the cornerstone of therapy for most patients with CKD, differences in their pharmacokinetic properties give some statins a safety advantage in patients with advanced CKD. Although most other lipid-lowering agents can be used safely with statins in combination therapy in patients with CKD, the fibrates are renally metabolized and require both adjustments in dose and very careful monitoring due to the increased risk of rhabdomyolysis. After reviewing the safety and dose alterations required in managing dyslipidemia in patients with CKD, a practical treatment algorithm is proposed.     

Statins and Renal Disease: Friend or Foe?

The role of statins in the treatment and prevention of cardiovascular diseases, such as coronary artery disease, acute coronary syndromes, diabetes, or stroke, is well established. However, there are still some questions regarding the role of statins in patients with chronic kidney disease (CKD). Dyslipidemia is a known cardiovascular risk factor in individuals without CKD. In these patients, however, the relation of dyslipidemia to cardiovascular risk is complex, and the underlying pathobiological mechanisms are complex. Statins have proven to be highly effective in patients with initial stages of CKD; however, their effects in patients with advanced-stage CKD have been neutral despite a low-density lipoprotein cholesterol–lowering effect. In this review, we summarize the findings of the recent clinical trials of statins in renal disease and make recommendations for our patients.     

Statins in the management of dyslipidemia associated with chronic kidney disease

The cause of death in the majority of patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) is accelerated cardiovascular disease and not renal failure per se, suggesting a role for statin therapy in this setting. During the past 6 years three large, randomized, placebo-controlled studies of three different statins have been conducted in the dialysis population-but two of these studies did not demonstrate any benefits of statin therapy, and the third study showed only marginally positive results. To understand why statins have failed to reduce cardiovascular events in patients with ESRD, the basic mechanisms underlying the pathogenesis of dyslipidemia in CKD must be critically examined. The observed negative results in the clinical trials of statin therapy might also reflect the biomarkers and targets that were chosen to be evaluated. The characteristics of dyslipidemia in patients with CKD not yet requiring dialysis treatment differ markedly from those of individuals with established ESRD and form the basis for therapeutic recommendations. The potential adverse effects associated with statin therapy are important to consider in the management of dyslipidemia in patients with CKD.     

Statins and kidney disease

The prevalence of chronic kidney disease (CKD) is increasing worldwide. This clinical and social problem is mainly related to the ongoing epidemic of obesity and metabolic syndrome resulting in hypertension and diabetes mellitus. CKD is a well-recognized risk multiplier for the development of cardiovascular disease (CVD), and it is widely known that CVD is the leading cause of morbidity and mortality in patients with CKD. Lipid metabolism abnormalities are commonly associated with CKD. These consist of increased levels of low-density lipoproteins (LDL), triglycerides, very-low-density lipoproteins (VLDL) and lipoprotein(a), and reduced levels of HDL cholesterol. Lipid abnormalities contribute to cardiovascular morbidity and mortality in CKD patients. Some evidence also suggests that dyslipidemia may contribute to the progression of renal disease associated with type 1 and type 2 diabetic as well as non-diabetic renal disease. In the general population, HMG-CoA reductase inhibitors (statins) reduce the cardiovascular risk and prevent CVD. Similar data from secondary analyses of CKD subgroups of larger prospective trials using statins suggest a beneficial effect on cardiovascular outcomes and - albeit with more conflicting evidence - the progression of renal disease. Statins reduce blood levels of LDL cholesterol but also have multiple effects above and beyond cholesterol lowering, including direct effects on vascular tissue, kidney, bone, and glucose metabolism. The evidence linking dyslipidemia management with statins to cardiovascular disease and the decline in renal function in CKD patients will be presented in this review.     

Nonlipid-lowering effects of statins

Optional statement Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.     

