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.     

Statin use in Brazil: findings and implications

Introduction and objectives: Statins have become an integral part of treatment to reduce cardiac events in patients with cardiovascular disease. However, their use within the public healthcare system in Brazil is unknown. Consequently, we sought to determine and characterize statin use in primary healthcare delivered by the public health system (SUS) in Brazil and evaluate associated patient factors to improve future use.

Methods: Cross-sectional study with a national representative sample from five Brazilian regions, derived from the National Survey on Access, Use and Promotion of Rational Use of Medicines using a multi-stage complex sampling plan. Patients over 18 years old were interviewed from July 2014 to May 2015. The prevalences of statin use and self-reported statin adherence were determined amongst medicine users. The associations between statin use and sociodemographic/health condition variables were assessed using logistic regression.

Results: A total of 8803 patients were interviewed, of whom 6511 were medicine users. The prevalence of statin use was 9.4% with simvastatin (90.3%), atorvastatin (4.7%) and rosuvastatin (1.9%) being the most used statins. Poor adherence was described by 6.5% of patients. Statin use was significantly associated with age ≥65 years old, higher educational level, residence in the South, metabolic and heart diseases, alcohol consumption and polypharmacy.

Conclusions: This is the first population based study in Brazil to assess statin use in SUS primary healthcare patients. Addressing inequalities in access and use of medicines including statins is an important step in achieving the full benefit of statins in Brazil, with the findings guiding future research and policies.     

A systematic review to assess adherence and persistence with statins

Objective: To identify and assess studies published over a 10 year period up to February 2016 which measure adherence or persistence with statins, to summarize their methods, strengths and weaknesses and to summarize evidence linking statin adherence/persistence with risk of cardiovascular events.

Methods: Electronic databases and abstracts from four major cardiovascular disease conferences were searched from January 2005 to February 2016. The study selection process was performed by two reviewers working independently. Studies were included if they reported data regarding patient adherence or persistence with statins in adults with primary hypercholesterolemia, using any type of study design or length of follow-up. One reviewer extracted the study data and assessed study quality, which was checked by a second reviewer independently. Given the heterogeneity between the included studies a narrative critique and summary is presented.

Results: We report on 84 real world studies which aimed to assess adherence or persistence with statins. The majority of studies concluded that good adherence/persistence was associated with reduction in cardiovascular events and mortality. In two studies high intensity statin regimens were associated with poorer patient adherence when compared to low intensity statins. Adherence and persistence with statin therapy also has an impact on hospitalization costs and other cardiovascular disease (CVD) related costs.

Conclusions: Adherence and persistence are associated with a reduction in CVD events and mortality. There was limited evidence to suggest that high intensity statin regimens are associated with poorer treatment adherence when compared to lower intensity regimens. Hence, more robust studies are required to establish this association. As recommended by the 2013 ACC/AHA, 2016 ESC and several other clinical guidelines, clinicians and pharmacy managers should regularly monitor statin therapy adherence.     

Lipid and other management to improve arterial disease and survival in end stage renal disease

Introduction: Arterial disease is common in advancing renal failure, culminating in myocardial infarction with cardiac failure, strokes and peripheral and renal artery disease. Attention to cardiac and arterial disease may slow deterioration of renal function. Management of risk factors can reduce these sequelae.

Areas covered: Modifiable risk factors for arterial disease and relevant pharmacotherapies.

Expert opinion: Cardiovascular disease is the biggest killer in renal failure. Statins are viewed as essential in symptomatic coronary disease and have been shown in non-renal patients to improve survival after myocardial infarction. Cochrane recommends statins in renal failure but not in end stage renal disease or transplant patients. Large well powered clinical trials focussed specifically on renal patients failed to demonstrate cardiovascular outcome or mortality benefits of statins when compared to placebo. Other lipid lowering pharmacotherapies are weaker and adverse effects may account for the absence of net clinical benefit in non-renal patients in published clinical trials. Patients should be started on a statin after myocardial infarction, regardless of lipid levels, but the risk of adverse effects in advanced renal failure with its comorbidities predicates employing only essential doses. Optimal antihypertensive and antithrombotic pharmacotherapy are also priorities.     

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.     

Cardiovascular pleiotropic effects of statins and new onset diabetes: is there a common link: do we need to evaluate the role of KATP channels?

Introduction: Statins are considered the main stay of treatment in the prevention of cardio-vascular morbidity and mortality. They have multiple pleiotropic effects, like stabilization of atherosclerotic plaques, inhibition of platelet aggregation, and vascular smooth muscle proliferation; in addition to their lipid lowering action. Statins manifest these pleiotropic effects because they activate KATP channels in the cardiac and vascular tissue.

Simultaneous activation of the KATP channels by statins in β cells of pancreas may inhibit insulin release which may lead to diabetes.

