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 the risk of Parkinson disease: an update on the controversy

Background: Parkinson disease (PD) is the second most common neuro- degenerative disease and the number of affected patients is growing. Until now, information on either risk factors (genetic or environmental) or neuro- protective agents is still scarce. Recently, hydroxymethylglutary-coenzyme A reductase inhibitors have been related to protective as well as to potential harmful effects with regard to the development of a PD diagnosis. Objective: To give an overview and comment on the data available so far on this topic. Methods: Relevant literature was identified using a PubMed search of articles published up to October 2008. Search terms included: ‘Parkinson disease’, ‘statins’, and ‘epidemiology’. Original articles were reviewed and relevant citations from these articles were also considered. Results/conclusion: Results of the available observational studies were inconsistent with most studies reporting a protective effect of statins on the risk of PD. Others found no altered risk of PD in statin users compared to non-users or even an increased risk. Studies largely varied in size and analysis methods. Thus, comparison of the results is difficult. Until now, no definite conclusion on this topic can be made.     

Memory restorative role of statins in experimental dementia: an evidence of their cholesterol dependent and independent actions

The study was aimed at investigating the effects of pitavastatin, simvastatin (lipophilic statins) and fluvastatin (hydrophilic statin) on memory deficits associated with Alzheimer's type dementia in mice. Dementia was induced with chronic administration of a high fat diet (HFD) or intracebroventricular streptozotocin (icv STZ, two doses of 3 mg/kg) in separate groups of animals. Memory of the animals was assessed by the Morris water maze (MWM) test. Brain thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH) levels were measured to assess total oxidative stress. Brain acetylcholinesterase (AChE) activity and total serum cholesterol levels were also measured. Icv STZ or HFD produced a significant impairment of learning and memory. Higher levels of brain AChE activity and TBARS and lower levels of GSH were observed in icv STZ- as well as HFD-treated animals. HFD-treated mice also showed a significant increase in total serum cholesterol levels. Pitavastatin and simvastatin each significantly attenuated STZ-induced memory deficits and biochemical changes; however, fluvastatin produced no significant effect on icv STZ-induced dementia or biochemical levels. Administration of any one of the three statins not only lowered HFD-induced rise in total serum cholesterol level but also attenuated HFD-induced memory deficits. Further pitavastatin and simvastatin administration also reversed HFD-induced changes in biochemicals level, while fluvastatin failed to produce any significant effect. This study demonstrates the potential of statins in memory dysfunctions associated with experimental dementia and provides evidence of their cholesterol-dependent and -independent actions.     

Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia

Rosuvastatin is a synthetic enantiomer that is hepatoselective, relatively hydrophilic and has minimal metabolism via the cytochrome P450 3A4 system (similar to pravastatin). Rosuvastatin, like atorvastatin, has a plasma half-life of about 20 h and is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The majority of HMG-CoA reductase inhibitory activity in plasma is associated with the parent rosuvastatin compound. In a Phase II study, rosuvastatin across a dose range of 1 - 80 mg lowered low-density lipoprotein cholesterol (LDL-C) by 34 - 65%. Phase III trials have demonstrated greater reductions in LDL-C for rosuvastatin compared to atorvastatin as well as greater increases in high-density lipoprotein cholesterol (HDL-C). The drug appears to be well tolerated at all doses up to 80 mg/day. A starting dose of 10 mg will reduce LDL-C by approximately 50%, which should adequately treat most patients to within the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) goals.     

Orlistat for the management of overweight individuals and obesity: a review of potential for the 60-mg,over-the-counter dosage

Orlistat, in the 60-mg over-the-counter dose, was recently approved by the FDA. This lipase inhibitor blocks absorption of ~ 25% of ingested fat and has ~ 85% of the efficacy of the 120-mg dose for weight loss. Over 16 weeks weight loss with diet and orlistat 60 mg averages ~ 5% of initial body weight. The 60-mg dose is better tolerated than the 120-mg dose and the gastrointestinal side effects are minimal when individuals consume < 30% of their energy from fat. In addition to facilitating modest weight loss, orlistat use decreases serum LDL-cholesterol values by ~ 10%. When taken three times daily before meals, orlistat 60 mg modifies lifestyle behavior, encourages lower fat-consumption and sets the stage for other healthy lifestyle changes.     

Statins more than cholesterol lowering agents in Alzheimer disease: Their pleiotropic functions as potential therapeutic targets

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative and nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin.     

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.     

The therapeutic potential of CETP inhibitors: a patent review

Introduction: Epidemiological studies have identified that high levels of low-density lipoprotein-cholesterol (LDL-C) and low levels of high-density lipoprotein-cholesterol (HDL-C) are two independent causes of cardiovascular disease (CVD). Statins, niacin and fibrate are used for the treatment of CVD. However, some defects are shown in the treatment process. Thus, there is a demand for better treatment strategies that confer preferable efficacy with fewer side effects. Cholesteryl ester transfer protein (CETP) promotes the movement of CEs from HDL to LDL and VLDL in exchange for triglycerides (TGs).

