Aleglitazar,a balanced PPARα/γ agonist,has no clinically relevant pharmacokinetic interaction with high-dose atorvastatin or rosuvastatin

Background: Aleglitazar, a dual PPAR-α/γ agonist, combines the lipid benefits of fibrates and the insulin-sensitizing benefits of thiazolidinediones.

Objective: To investigate the pharmacokinetic effects of co-administration of atorvastatin or rosuvastatin with aleglitazar.

Research design and methods: In a two-cohort, open-label, randomised, three-period crossover study, 44 healthy subjects received once-daily oral doses of aleglitazar 300 μg, statin (atorvastatin 80 mg or rosuvastatin 40 mg) and aleglitazar co-administered with each statin for 7 days. Plasma concentrations of each drug were measured and pharmacokinetic parameters determined on day 7 in each period.

Main outcome measures: Peak observed plasma concentration (C_max) and total exposures (AUC_{0 – 24}) of aleglitazar, atorvastatin and rosuvastatin.

Results: C_max and AUC_{0 – 24} to aleglitazar were similar, whether administered alone or in combination with a statin. Total exposure to either statin was unaffected by co-administration with aleglitazar. C_max treatment ratios for both statins exceeded the conventional no-effect boundary (1.25) when administered with aleglitazar.

Conclusions: Co-administration of aleglitazar with a statin does not alter the pharmacokinetic profile of either drug.     

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.

     

Drug–drug interaction with statins

3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors (the so-called statins: atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin and simvastatin) are a well-established class of drugs in the treatment of hypercholesterolemia. 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. Since statins are prescribed on a long-term basis, 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. Moreover, a combination of therapy between statins and other classes of lipid-lowering agents (e.g., ezetimibe, fibrates, resins and nicotinic acid) is recommended for some patients by current guidelines. Therefore, the potential for drug–drug interactions emerges as a relevant factor in determining the safety profile of statins. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions.     

Epidemiology and characteristics of adverse drug reactions caused by drug–drug interactions

Introduction: Drug–drug interactions (DDIs) arise in numerous different ways, involving pharmacokinetic or pharmacodynamic mechanisms. Adverse drug reactions are a possible consequence of DDIs and health operators are often unaware of the clinical risks of certain drug combinations. Many papers on drug interactions have been published in recent years, but most of them focused on potential DDIs while few studies have been conducted on actual interactions.

Areas covered: This paper reviews the epidemiology of actual DDIs in outpatients as well as in hospital settings and in spontaneous reporting databases. The incidence of actual DDIs is consistently lower than that of potential DDIs. However, the absolute number of patients involved is high, representing a significant proportion of adverse drug reactions. The importance of risk factors such as age, polypharmacy and genetic polymorphisms is also evaluated. The relevance and efficacy of tools for recognizing and preventing DDIs are discussed.

Expert opinion: Potential DDIs far outnumber actual drug interactions. The potential for an adverse interaction to occur is often theoretical, and clinically important adverse effects occur only in the presence of specific risk factors. Several studies have shown the efficacy of computers in early detection of DDIs. However, a correct risk–benefit evaluation by the prescribing physician, together with a careful clinical, physiological and biochemical monitoring of patients, is essential. Future directions of drug interaction research include the increasing importance of pharmacogenetics in preventing DDIs and the evaluation of interactions with biological drugs.     

Drug–drug interactions with statins: will pitavastatin overcome the statins’ Achilles’ heel?

Abstract

Background:

As the clinical complexity of patients at high cardiovascular risk and with multiple comorbid conditions increases, so does the potential for drug–drug interactions (DDIs). Large retrospective studies in various clinical settings have shown that an unacceptably large proportion of patients are coprescribed a statin with potentially interacting therapies, suggesting that the impact of polypharmacy on the safety profile of statins may be underappreciated.     

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.     