Areas covered: Literature published between 1980 and 2016 on cholesterol biosynthesis, new onset diabetes and on the pleiotropic effects of statins, was reviewed. A comprehensive search on PubMed, Embase and Cochrane databases was carried out.

Expert opinion: Statins exert their beneficial pleiotropic effects on the cardiovascular system by activating KATP channels in the cardiac and vascular tissue. However, simultaneous activation of KATP channels in the beta cells of pancreas leads to inhibition of insulin release. This disturbs the carbohydrate metabolism and probably leads to diabetes. In our opinion, use of stains should be more judicious and restricted to secondary prevention only.     

Statin intolerance – a question of definition

Introduction: Statin therapy is the backbone of pharmacologic therapy for low-density lipoproteins cholesterol lowering and plays a pivotal role in cardiovascular disease prevention. Statin intolerance is understood as the inability to continue using a statin to reduce individual cardiovascular risk sufficiently, due to the development of symptoms or laboratory abnormalities attributable to the initiation or dose escalation of a statin. Muscle symptoms are the most common side effects observed.

Areas covered: The main aim of this article is to present a review on published definitions of statin intolerance. In addition, a brief review on clinical aspects and risk factors of statin intolerance is provided and features for a common definition for statin intolerance are suggested.

Expert opinion: A definition of statin intolerance by major drug regulatory agencies is not available. In clinical studies, different definitions are chosen and results are not comparable; different medical associations do not agree on one common definition. There is an unmet need to establish a common definition of statin intolerance to ensure an appropriate clinical use of this important drug class. Further work is required to develop a consensus definition on statin intolerance that could have significant positive impact on both research and clinical management.     

What is the impact of the 2017 cochrane systematic review and meta-analysis that evaluated the use of PCSK9 inhibitors for lowering cardiovascular disease and mortality?

Introduction: In 2017, Schmidt et al. conducted a Cochrane systematic review and meta-analysis to evaluate the effect of using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to reduce low-density-lipoprotein- cholesterol (LDL-C) and cardiovascular disease (CVD). The Cochrane review was a systematic review and meta-analysis of 20 randomized, double-blinded trials that compared the use of PCSK9 inhibitors with statins/ezetimibe, ezetimibe, or placebo for a treatment duration of at least 24 weeks. The use of PCSK9 inhibitors lowered the risk for CVD (OR 0.86 (0.80 to 0.92)) but not mortality (OR 1.02 (0.91 to 1.14)) when compared to placebo.

Areas covered: The following article evaluates the recently published Cochrane review and clarifies the efficacy of PCSK9 inhibitors for improving cardiovascular morbidity and mortality.

Expert opinion: The Cochrane review discussed suggests that PCSK9 inhibitors are effective in lowering LDL-C and the risk of CVD but not the risk of mortality. The higher price of PCSK9 inhibitors is a further deterrent for using them as a substitute for statins – cholesterol lowering medications with history showing they lower mortality. Statins should remain the gold-standard cholesterol-lowering drug class until PCSK9 inhibitors become more affordable and demonstrate consistent efficacy for reducing CVD and mortality.     

Preventable statin adverse reactions and therapy discontinuation. What can we learn from the spontaneous reporting system?

Background: Statin treatment is often associated with poor adherence, which may be due to the onset of adverse drug reactions (ADRs). We investigated on potential risk factors related to preventable cases of statin-induced ADRs and to the discontinuation of statin therapy.

Methods: We performed a study using the database of Italian spontaneous reporting. The target population for the preventability assessment was all patients with suspected statin-induced ADRs deriving from Campania Region (a territory of Southern Italy) between 2012 and 2017. Additionally, a local sentinel surveillance site involving General Practitioners was selected to countercheck in routine clinical practice the role of ADRs for statin discontinuation.

Results: In total, 34 of 655 (5.19%) regional cases were preventable and among detected risk factors 90.0% was related to healthcare professionals’ practices and 10.0% to patient behaviour. In 81.4% (533/655) of cases, statin therapy was discontinued due to ADRs, mainly classified as not serious and associated with a positive prognosis. These results were also confirmed in the active sentinel site.

Conclusions: Our findings suggest an inappropriate use of statins among the identified preventable cases and a potential inappropriate statin discontinuation due to ADRs. These factors may be useful for targeting interventions to improve statin adherence.     

Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver

Introduction: Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity.

Areas covered: This review will focus on fibrates – PPARα agonists and their implication in causing liver injury.

Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.     

Statins can improve proteinuria and glomerular filtration rate loss in chronic kidney disease patients,further reducing cardiovascular risk. Fact or fiction?

