Statins in patients with chronic kidney disease: why,who and when?

Importance of the field: Patients with end-stage renal disease are at high risk of developing cardiovascular disease, which is characterized by early onset and rapid progression of atherosclerosis. Some analyses of large clinical trials have revealed that statins might reduce all-cause mortality and cardiovascular (CV) events in patients with chronic kidney disease (CKD). Preliminary studies have also suggested that they can reduce contrast-induced nephropathy (CIN) and the rate of loss of kidney function. However, the results concerning the efficacy and safety of statin therapy in patients with CKD, especially in those on renal replacement therapy, are still controversial.

Areas covered in this review: This review contains data on the atherosclerotic risk in patients with CKD; the role of statins in the reduction of CV risk in patients with CKD; the role of CIN; the effects of statins on retarding the progression of CKD; and the efficacy of statin therapy in CKD, dialysis and renal-transplant patients. We searched using the electronic databases [MEDLINE (1966 – June 2010), EMBASE and SCOPUS (1965 – June 2010), DARE (1966 – June 2010)]. Additionally, abstracts from national and international cardiovascular meetings were studied. Where necessary, the relevant authors of these studies were contacted to obtain further data. The main data search terms were: ‘statin/statins’, ‘dialysis’, ‘dyslipidemia’, ‘hemodialysis’, ‘kidney disease’, ‘microalbuminuria’, ‘clinical trials’, and ‘renal impairment’.

What the reader will gain: Readers will be acquainted with results of clinical trials, including the most recent ones (e.g., PLANETE I and II), and will be able to draw their own conclusions concerning the use of statins in CKD patients on the basis of the results of the studies presented and to compare them with the authors' suggestions presented in this review.

Take home message: Although the results of trials are conflicting, it is suggested that the benefits of statin use outweigh the drawbacks in patients with early-stage CKD, when the benefits can be effectively predicted. However, available large randomized clinical trials suggest a lack of efficacy in patients on renal replacement therapy.     

Statin drug interactions and related adverse reactions

Introduction: Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, their possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment.

Areas covered: This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions and related adverse reactions.

Expert opinion: Avoiding drug–drug interactions and consequent adverse drug reactions is essential in order to optimize compliance, and thus improve the treatment of patients at high cardiovascular risk. The different pharmacokinetic profiles among statins should be carefully considered, in order to understand the possible spectrum of drug interactions. The growing trend toward earlier statin treatment for the prevention of cardiovascular disease means that physicians must anticipate future polypharmacy when their patients require additional medications for comorbid conditions.     

Safety of fluvastatin in patients undergoing high-risk non-cardiac surgery

Importance of the field: In patients undergoing vascular surgery there is a high incidence of adverse cardiac events, due to sudden coronary plaque rupture. The non-lipid lowering or pleiotropic effects of statins can help reduce adverse cardiovascular events associated with vascular surgery.

Areas covered in this review: The evidence for perioperative use of fluvastatin, as well as other statins, in high-risk surgery patients is summarized in this review. Data on pharmacokinetics and metabolism is presented, together with considerations on possible drug interactions in the perioperative period.

What the reader will gain: The reader will gain a comprehensive understanding of the existing safety and efficacy data for fluvastatin and other statins in the perioperative period. The practical considerations of perioperative fluvastatin therapy will be presented, including potential side-effects and management of the early non-oral phase immediately post surgery. Finally, advice on when to initiate therapy and safety recommendations are offered.

Take home message: In patients scheduled for high-risk vascular surgery, fluvastatin improves postoperative outcome, reducing the incidence of myocardial damage by ～ 50% in the first 30 days following vascular surgery. In comparison with placebo, fluvastatin was not associated with a rise in liver enzymes or creatine kinase levels. To bridge the non-oral phase, an extended-release formula is recommended.     

