Expert opinion: the therapeutic challenges faced by statin intolerance

Introduction: Statin intolerance is largely defined by muscle related symptoms, leading to intolerability and cessation. The nocebo effect coupled with the challenges of diagnosing statin myopathy undermines drug adherence that is critical for achieving the benefits of lipid-lowering and cardiovascular risk reduction. A temporal relationship should be made between the initiation of therapy and development of symptoms to aid in diagnosis. The mainstay of treatment is statin cessation or statin dose reduction and evaluation of alternative causes for muscle related symptoms. Most symptoms usually resolve within 2 weeks of discontinuing therapy. The patient can be re-challenged with the same statin at a lower dose or an alternative statin. Non-statin lipid lowering therapies offer an alternative to patients who cannot tolerate statins.

Areas covered: We discuss current guideline-focused management of patients with statin intolerance.

Expert opinion: When initiating statin therapy, attention to risk factors for statin intolerance is strongly recommended. Most patients will tolerate some degree of statin therapy; thus statin re-challenge is advisable. If alternative dosing regimens are not tolerated, non-statin medications are acceptable alternatives. To limit errors in the diagnosis of statin intolerance, improvements in clinician-patient communication about the side effects and benefits of statins should be attempted.     

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.     

Muscle and statins: from toxicity to the nocebo effect

Introduction: Although statins have a satisfactory safety profile and are well tolerated, many statin-treated patients report muscle symptoms in clinical practice which contribute to drug discontinuation and, consequently, adverse cardiovascular outcomes.

Areas covered: This narrative review will cover the definition and prevalence of statin intolerance, the clinical spectrum of statin-associated muscle symptoms (SAMS) with special focus on patients with only mild myalgias, the complexity of statin muscle intolerance diagnosis and provide an overview on the nocebo effect of particular importance for physicians.

Expert opinion: Many patients are unable to tolerate statin therapy, with SAMS being the most common cause of statin intolerance. The reported incidence of SAMS was consistently lower in randomized placebo-controlled trials than in observational studies. These results strongly suggested that SAMS were not always due to by the pharmacologic effects of statin therapy. Convincing patients that their muscle symptoms might be due to causes other than statin treatment is sometimes difficult. Furthermore, clinicians should not prematurely discontinue statin therapy before considering other possible causes, including the nocebo effect.     

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.     

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.     

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.     

The potential role of statins in preeclampsia and dyslipidemia during gestation: a narrative review

Introduction: Statins have several pleiotropic effects that have the potential to be beneficial during pregnancy. This study evaluates the available evidence for the teratogenicity of statins, and their utility in treating preeclampsia and dyslipidemia in pregnancy, as good alternatives in these domains are currently lacking.

Areas covered: The possible teratogenicity of statins is a primary focus of this paper. We also evaluated for some possible non-teratogenic effects, such as changes in birth weight and rates of spontaneous abortion, among mothers exposed to statins during pregnancy. Regarding potential uses, this study mainly discusses statin utility in preventing and treating preeclampsia and treating dyslipidemia in pregnancy. Within the latter, we explore the relationship between dyslipidemia and preeclampsia, the potential consequences of delaying statin therapy where indicated, and the impact of supra-physiological levels of cholesterol in utero on offspring. The literature search was conducted using Embase, Web of Science, PubMed, and Scopus.

Expert opinion: Based on current evidence, statins are likely not teratogenic. Limited, but promising evidence exists for their efficacy in treating and preventing preeclampsia. In utero exposure to high cholesterol may negatively impact offspring, and should be thoroughly investigated.     

Statins as potential treatment for cholesterol gallstones: an attempt to understand the underlying mechanism of actions

Introduction: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decreases in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. Cholesterol gallstones are a common problem, resulting in hospital admission and surgery, throughout western healthcare systems.

Areas covered: This review describes the mechanisms, and addresses the potential, for statins to be used as a treatment for gallstones. Medline was searched for the risk factors and treatment of cholesterol gallstones.

Expert opinion: Obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), insulin resistance and high-fat diets (unsaturated fats) rich in cholesterol are all associated risk factors for cholesterol gallstones. In view of the high prevalence of cholesterol gallstones, there is an urgent need to understand whether pharmacological therapies can be harnessed for the treatment of cholesterol gallstones. Gallstones are shown to be associated with an increased risk, not only of mortality, but also of CVD. Statins, widely used in prevention of CVD and hypercholesteremia, have been shown to dissolve cholesterol gallstones in animal models and human studies, highlighting the potential for a pharmacological therapy for gallstones. More studies are required to understand the role of statins in the treatment of gallstones and for comparison with current treatment strategies.     

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.     