Colesevelam: Potential Uses for the Newest Bile Resin

Colesevelam is the newest bile resin with a unique chemical structure. It binds to bile acids with higher affinity than traditional bile acid sequestrants and has fewer gastrointestinal side effects and drug interactions. Colesevelam is safe and efficacious alone or in combination with HMG‐CoA reductase inhibitors (statins) in reducing low‐density lipoprotein cholesterol (LDL‐C) levels. Despite this, the role of colesevelam in the treatment of hyperlipidemia remains limited, particularly in the face of new lipid lowering agents. As guidelines for cholesterol control become more stringent, the need to maximize therapeutic benefit through combination therapy will become increasingly more important. Colesevelam has a dose‐sparing effect on statin therapy, potentially decreasing the risk of unwanted side effects or drug‐drug interactions associated with statin use. This makes colesevelam a viable option for addition to a statin regimen when goal LDL‐C levels cannot be achieved with a statin alone. Additionally, anecdotal reports indicate that colesevelam may have potential benefits in certain patient populations that cannot tolerate other lipid lowering therapies, including organ transplant recipients, cholestatic liver disesase, and end‐stage renal disease. By recognizing the potential utility of colesevelam, clinicians can better manage those patients who are not able to tolerate first‐line therapies.     

Cholesterol-independent effects of statins and new therapeutic targets: ischemic stroke and dementia

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins", are used as cholesterol-lowering agents worldwide. Statins inhibit cholesterol biosynthesis, leading to enhanced uptake of low-density lipoprotein (LDL) from the circulation via LDL receptors. This strong cholesterol-lowering action contributes to the beneficial effects of statins. For example, large clinical trials have demonstrated that statins significantly reduce cardiovascular risk. Recent research has shown that statins have other multiple actions involved in endothelial function, cell proliferation, inflammatory response, immunological reactions, platelet function, and lipid oxidation. These "pleiotropic actions" of statins probably provide a significant contribution to the reduction of cardiovascular events. This review summarizes the pleiotropic actions of statins in both basic and clinical studies. It also considers the potential for statin therapy in the treatment of stroke and dementia.     

Women do benefit from lipid lowering: latest clinical trial data

Cardiovascular disease is the leading cause of morbidity and mortality among women in industrialized nations. Optimizing cardiovascular risk reduction is therefore of paramount importance, particularly among postmenopausal women, in whom the incidence of cardiovascular disease is highest. Accumulated data from a series of landmark trials unequivocally demonstrate the efficacy of statin therapy in the primary and secondary prevention of cardiovascular outcomes in both men and women. Moreover, the recently released Heart Protection Study provides substantive evidence that lowering low-density lipoprotein cholesterol below levels currently defined as optimal by National Cholesterol Educational Program guidelines is strongly associated with further cardiovascular risk reduction, and that this benefit accrues in all subgroups of patients, including women and the elderly. Despite the ability of hormone replacement therapy to improve serum lipid profiles, randomized trials of hormone therapy have demonstrated no benefit in reducing coronary outcomes among postmenopausal women. In contrast, data from over 8,000 women enrolled in the statin trials demonstrate that lipid lowering with statins is as effective at reducing cardiovascular outcomes in women as it is in men and suggest that statins should be considered standard of care for the prevention of adverse cardiovascular events in women at risk for coronary heart disease.     

Treating mixed hyperlipidemia and the atherogenic lipid phenotype for prevention of cardiovascular events

Statins reduce cardiovascular events and cardiovascular and total mortality in persons at risk for and with coronary disease, but there remains a significant residual event rate, particularly in those with the atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol. Large outcome trials designed to assess the value of combining statins with other agents to target HDL cholesterol and non-HDL cholesterol will not be completed for a few years, but there is ample evidence for the clinician to consider combination therapy. The choices for therapies to supplement statins include niacin, fibrates, and omega-3 fatty acids. We present the argument that after therapeutic lifestyle changes, the first priority should be the maximally tolerated effective dose of a potent statin. Evidence supports the addition of niacin as the second agent. In some situations, high-dose omega-3 fatty acid therapy could be the first agent added to statins. Although fibrate monotherapy alone or in combination with non-statin low-density lipoprotein cholesterol-lowering agents can be effective in mixed hyperlipidemia when statins are not tolerated, the combination of statin + fibrate should be considered second-line therapy until the efficacy and safety are established.     

Can we prolong life of patients with advanced chronic kidney disease: what is the clinical evidence?