Areas covered: In this review, we reviewed the development and therapeutic applications of CETP inhibitors. A comprehensive review of the patents and pharmaceutical applications between 2009 and 2017 has been highlighted.

Expert opinion: Recently, CETP inhibitors have attracted considerable interest in atherosclerosis-related disease. There are four drugs (torcetrapib, anacetrapib, evacetrapib and dalcetrapib) that have been clinically evaluated in phase III clinical trials and showed promising results in raising HDL-C levels, but there were suboptimal performances in reducing the risk of cardiovascular events with all the compounds. The correlation between plasma HDL-C levels and CVD incidence needs further verification. The timeline is still long for CETP inhibitors to emerge from the treatment of CVD.     

Limits and perspective of oral therapy with statins and aspirin for the prevention of symptomatic cholesterol gallstone disease

The prevalence of gallstones disease in Western countries is 10 – 15%. Gallstones can be one of two types – cholesterol or pigment – with cholesterol gallstones representing nearly the 80% of the total. Cholesterol and pigment gallstones have different predisposing factors: cholesterol gallstones are related to supersaturated bile in cholesterol, whereas black pigment gallstones are related to hyperbilirubinbilia factors (hemolysis, etc.); these are necessary, but not sufficient, factors to produce gallstones in vivo. Gall bladder mucosa factors (gall bladder secretion of mucin, local bile stasis and production of endogenous biliary β-glucuronidase) may coexist with the aforementioned factors and facilitate gallstone nucleation and growth. The gold-standard treatment for symptomatic gallstones is laparoscopic cholecystectomy. Several studies have reported a significant reduction in the onset of symptomatic gallstones disease in patients undergoing chronic therapy with statins, which can reduce bile cholesterol saturation. Aspirin, which has been shown to reduce the local production of gall bladder mucins (mucosal or parietal factors of gallstone formation) in animal experimental models, does not appear to reduce the risk of symptomatic gallstones disease when tested alone. The new horizon of oral therapy for the prevention of symptomatic gallstone disease needs to evaluate the long-term effect of statins and chronic aspirin administration in patients with dyslipidemia and/or atherosclerosis.     

Non-adherence to statin therapy: a major challenge for preventive cardiology

Background: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular disease, the leading cause of death worldwide. In the last twenty years, effective lipid-lowering therapies, particularly statins, have become widely available to prevent and reverse the progression of disease. However, there is a significant gap between expected and actual benefits; this may be attributed to poor adherence to statin therapy. Objective: To define the extent, causes (including psychological aspects), consequences and management of non-adherence to statins. Methods: Literature using PubMed and Medline up to and including 30 July 2009. Results: Adherence to statin therapy is suboptimal in both primary and secondary prevention of cardiovascular disease. Causes vary, and include patient factors (e.g., comorbidities, financial constraints, psychological issues), practitioner factors (e.g., poor knowledge of adherence, time constraints, poor communication skills and patient–doctor working alliance) and system factors (e.g., medication costs, lack of clinical monitoring, drug side effects). Non-adherence is associated with adverse health outcomes and increased costs of healthcare. A framework, based on a multidisciplinary approach, for addressing non-adherence, including managing the statin-intolerant patient, is presented. Conclusions: Non-adherence to statins is a significant issue for the prevention and treatment of cardiovascular disease. Increased awareness of the causes and solutions for overcoming non-adherence, including safer prescribing, improvement in physician–patient alliance and reduction in drug costs, will enhance the cost-effectiveness of the use of statins and significantly improve patient care and outcomes.     

Attainment of optional low-density lipoprotein cholesterol goal of less than 70 mg/dl and impact on prognosis of very high risk stable coronary patients: a 3-year follow-up

Objectives: We aimed to investigate the proportion of very high-risk patients with coronary heart disease (CHD) who achieve the optional low-density lipoprotein cholesterol (LDL-C) target of < 70 mg/dl (1.8 mmol/liter), the factors that influence the success rate and the impact on their prognosis.

Research design and methods: We enrolled 1337 consecutive patients with stable CHD. Fasting lipids were determined and all cardiovascular events were recorded during a median follow-up of 33 months.

Results: The majority (86.5%) of patients were taking lipid-lowering medication (95.5% statins), but only 50.6% had LDL-C levels of < 100 mg/dl (2.6 mmol/liter). In total, 941 (70.4%) patients were considered very high risk and only 15.1% of them had LDL-C levels of < 70 mg/dl. Τhe use of intensive lipid-lowering medication was associated with 12-fold (95% CI 6.98 – 20.76; p < 0.001) higher possibility in achieving LDL-C levels of < 70 mg/dl. Attainment of LDL-C levels of < 70 mg/dl by patients at very high risk were independent predictors of all cardiovascular events (HR = 0.34, 95% CI 0.17 – 0.70; p = 0.003).

Conclusions: The vast majority of very high-risk patients do not achieve the optional LDL-C goal; this is mainly due to the suboptimal uptitration of statin dose and is translated into loss of clinical benefits.     