Simvastatin interactions with other drugs

Introduction: Statins, the mainstay of lipid-lowering therapy, are among the most commonly used drugs due to their beneficial effects in cardiovascular morbidity and mortality. Simvastatin, one of the most well-studied statins, is available in several generic forms both as monotherapy and with ezetimibe and is frequently prescribed worldwide. Despite its overall favorable risk profile, several previously stated concerns regarding high-dose simvastatin were recently formalized by the Food and Drug Administration (FDA).

Areas covered: This paper discusses the interactions between simvastatin and other drugs and presents the latest FDA recommendations regarding the safe use of this statin. Relevant articles were identified through a PubMed search (up to December 2011). Furthermore, the latest FDA warning (June 2011) regarding simvastatin use was taken into account.

Expert opinion: Simvastatin may have serious side effects particularly when used in high doses and in combination with certain drugs. Physicians need to adjust the recent recommendations made by the FDA in clinical practice in order to prevent treatment complications.     

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.     

Statins and the potential for higher diabetes mellitus risk

ABSTRACT

Introduction: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for cardiovascular disease (CVD) prevention. Long-term use of statins has been linked to the development of diabetes mellitus (DM) which increases CVD risk.

Areas covered: We discussed the reported incidence of DM in statin users, various possible mechanisms responsible for the development of DM and the clinical implications of this association on CVD risk. Relevant supporting literature was identified using MEDLINE/EMBASE search.

Expert opinion: Data from available RCTs and observational studies suggest a 10–45% higher risk of new-onset DM with statin use compared to nonusers. Several cellular, molecular, and genetic mechanisms, and lifestyle changes have been studied and discussed as potential underlying mechanisms responsible for this elevated DM risk with statin therapy. The mode of the diabetogenic action of statins is still unclear and an interplay of pancreatic and peripheral effects in the pathogenesis of DM is a possibility. Despite these observations, the CVD preventative benefit of statin treatment outweighs the CVD risk associated with of development of new DM. There is a need for further research to identify the exact mechanisms involved so as to specifically target causative factors and individualize treatment.     

The controversy of a wider statin utilization: why?

Introduction: Several medical journals published viewpoints and counter-viewpoints supporting or opposing a wider utilization of statins for primary prevention. The objective of this article is not to weigh in the benefits versus risks of statin use, but to discuss various aspects of this controversy.

Areas covered: This review discusses the challenges in examining the pleotropic effects/adverse events of statins. It also discusses the pitfalls in assessment of adverse events in randomized controlled trials and observational studies.

Expert opinion: The challenges in solving this controversy include that the pleotropic effect of statins results in an extremely wide spectrum of reported benefits or adverse events, the reported harms/benefits are contradictory, there is basic research ground supporting both sides of the controversy, it is difficult to separate if adverse events are due to statins or due to lower cholesterol, and that there is a lack of standardized definition of statin-associated adverse events and their methods of ascertainment. Both randomized controlled trials and observational studies have pitfalls and caveats in assessment of adverse events. Understanding the points of debate is of paramount significance to enable clinicians to individualize patient care.     

Statins and muscle pain

ABSTRACT

Introduction: Statins remain among the most frequently prescribed drugs and constitute a cornerstone in the prevention of cardiovascular disease. However, muscle symptoms are often reported from patients on statins. Muscle symptoms are frequently reported as adverse events associated with statin therapy.

Areas covered: In the present narrative review, statin-associated muscle pain is discussed. It elucidates potential mechanisms and possible targets for management.

Expert opinion: In general, the evidence in support of muscle pain caused by statins is in some cases equivocal and not particularly strong. Reported symptoms are difficult to quantify. Rarely is it possible to establish a causal link between statins and muscle pain. In randomized controlled trials, statins are well tolerated, and muscle-pain related side-effects is similar to placebo. There are also nocebo effects of statins. Exchange of statin may be beneficial although all statins have been associated with muscle pain. In some patients reduction of dose is worth trying, especially in primary prevention Although the benefits of statins outweigh potential risks in the vast majority of cases, careful clinical judgment may be necessary in certain cases to manage potential side effects on an individual basis.     