The risk of death in patients with advanced chronic kidney disease (CKD) is markedly higher than in the population without CKD, even in patients suffering from advanced cardiovascular disease. Among several clinical features of CKD, the following are considered the most important areas of therapeutic intervention: hypertension, lipid abnormalities, mineral and bone disorders of CKD (previously known as renal osteodystrophy), renal anemia, and uremic toxicity. However, numerous treatment strategies, which are applied based on the understanding of underlying pathologies, did not result in significantly improved prognosis. These strategies include lowering of blood pressure, use of statins, control of hyperphosphatemia and hyperparathyroidism, erythropoesis-stimulating agents, use of better and more biocompatible dialysis membranes, and higher dialysis dose. In this critical review, we discuss the most important, large clinical trials, in which the above therapies failed to show desirable results and to reduce mortality in patients with advanced CKD.     

Genetic polymorphisms in emerging cardiovascular risk factors and response to statin therapy

Current strategies for both the primary and secondary prevention of coronary heart disease (CHD) focus on the traditional risk factors, such as hypertension, smoking cessation, and cholesterol, as the primary determinants of the cardiac risk profile, with particular emphasis on the reduction of low-density lipoprotein cholesterol (LDL-C) to targeted goal levels as endorsed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII). Large primary and secondary prevention trials with the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated varying reductions in cardiovascular events associated with similar changes in LDL-C levels, suggesting statins may possess additional beneficial effects on other risk factors.Retrospective analyses of many statin trials have evaluated the association between several polymorphic candidate genes (apolipoprotein E, stromelysin-1, -fibrinogen, cholesteryl ester transfer protein, lipoprotein lipase, hepatic lipase, and platelet glycoprotein III) which have been identified as predictors of disease severity and both metabolic and clinical response to statin therapy. These results suggest that statin therapy improves plasma lipid profiles in all patients, but preferentially benefits individuals who carry a high risk, variant genotype for these risk factors as compared to individuals with the wild-type genotype. These observations suggest that determining individual patient genotype may be useful in optimizing the benefits of statin therapy. These hypothesis-generating data need to be prospectively evaluated in genotyped patients.     

A triumvirate of targets in the prevention and treatment paradigm for cardiovascular disease

Statins have revolutionized the management of cardiovascular disease (CVD). Reductions in low-density lipoprotein cholesterol (LDL-C) with statin therapy have been shown to reduce significantly the risk of CVD in primary and secondary prevention trials. Recent evidence from clinical trials supports the concept that lower LDL-C levels, below current guideline targets, provide additional protection against cardiovascular (CV) events. In addition evidence is accumulating that increasing high-density lipoprotein cholesterol (HDL-C) and decreasing the level of chronic inflammation are important targets in CVD risk reduction. Recent studies have investigated the effectiveness of statins in terms of their ability to concomitantly reduce LDL-C, increase HDL-C and lower C-reactive protein (CRP). Results demonstrate that the more effective statins have beneficial effects on this triumvirate of potential treatment targets. Furthermore, the overall safety and tolerability profile is comparable among available statins. This paper examines recent data highlighting the role that statins and other lipid-lowering agents can play in this new treatment paradigm.     

JUPITER and satellites: Clinical implications of the JUPITER study and its secondary analyses

The justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin(JUPITER) study was a real breakthrough in primary cardiovascular disease prevention with statins,since it was conducted in apparently healthy individuals with normal levels of low-density lipoprotein cholesterol(LDL-C <130 mg/dL)and increased inflammatory state,reflected by a high concentration of high-sensitivity C-reactive protein(hs-CRP≥2 mg/L).These individuals would not have qualified for statin treatment according to current treatment guidelines.In JUPITER,rosuvastatin was associated with significant reductions in cardiovascular outcomes as well as in overall mortality compared with placebo.In this paper the most important secondary analyses of the JUPITER trial are discussed,by focusing on their novel findings regarding the role of statins in primary prevention.Also,the characteristics of otherwise healthy normocholesterolemic subjects who are anticipated to benefit more from statin treatment in the clinical setting are discussed.Subjects at"intermediate"or"high"10-year risk according to the Framingham score,those who exhibit low post-treatment levels of both LDL-C(< 70 mg/dL)and hs-CRP(<1 mg/L),who are 70 years of age or older,as well as those with moderate chronic kidney disease(estimated glomerular filtration rate <60 mL/min every 1.73 m2)are anticipated to benefit more from statin treatment.Unlikely other statin primary prevention trials,JUPITER added to our knowledge that statins may be effective drugs in the primary prevention of cardiovascular disease in normocholesterolemic individuals at moderate-to-high risk.Also,statin treatment may reduce the risk of venous thromboembolism and preserve renal function.An increase in physician-reported diabetes represents a major safety concern associated with the use of the most potent statins.     