Inhibition of pre-protein convertase serine kexin-9 (PCSK-9) as a treatment for hyperlipidaemia

Introduction: Pre-protein convertase subtilisin kexin (PCSK)-9 is a newly discovered protein involved in intracellular and extracellular regulation of low-density lipoprotein receptor (LDLR) expression. Autosomal dominant activating mutations in PCSK-9 cause familial hypercholesterolaemia whereas inactivating mutations in man reduce LDL cholesterol (LDL-C) and are associated with a decreased lifetime risk of cardiovascular events.

Areas covered: As PCSK-9 binds to the LDLR, a number of approaches involving small molecule or peptide inhibition of binding, antibody-mediated inactivation of binding and the use of antisense oligonucleotides are being investigated as therapeutic approaches to lower LDL-C in man. This article reviews the biochemistry and physiology of PCSK-9 and details the efforts made to design novel molecules with the ability to inhibit PCSK-9 activity. Work in animal models has confirmed that reducing PCSK-9 expression can reduce atherosclerosis in mice, rats and primates. Monoclonal antibodies such as REGN-727 and AMG-145 have been shown to reduce LDL-C in patients with familial hypercholesterolaemia already treated with statins or healthy normocholesterolaemic controls.

Expert opinion: PCSK-9 inhibition is a potentially interesting novel addition to the armamentarium of LDL-C reducing drugs. Its effects in reducing LDL-C will need to be confirmed to reduce CVD events in large-scale clinical trials.     

Rho kinase as potential therapeutic target for cardiovascular diseases: opportunities and challenges

Rho kinase (ROCK) belongs to a family of Ser/Thr protein kinases that are activated via interaction with the small GTP-binding protein RhoA. Growing evidence suggests that RhoA and ROCK participate in a variety of important physiological functions in vasculature including smooth muscle contraction, cell proliferation, cell adhesion and migration, and many aspects of inflammatory responses. As these processes mediate the onset and progression of cardiovascular disease, modulation of the Rho/ROCK signalling pathway is a potential strategy for targeting an array of cardiovascular indications. Two widely employed ROCK inhibitors, fasudil and Y-27632, have provided preliminary but compelling evidence supporting the potential cardiovascular benefits of ROCK inhibition in preclinical animal disease models and in the clinic. This review summarises the molecular biology of ROCK and its biological functions in smooth muscle, endothelium and other vascular tissues. In addition, there will be a focus on recent progress demonstrating the benefits of ROCK inhibition in several animal models of cardiovascular diseases. Finally, recent progress in the identification of novel ROCK inhibitors and challenges associated with their development for clinical use will be discussed.     

DHA derivatives of fish oil as dietary supplements: a nutrition-based drug discovery approach for therapies to prevent metabolic cardiotoxicity

Introduction: During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA-enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease.

Areas covered: This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases.

Expert opinion: The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease.     

MicroRNAs： a novel class of potential therapeutic targets for cardiovascular diseases

Currently, cardiovascular diseases remain one of the leading causes of morbidity and mortality in the world, indicating the need for innovative therapies and diagnosis for heart disease. MicroRNAs (miRNAs) have recently emerged as one of the central players in regulating gene expression. Numerous studies have documented the implications of miRNAs in nearly every pathological process of the cardiovascular system, including cardiac arrhythmia, cardiac hypertrophy, heart failure, cardiac fibrosis, cardiac ischemia and vascular atherosclerosis. More surprisingly, forced expression or suppression of a single miRNA is enough to cause or alleviate the pathological alteration, underscoring the therapeutic potential of miRNAs in cardiovascular diseases. In this review we summarize the key miRNAs that can solely modulate the cardiovascular pathological process and discuss the mechanisms by which they exert their function and the perspective of these miRNAs as novel therapeutic targets and/or diagnostic markers. In addition, current approaches for manipulating the action of miRNAs will be introduced.     

Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment

18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.     

The safety and effectiveness of statins as treatment for HIV-dyslipidemia: the evidence so far and the future challenges

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 decrease in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. HIV-dyslipidemia is a common problem with extensive use of combination antiretroviral therapy (CART), and is associated with an increase in incidence of cardiovascular disease (CVD), resulting in hospital admission and surgery throughout the western healthcare systems.

Areas covered: This review describes the effectiveness and safety of statins in the treatment of HIV-dyslipidemia. Medline was searched for different statins as treatment for HIV-dyslipidemia.

Expert opinion: Dyslipidemia in patients with HIV is different from the normal population, due to the fact that HIV treatment may not only cause dyslipidemia, but may also interact with lipid lowering medication. Statin-unresponsive HIV-dyslipidemia can be treated with the addition of ezetimibe, fenofibrate, fish oil and niacin. Current guidelines recommend the use of pravastatin and atorvastatin as first-line therapy, whereas European guidelines include rosuvastatin. There is an urgent need to confirm whether the use of statins in HIV-dyslipidemia is associated with an increase in the incidence of diabetes; this is significant because HIV patients are known to be insulin-resistant. HIV is also associated with Non-alcoholic Fatty Liver Disease (NAFLD), a condition known to be associated with insulin resistance. Further clinical trials are urgently needed to assess the impact of statins on CVD in HIV patients, and future challenges for researchers in this area are enormous.