CARDS on the table: should everybody with type 2 diabetes take a statin?

ABSTRACT

Background: Vascular complications are a major cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The recently published Collaborative Atorvastatin Diabetes Study (CARDS) showed that atorvastatin (10?mg, once daily vs. placebo) markedly reduces vascular events in this high-risk population. The participants (?n = 2838) were fairly typical T2DM patients without cardiovascular disease and with at least one other risk factor: hypertension, retinopathy, albuminuria or current smoking. In the treatment group, coronary events were reduced by 36% (?p = 0.001) and stroke by 48% (?p = 0.001). The trial was terminated two years early on ethical grounds. The number needed to treat (NNT) was 27 for four years to prevent one event. However, the benefit may have been greater since a proportion of the placebo group received statin therapy. The benefit from statin treatment was independent of sex, age, baseline lipid levels, systolic blood pressure, retinopathy, albuminuria, smoking or HbA_1c. The frequency of adverse events did not differ between the groups. These findings support those of other statin trials.

Scope: CARDS does not comment on renal function. However, other trials suggest that statins preserve renal function in those with and without DM. We discuss the CARDS study in this context in this brief overview paper.

Conclusions: the evidence shows that we need to control glucose to prevent microvascular complications, to lower cholesterol to prevent macrovascular disease and to lower blood pressure to prevent both. It may be that the benefit of statins extends beyond a threshold low-density lipoprotein cholesterol level in patients with T2DM. More trials are needed in this field.     

Safety review of combination drugs for hyperlipidemia

Introduction: Despite statin monotherapy, many high-risk patients are not at recommended low-density lipoprotein cholesterol goals. Moreover, these patients are also likely to exhibit an atherogenic dyslipidemia characterized by decreased high-density lipoprotein cholesterol and elevated triglycerides. As a consequence, combination lipid-altering drug therapies are frequently required to improve the lipid profile. The long-term safety and tolerability of these combination therapies are key determinants for good compliance and cardiovascular benefits.

Areas covered: This review summarizes the safety data published on combination drugs for the treatment of hyperlipidemia by examining the various combinations with a statin and also the other combination therapies used when statin treatment is not tolerated. The reader will gain insight into the incidence and severity of the major adverse events expected with combination therapies and the recommendations on the use of these combined treatments. A specific focus is made on muscle-related side effects.

Expert opinion: The existing data suggest that ezetimibe, bile acid sequestrants and ω-3 fatty acids appear unlikely to increase the risk of adverse events, particularly myopathy, when used in combination with a statin, even with a high-dose statin. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be safe, prescribing a combination of these drugs with high-dose statins needs caution and requires giving careful information to the patient.     

Pharmacogenomics and adverse drug reactions: the case of statins

Introduction: The use of genomics to predict adverse drug reactions (ADRs) has been the subject of much research over the last decade. Concerns about the muscular safety of statins, a highly prescribed group of drugs, are partially related to their high exposure. Many studies have identified a variety of genetic markers related to statin-induced myopathy. However, only polymorphisms in the SLCO1B1 gene (which encodes the carrier responsible for the hepatic uptake of statins, which, in turn, contributes to the regulation of plasma levels of SLCO1B1) were strongly associated with statin-induced muscular adverse effects. These was found to be most prominent for simvastatin. The strength of these findings relies on the use of modern genetic approaches, such as well-designed, case-controlled and genome-wide association studies. Nevertheless, the clinical use of this information is far from known at present and needs to be evaluated.

Areas covered: The links between genetic polymorphisms (i.e., SLCO1B1 gene) and statin-induced muscle ADRs and the methodological issues involved in the establishment of such an association are explored.

Expert opinion: Despite there being a statin–gene association for myopathy, in the case of some statins the usefulness of this information still needs to be proven.     

Impact of gender on statin efficacy

ABSTRACT

Objective: To determine the impact of statin therapy on the combined endpoint of cardiovascular events in women and men separately.