Cardiovascular disease in patients with renal disease: the role of statins

ABSTRACT

Objectives: Atherosclerosis is common in patients with chronic kidney disease (CKD), and cardiovascular disease (CVD) represents a major cause of death. The National Kidney Foundation guidelines favour the use of statin therapy for treatment of dyslipidaemia in patients with CKD. Much evidence supports statin therapy for reducing CVD and improving outcomes in the general population, but there is less evidence in patients with CKD. Consequently, prevention of CVD in CKD is based primarily on extrapolation from non-CKD trials. Significantly, in trials specifically designed to investigate patients with CKD, evidence is emerging for improved cardiovascular outcomes with statin therapy. This review describes available data relating to cardiovascular outcomes and the role of statins in patients with CKD, including pre-dialysis, dialysis, and renal transplant patients.

Research design and methods: The PubMed database was searched (1998–present) to ensure comprehensive identification of publications (including randomised clinical trials) relevant to CKD patients, patterns of cardiovascular outcome in such patients and their relationship to lipid profile, and the role of statins for the prevention and treatment of cardiovascular complications.

Results: There are conflicting data on the relationship between dyslipidaemia and cardiovascular outcomes, with one major study of statin therapy (4D – Deutsche Diabetes Dialyse Studie) providing equivocal results. Further studies, including AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events; NCT00240331) in patients receiving haemodialysis, and SHARP (Study of Heart And Renal Protection; NCT00125593) in patients with CKD including those on dialysis, should help to clarify the role of statin therapy in these populations.

Conclusions: More studies are needed to elucidate the role of statins in improving cardiovascular outcomes for CKD patients. It is anticipated that ongoing clinical trials geared towards the optimal prevention and treatment of CVD in patients with CKD will help guide clinicians in the management of CKD.     

Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins

1. Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events.

2. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug–drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use.

3. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.

     

Treatment of dyslipidemia in kidney transplantation

ABSTRACT

Introduction: Lipid disorders are frequent after kidney transplantation (KT) and KT recipients are considered at high- or very-high cardiovascular risk. Among many concurring factors, a major role is played by immunosuppressants.

Areas covered: General measures to manage lipid disorders first include physical activity and diet counseling. Modulating the doses of immunosuppressants also improves dyslipidemia. When lipid-lowering drugs are necessary to control elevated plasma cholesterol and/or triglycerides, statins are the cornerstone for managing hypercholesterolemia. However, side-effects (e.g. myopathy, new-onset diabetes, and kidney graft dysfunction) may occur. In these cases, ezetimibe (which does not affect kidney function) alone or on top of statins for the severe cases, is suggested by the most recent Guidelines. Proprotein convertase subtilisin/kexin type9 inhibitors are promising but expensive and their use in KT is still limited.

Expert opinion: In KT recipients, statins should be used cautiously. Rather than using high-dose statin in difficult patients, an association with ezetimibe is suggested. While fibrates, niacin, and resins do not play a relevant role due to their erratic efficacy and common side-effects, new lipid-lowering drugs are emerging but their safety and efficacy in KT patients still need to be assessed.     

Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance,metabolic syndrome and type 2 diabetes mellitus

Introduction: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy.

Areas covered: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin–fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial.

Expert opinion: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.     

LDL-C reductions and goal attainment among naive statin users in the Netherlands: real life results*

ABSTRACT

Objective: The effectiveness of statin therapy in a real life setting may differ from that in clinical trials, as physicians make non-randomised treatment decisions for patients with less uniform and possibly different characteristics. We therefore performed a study to compare the effectiveness of different statins and doses in routine clinical practice with respect to total serum cholesterol and LDL-cholesterol (LDL-C) reduction and goal attainment according to European guidelines on the prevention of cardiovascular disease (CVD).

Research design and methods: Naive statin users starting treatment in 2003 and 2004 with LDL-C measurements at baseline and between 30 and 365 days after start of treatment were extracted from the PHARMO database. During treatment with their initial statin dose LDL-C reduction and attainment of cholesterol goals were compared between different statins and doses.

Results: Of 2303 identified naive patients, approximately 30% were allocated to the high CVD-risk group. Average LDL-C reductions were 48%, 42%, 39%, and 32% at mean doses of 11 mg rosuvastatin, 17 mg atorvastatin, 22 mg simvastatin and 35 mg pravastatin, respectively. The proportion of patients attaining cholesterol goals was 75% for rosuvastatin, 68% for atorvastatin, 56% for simvastatin, and 42% for pravastatin. Dose comparisons showed greater LDL-C reduction and increased goal attainment for rosuvastatin 10 mg compared to other statins at most doses (adjusted p < 0.05).

Conclusions: In a real life setting, both LDL-C reduction and the proportion of patients attaining cholesterol goals appear to be significantly increased among users of rosuvastatin compared to other statins. These results confirm and extend reported clinical trial results to a real world setting.     

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

Introduction: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk.

Areas covered: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence.

Expert opinion: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.