Introduction: The prevalence of chronic kidney disease (CKD), a risk factor for cardiovascular disease (CVD), is increasing worldwide. Statin treatment, the cornerstone of prevention or treatment of CVD, might have beneficial effects on urine protein excretion and renal function as determined by the glomerular filtration rate, whereas it might protect from acute kidney injury (AKI), mainly due to contrast-induced AKI. These beneficial effects on CKD may not be drug class effects; specific statins at specific doses may help prevent CKD deterioration and reduce CVD risk. We analysed all statin studies that had renal and CVD endpoints as main outcome measures. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched up to February 2015.

Areas covered: We consider the effects of statins on microalbuminuria, proteinuria, glomerular filtration rate, AKI associated with angiography or percutaneous coronary intervention and on CVD event rates in patients with CKD.

Expert opinion: Current evidence points towards the need to prescribe high-potency statins in patients with CKD, before a major decline in kidney function occurs. This may reduce CVD risk and delay the progress of CKD. Administration of either atorvastatin or rosuvastatin can prevent contrast-induced AKI before angiography or percutaneous coronary intervention. The combination of simvastatin + ezetimibe may decrease vascular events in patients with advanced CKD.     

Evaluating bempedoic acid for the treatment of hyperlipidaemia

Introduction: Despite the effectiveness of statins in the treatment of lipid disorders, residual risk still exists, and hitherto studies where additional drugs were added to statin therapy have been mainly negative or the outcomes were very modest. Therefore there is still a need for new and effective oral agents in the combination therapy of lipid disorders.

Areas covered: The review covers the current state of knowledge on the mechanism of action of bempedoic acid (ETC-1002) and results from recent clinical studies.

Expert opinion: ETC-1002 is a novel oral lipid-lowering therapy. The reduction of both low-density lipoprotein cholesterol (LDL-C) and high sensitivity C-reactive protein (hsCRP) demonstrated by ETC-1002 in clinical trials suggests that agent may have the potential for CV risk reduction. Adverse effects of current lipid-lowering agents can be dose-limiting, and combination approaches to lipid-lowering may often be utilized for optimal CV risk reduction. Because of this, new lipid-modulating drugs are urgently required. ETC-1002 has a unique mechanism of action (adenosine triphosphate-citrate lyase inhibition). It has been shown to be safe in combination with statins as well as ezetimibe, and appears to effectively lower LDL-C and has the potential to reduce the risk of muscle-related adverse events, which can limit the utilization and effectiveness of statin therapy.     

Characterization of drug-drug interactions in patients whose substance intake was objectively identified by detection in urine

Background: Identification of drug-drug interactions (DDIs) typically relies on patient medication lists which are prone to inaccuracies. This study describes use of a mass spectrometry test to detect recently ingested substances in urine with subsequent identification of DDIs.

Research design and methods: This was a retrospective analysis of the prevalence of DDIs identified in patients with chronic pain, addiction and/or behavioral health conditions in the U.S. Relationships between patient demographics, polypharmacy and the occurrence of DDIs were also described.

Results: Of 15,004 patients, 2964 (20%) had a DDI identified. There was a positive association between the number of substances detected in urine and the number of interactions identified (r = 0.5033, p-value = 0.0001). Of patients with polypharmacy, 15.6% had contraindicated or severe interactions identified compared to only 3.2% of those without polypharmacy. For polypharmacy patients, the youngest population studied had a much higher likelihood of having one or more DDIs identified compared to the other age groups (p-value = 0.0002).

Conclusions: By utilizing a mass spectrometry test to objectively detect recently ingested substances followed by identification of DDIs, healthcare providers may be able to better characterize the true incidence of DDIs. Study findings may not be generalizable to healthcare populations outside of pain management, addiction treatment, and behavioral health.     

An evaluation of pitavastatin for the treatment of hypercholesterolemia

Introduction: Statins are the first line of therapy to reduce low-density lipoprotein cholesterol (LDL-C) in order to decrease cardiovascular events. Pitavastatin is the latest statin to be introduced to the market.

Areas covered: In this article, the authors review the efficacy, safety, and tolerability of pitavastatin. The authors also review a recent cardiovascular outcome study.

Expert opinion: Pitavastatin produces dose-dependent reductions in LDL-C at lower doses than other statins. The maximum approved dose of 4 mg reduces LDL-C by about 40–49% in different patient groups and is equivalent to atorvastatin 20 mg in this effect. Pitavastatin undergoes minimal metabolism so drug–drug interactions are less likely than with many other statins, but it can interact with some drugs that inhibit drug transporters. Compared with other statins, it has been associated with greater increases in high-density lipoprotein cholesterol and it was found to be less likely to cause new onset diabetes. In a recent study in Japanese patients with stable coronary artery disease, pitavastatin 4 mg was more effective than pitavastatin 1 mg in reducing cardiovascular events. Therefore, the highest dose may be preferred in high-risk patients.