Research design and methods: A systematic literature search through May 2006 was conducted to identify randomized, controlled statin trials evaluating the gender specific incidence of cardiovascular events. Weighted averages were reported as relative risks (RRs) with 95% confidence intervals (CI) calculated via random-effects model.

Main outcome measures: The primary outcome measured was a composite endpoint of all cardiovascular events. Secondary outcomes measured included death, myocardial infarction (MI), and stroke.

Results: Fifteen trials were included in this meta-analysis. Cardiovascular events were reduced in men (RR 0.76 [95% CI 0.70, 0.81]) and women (RR 0.79 [95% CI 0.69, 0.90]). Reductions in mortality, MI, and stroke predominantly contributed to the reduction in cardiovascular events in men taking statins. Women did not have a reduction in mortality or stroke, suggesting that the reductions in cardiac events may have been predominantly due to reductions in need for revascularization and/or unstable angina.

Conclusions: Statins reduced the risk of cardiovascular events in men and women, but women on statins may not have reductions in mortality and stroke like their male counterparts.     

Drug safety evaluation of rosuvastatin

Introduction: Rosuvastatin is a highly efficacious statin approved for use throughout the world. Rosuvastatin has been exhaustively evaluated in the setting of a broad variety of dyslipidemias and cardiovascular disease states in clinical trials encompassed within the GALAXY program.

Areas covered: The efficacy and adverse event profile of rosuvastatin are evaluated based on the results of randomized, controlled clinical trials and observational studies available in the Medline database.

Expert opinion: Rosuvastatin is a safe and efficacious lipid modifying drug in a broad variety of patient populations (men and women, irrespective of race) for treating multiple forms of dyslipidemia. Rosuvastatin reduces atherogenic lipoproteins and triglycerides and increases high-density lipoprotein cholesterol better than other statins. Compared to other statins, it has no excess signal for liver, skeletal muscle or renal toxicity. This is supported by evidence from both an extensive clinical trial program as well as post-marketing surveillance. The incidence of myalgia with this drug is comparable to that observed with other statins. Rosuvastatin does not depend on cytochrome P450 3A4-dependent metabolism and has a favorable drug interaction profile. Care must be taken to reduce the dose of rosuvastatin in patients of Asian ancestry or with stage IV chronic kidney disease (severe renal insufficiency), as well as patients being treated with protease inhibitors or cyclosporine.     

Colesevelam hydrochloride in clinical practice: a new approach in the treatment of hypercholesterolaemia

ABSTRACT

Objective: Hypercholesterolaemia is a major risk factor for atherosclerosis and coronary heart disease. Treatment with lipid lowering agents reduces the risk of vascular events. Colesevelam is a novel bile acid sequestrant (BAS) indicated for the treatment of hypercholesterolaemia, either as monotherapy or in combination with statins.

Scope: This article reviews the efficacy, tolerability and safety of colesevelam in clinical practice. The literature search was based on a PubMed search up to January 2008.

Findings: Colesevelam, used alone or in combination with other hypolipidaemic agents (statins, ezetimibe and fenofibrate), has an overall favourable effect on lipid profile. Specifically, colesevelam reduces total and low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B levels and increases high-density lipoprotein cholesterol and apolipoprotein AI. However, colesevelam may slightly raise triglyceride levels. Colesevelam can improve glycaemic control in diabetic patients. Moreover, it may have anti-inflammatory properties, as it can reduce high sensitivity C-reactive protein concentration. Colesevelam almost lacks the intense side effects of previously used BASs, thus resulting in better patient compliance. However, the dose regimen consisting of up to 7 tablets/day and high cost may limit its use.

Conclusions: Colesevelam is a safe alternative for those intolerant to other lipid lowering medication. This BAS also provides an option for patients who do not reach their LDL-C goal despite treatment with a statin.     