Safety of amide local anesthetics: new trends

Importance of the field: Local anesthetics have become one of the most common drugs used in daily practice worldwide. Neurologic and cardiovascular events are the most frequent adverse reactions related to local anesthetics use. Recently, new trends have been developed on this topic.

Areas covered in this review: We performed an overview of the data available so far on local anesthetics adverse reactions. Relevant literature was identified using PubMed search of articles published up to November 2009, including experimental studies, case reports or clinical studies when available. Search terms included: ‘local anaesthetics’, ‘adverse drug reaction’, ‘pharmacovigilance’ and ‘complication’.

What the reader will gain: Neurologic, cardiovascular and allergic reactions remain the most frequent adverse drug reactions related to local anesthetics in the literature. Studies based on pharmacovigilance systems have highlighted the frequency of adverse reactions little known until now, such as failure of block. Lipid emulsions are included into algorithm for cardiac resuscitation. Recent studies have demonstrated the myotoxicity and chondrotoxic effects of long-acting local anesthetics.

Take home message: Physicians must keep in mind all these adverse reactions to better prevent their occurrence and give the most appropriate treatment.     

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.     

秋水仙碱与他汀类潜在药物相互作用处方风险分析

目的 分析秋水仙碱与他汀类潜在药物相互作用(potential drug-drug interactions,pDDIs)处方,进行风险评估并制定预防措施。方法 检索知网、维普、万方、PubMed和Elsevier数据库关于秋水仙碱与他汀类相互作用致不良反应的个案和研究报道,进行文献分析;通过医院合理用药软件抽取2020年1月—2022年10月秋水仙碱联合他汀类药物的所有门诊处方,鉴别出潜在药物相互作用并进行严重性分级。结果 检索到该药物相互作用致不良反应个案报道22例,病例对照研究1篇,观察性队列研究2篇;不良反应以老年人居多,男性多于女性;发生时间集中在联合用药21 d内,3例患者死亡;高剂量、高龄、男性和肝/肾功能不全可能增加该pDDIs发生风险;遵义医科大学附属医院共收集到秋水仙碱联合他汀类药物处方72张,其中阿托伐他汀65张,瑞舒伐他汀6张,辛伐他汀1张,危险程度分级均为严重;1例患者联合使用秋水仙碱和阿托伐他汀4个月后出现肌病,1个月后好转;临床药师制定了7项预防措施。结论 遵义医科大学附属医院秋水仙碱与他汀类处方存在pDDIs,需积极实施预防措施并加强监测,尤其是联合用药...     

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 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.     

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.     

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.     

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.     

Pharmacotherapy of the third-generation AEDs: lacosamide,retigabine and eslicarbazepine acetate

Introduction: The search for new, more effective antiepileptic drugs (AEDs) continues. The three most recently approved drugs, the so-called third-generation AEDs, include lacosamide, retigabine and eslicarbazepine acetate and are licensed as adjunctive treatment of partial epilepsy in adults.

Areas covered: For the above three AEDs, their mechanisms of action, pharmacokinetic characteristics, drug–drug interactions, pharmacotherapeutics, dose and administration and therapeutic drug monitoring are reviewed in this paper.

Expert opinion: Lacosamide and retigabine act through novel mechanisms, while eslicarbazepine acetate, a pro-drug for eslicarbazepine, acts in a similar manner to several other AEDs. All three AEDs are associated with linear pharmacokinetic and rapid absorption and undergo metabolism. Their drug–drug interaction profile is low (lacosamide and retigabine) to modest (eslicarbazepine) in propensity. At the highest approved doses for the three AEDs, responder rates were similar. The most commonly observed adverse effects compared with placebo were dizziness, headache, diplopia and nausea for lacosamide; dizziness, somnolence and fatigue for retigabine and dizziness and somnolence for eslicarbazepine acetate. The precise role that these new AEDs will have in the treatment of epilepsy and whether they will make a significant impact on the prognosis of intractable epilepsy is not yet known and will have to await further clinical experience.     

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.