Role and significance of statins in the treatment of hypertensive patients

ABSTRACT

Background: Statins are the first-line drug therapy in the treatment of hypercholesterolemia. The beneficial clinical impact of statins on the cardiovascular system results not only from their lipid-lowering action but also from other effects. Recently, it has been suggested that statins can reduce blood pressure, especially in hypertensive patients.

Aim: The role of the hypotensive action of statins and other mechanisms which reduce cardiovascular risk in hypertensive patients are discussed in this review.

Methods: Electronic databases searched were [MEDLINE (1966 – February 2009), EMBASE and SCOPUS (1965 – February 2009), DARE (1966 -- February 2009)]. Additionally, abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. The main data search terms were: blood pressure, hypertension, hypercholesterolemia and statins.

Findings: At present, it is difficult to unequivocally assess the impact of statins on blood pressure. However, according to most authors, the impact of statins on the decrease in BP is slight, but significant, especially among patients with hypertension.     

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.     

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.     

Emerging anti-inflammatory drugs for atherosclerosis

Introduction: Cardiovascular disease is the most common cause of morbidity and mortality worldwide. Inflammation is responsible for initiation and progression of atherosclerosis, and leads to plaque vulnerability. Evidence-based therapies reduce the risk of initial and recurrent cardiovascular events but many patients experience recurrent events due to the failure of conventional therapies to adequately address inflammation.

Areas covered: Statins were originally developed for their LDL cholesterol-lowering effects, but are now thought to improve cardiovascular morbidity and mortality through anti-inflammatory effects as well. Drugs that inhibit the various inflammatory pathways responsible for atherosclerosis are the subject of current research. These include antioxidants, phospholipase A₂ inhibitors, leukotriene pathway inhibitors, CCL2-CCR2 pathway inhibitors, non-specific anti-inflammatory drugs (i.e., methotrexate), IL-1 inhibitors and p-selectin inhibitors.

Expert opinion: Currently, only three anti-inflammatory drugs (methotrexate, darapladib and canakinumab) are being investigated in Phase III clinical trials of atherosclerosis. The development of cardiovascular drugs requires long, expensive Phase III trials to demonstrate incremental improvement in cardiovascular events. Imaging end points and soluble biomarkers accelerate Phase II development, but further validation is needed before these can be used as surrogate end points in the large trials leading to drug approval. Improved access to currently available therapies like statins would decrease the burden of cardiovascular disease worldwide.     

Perspectives on low-density lipoprotein cholesterol goal achievement

ABSTRACT

Background: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of coronary heart disease (CHD). European and US guidelines now recommend lower LDL-C levels, particularly in high-risk patients. Although LDL-C treatment goals to reduce the risk of CHD are clear, many patients do not reach their LDL-C goals.

Objectives: Examine consensus guideline targets for LDL-C lowering in patients at high or very high cardiovascular risk; examine cholesterol goal achievement in clinical practice; evaluate the effectiveness of ezetimibe/statin and other adjunctive lipid-lowering treatments in achieving LDL-C goals; and consider ongoing controversies and the randomized controlled trials that may help to resolve or better illuminate them.

Methods: An English-language PubMed search was conducted to identify prospective randomized controlled trials, open-label studies, and retrospective and observational studies from 2001 (same year that the executive summary of the National Cholesterol Education Program's Adult Treatment Panel III was published) to present for an analysis of the effects of adjunctive therapies on LDL-C lowering and goal attainment in patients at elevated cardiovascular risk.

Results: Elevated LDL-C is the primary target of lipid-lowering therapy; aggressive lowering is of great benefit to those at high risk. Statins are recommended first-line lipid-lowering agents, with a long, well-regarded history of efficacy and safety. Not all patients, however, can achieve recommended LDL-C goals simply using starting doses of statins. For such patients, more intensive therapy utilizing high-dose statins or combination therapy, including statins combined with other lipid-lowering agents, such as ezetimibe, bile acid resins (BARs), or niacin, is warranted. Potential limitations of the present review include possible publication bias and the focus on pharmacotherapy rather than lifestyle modification and the important objective of multiple risk-factor modification to reduce absolute global cardiovascular risk.

Conclusions: With a well-established link between elevated LDL-C and cardiovascular risk, aggressive LDL-C lowering becomes particularly important. Patients needing intensive LDL-C lowering to achieve goals will often require adjunctive treatments, including ezetimibe, BARs, or niacin along with statins. Given both their high mg: mg potency in lowering LDL-C and favorable tolerability and patient acceptance/adherence profile, ezetimibe/statin combination regimens arguably provide the greatest likelihood for patients to reach new, lower LDL-C targets; however, efficacy and safety data of any adjunctive treatment, along with drug costs and patient adherence to treatment (partly related to complexity of the regimen) all need to be considered when determining the optimal regimen to achieve LDL-C goals in individual patients according to their baseline absolute cardiovascular risk, LDL-C level, and consensus LDL-C targets.     

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.     