Does it matter whether or not a lipid-lowering agent inhibits Rho kinase?

Lipid-lowering agents, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, also known as statins, have been shown to reduce cardiovascular events. However, evidence from recent clinical trials suggests that some of the beneficial effects of statins may be unrelated to changes in low-density lipoprotein cholesterol. In animal studies, many of the cholesterol-independent or “pleiotropic” effects of statins are mediated by inhibition of Rho kinase (ROCK). Indeed, ROCK has been implicated in the regulation of vascular tone, proliferation, inflammation, and oxidative stress. To what extent ROCK activity is inhibited in patients on lipid-lowering therapy, and in particular on statins, is not known, but it may have important clinical and therapeutic implications. This review attempts to make the case that, in addition to lipid lowering, inhibition of ROCK contributes to some of the benefits of statin therapy in patients with cardiovascular disease.     

Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio?

Statins effectively lower low-density lipoprotein cholesterol levels and the risk of cardiovascular disease (CVD) events, and because of this they have become a standard treatment for dyslipidemia and atheroprevention. Unfortunately, statin monotherapy may fail to normalize high triglycerides and low high-density lipoprotein cholesterol, and it prevents only a minority of CVD events. Further treatment of lipid disorders that remain after statin monotherapy should help reduce the residual CVD risk. Fibrate monotherapy lowers high triglyceride levels, raises low high-density lipoprotein cholesterol, and reduces CVD risk; therefore, fibrates are recommended as an adjunct to statins for treatment of residual dyslipidemia and residual CVD risk. This review provides an update on the benefits and risks of fibrate monotherapy and addresses the benefits and risks of adding fibrates to statins.     

Regional evidence and international recommendations to guide lipid management in Asian patients with type 2 diabetes with special reference to renal dysfunction

The anticipated increase in the prevalence and incidence of type 2 diabetes in Asia, and its associated cardiovascular–renal complications, will place a significant burden on patients, caregivers, and society. Despite the proven effectiveness of lipid management in reducing these complications, there are major treatment gaps, especially in Asian patients with young‐onset diabetes and chronic kidney disease (CKD). Recent international guidelines recommended the adoption of absolute risk estimation of atherosclerosis and cardiovascular disease to guide treatment intensity. These recommendations replaced the previous strategy of using low‐density lipoprotein cholesterol targets to guide initiation and intensification of lipid lowering, albeit still widely practiced in Asia. The latest guidelines also highlight the high risk of atherosclerosis and cardiovascular disease (ASCVD) for people with diabetes, who should be protected with statins, except for young patients without other risk factors, who will need yearly monitoring of blood lipid levels. Given the propensity of Asian patients with diabetes to develop CKD and the amplifying effect of CKD on ASCVD, the use of statins in Asian patients is particularly important. Due to interethnic differences in drug metabolism, rosuvastatin, which is largely cleared by the kidney, should be prescribed in low dosages (5–10 mg daily) in Asian populations. Conversely, epidemiological and experimental data confirm pleotropic and organ‐protective effects of atorvastatin, with proven safety in Asian populations within a daily dose range of 10–40 mg. Thus, there is a need for Asian countries to review and align their lipid‐lowering treatment guidelines to reduce the substantial burden of diabetes in the Asian region.     

What is the evidence in favor of low-dose statin therapy in 2008?

Coronary heart disease (CHD) remains a major cause of death in the United States, and despite continued improvements in cardiovascular care, CHD rates remain unacceptably high. Modification of cardiovascular risk factors is the major strategy for reducing coronary disease and clinical events. Lipid modification therapy has played an important role in cardiovascular risk reduction, and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are among the most important cardioprotective medications. Early clinical trials of statin therapy utilized low or modest doses of statins. More recent trials, however, have compared low-dose with high-dose statin therapy in individuals with CHD and found high-dose statin therapy to confer more benefits. Is there, then, still a role for low-dose statin therapy? This article summarizes statin clinical trials and focuses on the potential role for low-dose statin therapy in cardiovascular risk reduction.