Current role of statins in the treatment of essential hypertension

Importance of the field: Hypertension and hyperlipidemia often co-exist and seem to be interrelated through common pathophysiological pathways. Drugs employing beneficial effects in both conditions could be advantageous in a concerted effective management of patients at high cardiovascular risk. Statins are known to enhance cardiovascular protection beyond their lipid-lowering capacity.

Areas covered in this review: MEDLINE was searched, up to January 2010, for studies assessing the effect of statin treatment on blood pressure control in various populations or animal models of hypertension. The potential mechanisms implicated in the putative antihypertensive action of statins are also reviewed.

What the reader will gain: To learn about the role of statins as potential antihypertensive drugs in various populations. Clinical advice for the use of statins either as monotherapy or in combination with antihypertensive drugs in high-risk populations is also provided.

Take home message: Statins may exert a mild, but clinically relevant, antihypertensive effect which is probably mediated by mechanisms that are independent of their lipid-lowering effects. Patients with high BP levels at baseline as well as those treated with ACE inhibitors and calcium channel blockers are expected to benefit more in this regard.     

Effects of statins on all-cause mortality at different low-density-lipoprotein cholesterol levels in Asian patients with type 2 diabetes

Objective: To investigate the effects of statins on all-cause mortality risk at different low-density lipoprotein cholesterol (LDL-C) levels, and to compare the mortality risk between statin users and non-users with identical LDL-C levels in a type 2 diabetes cohort.

Methods: In total, 10,582 outpatients aged ≥18 years with type 2 diabetes mellitus (T2DM) between 2009 and 2012 were enrolled in this retrospective cohort study in central Taiwan. All-cause mortality events were followed up until the end of 2014. According to the medical records during the follow-up period, the patients were classified into statin (+) and statin (?) groups. Patients were categorized into different LDL-C segments based on their mean LDL-C levels during the 2.8-year follow-up.

Results: Non-cardiovascular mortality accounted for more than half the deaths. Overall, statin therapy significantly reduced the all-cause mortality risk in both univariable and multivariable models (hazard ratios?=?0.39 and 0.38, respectively). Sub-group analyses showed that the lowest mortality risk occurred in the 80–89?mg/dL segment in the statin (?) group and in the 90–99?mg/dL segment in the statin (+) group. Statin therapy significantly reduced the mortality risk at all LDL-C levels except for low LDL-C (<60?mg/dL).

Conclusions: In addition to reducing LDL-C levels, statin therapy reduced all-cause mortality risk in Taiwanese patients with T2DM. Statins further reduced the mortality risk at most LDL levels. However, at low LDL-C levels, the positive effects of statins may have been nullified.     

Statin use and cancer risk: a comprehensive review

Importance of the field: HMG-CoA inhibitors (statins), a class of drugs that reduce cholesterol, are used to manage and prevent coronary heart disease. They are among the most commonly prescribed drugs worldwide. Contrary to early concerns over the carcinogenicity of statins, a growing body of evidence suggests statins may in fact have a chemopreventive potential against cancer.

Areas covered in this review: In this paper, we review evidence on the association between statin use and cancer risk. Specifically, we report on clinical trials and observational studies that measured all cancer or site-specific cancers of the breast, colorectal, lung, prostate and reproductive organs associated with statin use.

What the reader will gain: An understanding of the evidence, including strengths and limitations, to support an association between statins and cancer. Information on the current state of the field and future directions are also discussed.

Take home message: Few strong or consistent associations between statins and cancer incidence overall or for any of the sites reviewed were detected. Data for any effects of statins on cancer prognosis and secondary prevention are lacking; with the exception of consistent evidence that statins are associated with reduced risk of advanced/aggressive prostate cancer. Statins appear safe in relation to cancer risk but any chemopreventive effect in humans remains to be established and should not be recommended outside the context of clinical trials. It is encouraging that numerous trials are ongoing. The prospect of reducing the incidence and burden of some of the most prevalent cancers with safe, affordable and tolerable medication that already reduces the risk of the leading cause of death and cardiovascular disease warrants further exploration in clinical trials and observational studies of prognosis and survival.