Perioperative statin therapy

Introduction: The lipid lowering class of drugs known as “Statins” are being increasing recognized for their pleiotropic effects which include anti-inflammation, antioxidant, vasodilatation, improved endothelial function and stabilization of atherosclerotic plaques. These effects may counteract, to some extent, the deleterious impact of surgical stress on various organ systems during the perioperative period.

Areas covered: A literature review was undertaken to examine current evidence for the effect of perioperative statin use on postoperative morbidity and mortality. A search of PubMed, Medline and Scopus databases was performed using a combination of search terms including statins and perioperative risk reduction, outcomes, morbidity and mortality. Further searches were made on specific areas such as statins and thrombosis, kidney injury, renal protection, cancer, cost and safety.

Expert opinion: Current evidence supports a reduction in cardiovascular morbidity and mortality associated with perioperative statin use in high risk patients undergoing non cardiac surgery and this represents a very cost effective application of statin therapy with few adverse events reported. Data is emerging that point to other benefits such as renal protection but this requires further confirmation from prospective studies. Future research needs to address the questions of the optimal type, timing and dosage of statin therapy as well as whether there are problems associated with abrupt withdrawal and adverse effects associated with long term use.     

The clinical impact of pitavastatin: comparative studies with other statins on LDL-C and HDL-C

Introduction: Statins are currently the most effective drugs for lowering low-density lipoprotein cholesterol (LDL-C) and represent the first choice for treating hypercholesterolemia. Pitavastatin was launched as a new statin on the Japanese market in 2003, followed by Korea, Thailand, China, the United States and Europe. This review summarizes and evaluates new insights into pitavastatin, from clinical trials since 2010.

Areas covered: This article reviews studies that compare pitavastatin with various other statins: i) Randomized Head-to-Head Comparison of Pitavastatin, Atorvastatin, and Rosuvastatin for Safety and Efficacy (Quantity and Quality of LDL): the PATROL Trial; ii) various Phase III clinical trials in Western countries; iii) The Comparison of Preventive Effect on Cardiovascular Events With Different Statins (CIRCLE) study; and iv) The Livalo Effectiveness and Safety (LIVES) Study Extension. Pitavastatin was found to have a similar LDL-C-lowering effect to other strong statins but also had a strong HDL-C-elevating effect and did not worsen glucose metabolism.

Expert opinion: Pitavastatin has been launched in various countries around the world as a statin with potent LDL-C-lowering activity that is virtually unmetabolized by the cytochrome P450 family, with relatively few drug–drug interactions and no adverse effects on blood glucose. Pitavastatin thus appears well suited to long-term use.     

HMG-CoA Reductase inhibitors: an updated review of patents of novel compounds and formulations (2011-2015)

Introduction: Statins are remarkably safe and efficient medications that are the mainstay of hypercholesterolemia treatment and have proven to be an invaluable tool to lower the risk of acute cardiovascular events. These compounds are inhibitors of 3-hydroxy-methylglutaryl CoA reductase (HMG-R), the rate-limiting enzyme in cholesterol biosynthesis. In spite of their success, they present undesirable side effects and are now loosing patent protection, which provides a great opportunity for the development of new and improved statins.

Areas covered: This review summarizes the new patents for HMG-R inhibitors for the 2011–2015 period. Combinations of existing statins with other drugs are also addressed, as well as novel applications of existing statins.

Expert opinion: Recent efforts for the discovery of HMG-CoA-R inhibitors has resulted in several new molecules. Most of these are based on commercially available statins, including sterol and terpenoid derivatives. A few peptides have also been patented. However, the origin of the side effects caused by previous statins continues to be, to a large extent, unknown. Although the patents published in the past 5 years are promising, and might result in new drugs, there is still no way to know if they will present reduced toxicity. Only future clinical trials will answer this question.     

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.     

Emerging drugs for hyperlipidaemia: an update

Introduction: Hypercholesterolaemia is a significant risk factor for cardiovascular disease (CVD), a major cause of morbidity and mortality. Up to now, the appropriate management has been aggressive hypolipidaemic therapy, particularly with statins, aiming at certain low-density lipoprotein cholesterol (LDL-C) levels for each patient population. This strategy has reduced CVD-related morbidity and mortality. However, many cardiovascular events still occur, probably as a consequence of lipid disorders other than high LDL-C concentration or other risk factors. Because statins do not eliminate the residual CVD risk, there seems to be place for novel lipid modifying drugs with different mechanisms of action.

Areas covered: This review is an update since 2010 regarding lipid-modifying drugs in development and their potent role in clinical practice. It focuses on cholesterol ester transfer protein inhibitors, mainly anacetrapib and evacetrapib, microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides, pre-protein convertase subtilisin kexin-9 inhibitors and high-density lipoprotein mimetics.

Expert opinion: Several novel lipid-modifying drugs may be beneficial for certain patient populations. However, ongoing and future studies with clinical outcomes will clarify their actual role in clinical practice.     

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.     

Statins and their increased risk of inducing diabetes

Introduction: Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes (NOD) in randomized controlled trials and meta-analyses.

Areas covered: This review provides an update based on recent outstanding evidence on the statin effect on the risk of diabetes. It also describes mechanisms potentially explaining adverse effects of statins on glucose homeostasis. PubMed was searched for original articles and reviews published from January 2010 (inclusive) to May 2015 (inclusive), which include the Search terms statins, diabetes, glucose, and insulin. NOD risk seems to be more relevant with high-intensity rather than with low-intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes. It appears that statins adversely affect glucose homeostasis in parallel with their 3-hydroxy-3-methylglutaryl-coenzyme A inhibition capacity. It was suggested that lipophilic statins are more diabetogenic than the hydrophilic ones. Mechanisms explaining statin diabetogeneicity include impaired insulin secretion by pancreatic β cells together with increased insulin resistance of various tissues.

Expert opinion: The CV outcome benefits from statin use outweigh the diabetes menace. However, patients at risk for the development of diabetes should be prescribed statins with caution.     

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.     

Advancing therapy for hypercholesterolemia

Importance of the field: Hypercholesterolemia holds a key role in the development and progression of atherosclerosis and is a causative factor of coronary artery disease. Current guidelines for cholesterol treatment target low-density cholesterol (LDL-C) as the primary goal of therapy. Despite advances in the pharmacotherapy of atherosclerosis, the most successful agents used to treat this disease – HMG CoA reductase inhibitors – remain ineffective for the primary or secondary prevention of myocardial infarction in 50 – 60% of patients. Advancing therapy for hypercholesterolemia with new-emerging drugs either as monotherapy or in combination will hopefully improve cardiovascular outcomes.

Areas covered in this review: The two major sources of cholesterol in the human body are: i) biosynthesis of cholesterol by the liver; and ii) absorption by the intestines. Both play a pivotal role in the overall balance of cholesterol. A recent and more effective therapeutic strategy is to treat both sources of cholesterol simultaneously with a complementary mechanism of action. The present article presents cholesterol metabolism and reviews new emerging lipid-lowering drugs and therapies that: i) lower LDL-C; ii) lower triglycerides; and iii) increase high-density lipoprotein cholesterol.

What the reader will gain: This review summarizes the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of using new emerging lipid-lowering drugs either alone or co-administered with statins in controlling cholesterol levels.

Take-home message: An elevated concentration of LDL-C plays a causal role in the development of cardiovascular disease. The new aggressive cholesterol treatment goals call for a more advanced therapeutic approach to maximize the cardiovascular benefits associated with lower LDL-C levels.     

Fibrate therapy in the management of dyslipidemias,alone and in combination with statins: role of delayed-release fenofibric acid

Importance of the field: Optimization of lipid management is a crucial aspect in the treatment of cardiovascular disease. Currently, HMG-CO reductase inhibitors (statins) are a mainstay of therapy. While this class of drugs has proven efficacy at lowering low-density lipoprotein cholesterol (LDL-C), their effects on other important lipid parameters, such as high-density lipoprotein cholesterol (HDL-C) and triglycerides, are less robust.

Areas covered in this review: The current paper will address the significance of these secondary targets and review currently available therapies, including a new formulation of delayed-release fenofibric acid. A comprehensive MEDLINE search (1966 to September 2009) was performed.

What the reader will gain: The reader will gain a comprehensive review of the importance of secondary cholesterol targets, as well as the effectiveness of currently available therapies to address non-LDL-C. The role of the newly released fenofibric acid will also be addressed, as well as its potential use in combination therapy with a statin.

Take home message: Adequate treatment of lipid parameters beyond LDL-C is an essential component in the treatment of dyslipidemia. The fibrate class of drugs has proven efficacy in improving secondary targets; however, concerns regarding severe myopathy and rhabdomyolysis have limited their combination with statins. Recently, a new fibrate derivative, fenofibric acid, has become available. Studies to date reflect a positive safety and tolerability profile when combined with statins. This may offer a new tool to address the important secondary cholesterol targets that are becoming increasingly recognized as important contributors to cardiovascular outcomes.     

Ezetimibe plus simvastatin for the treatment of hypercholesterolemia

Introduction: Cardiovascular disease is a major cause of death, and hypercholesterolemia is a major risk factor. Statins, with simvastatin among the most widely used, have ample evidence demonstrating prevention of cardiovascular events and mortality. Ezetimibe is effective at improving serum lipids in combination with statins or alone, but its role has been controversial.

Areas covered: Here, we provide an overview of the pharmacokinetics and pharmacodynamics of each component of the combination, as well as pharmacogenetic contributors. Regarding clinical efficacy, our focus will be on the post-marketing clinical trials of ezetimibe–simvastatin combination therapy. We broach the controversy around the role of ezetimibe, particularly in light of the results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).

Expert opinion: Ezetimibe in combination with simvastatin or other statins provides an excellent means of incremental lipid-lowering effect, although the clinical benefit has been uncertain. IMPROVE-IT is the first to demonstrate incremental cardiovascular risk reduction with the addition of ezetimibe to simvastatin. What the literature lacks is evidence around the common use of ezetimibe as monotherapy or add-on therapy to lower doses of statins in patients who fail to achieve adequate lipid lowering or do not tolerate high-dose statins.     

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.