bims-mitost Biomed News
on Mitochondrial toxicity and statins
Issue of 2019–04–14
six papers selected by
Yvonne Will
  1. Statins Do Not Directly Inhibit the Activity of Major Epigenetic Modifying Enzymes.
  2. Prescription of statins in suspected non-alcoholic fatty liver disease and high cardiovascular risk, a population-based study.
  3. Effects of simvastatin and fenofibrate on butyrylcholinesterase activity in the brain, plasma, and liver of normolipidemic and hyperlipidemic rats.
  4. Effects of Statins to Reduce All-Cause Mortality in Heart Failure Patients: Findings from the EPICAL2 Cohort Study.
  5. The Potential Use of Metformin, Dipyridamole, N-Acetylcysteine and Statins as Adjunctive Therapy for Systemic Lupus Erythematosus.
  6. Evidence of heterogeneity in statin-associated type 2 diabetes mellitus risk: A meta-analysis of randomized controlled trials and observational studies.
  1. Cancers (Basel). 2019 Apr 10. pii: E516. [Epub ahead of print]11(4):
    Statins Do Not Directly Inhibit the Activity of Major Epigenetic Modifying Enzymes.
    Stephanie Bridgeman, Wendy Northrop, Gaewyn Ellison, Thiru Sabapathy, Phillip E Melton, Philip Newsholme, Cyril D S Mamotte.
      The potential anticancer effects of statins-a widely used class of cholesterol lowering drugs-has generated significant interest, as has the use of epigenetic modifying drugs such as HDAC and DNMT inhibitors. We set out to investigate the effect of statin drugs on epigenetic modifications in multiple cell lines, including hepatocellular carcinoma, breast carcinoma, leukemic macrophages, cervical adenocarcinoma, and insulin-secreting cells, as well as liver extracts from statin-treated C57B1/6J mice. Cells or cell extracts were treated with statins and with established epigenetic modulators, and HDAC, HAT, and DNMT activities were quantified. We also examined histone acetylation by immunoblotting. Statins altered neither HDAC nor HAT activity. Accordingly, acetylation of histones H3 and H4 was unchanged with statin treatment. However, statins tended to increase DNMT activity. These results indicate that direct inhibition of the major classes of epigenetic modifying enzymes, as previously reported elsewhere, is unlikely to contribute to any anticancer effects of statins. This study concerned global effects on epigenetic enzyme activities and histone acetylation; whether statins influence epigenetic modifications in certain genomic regions, cannot be ruled out and remains to be investigated.
    Keywords:  DNA methylation; DNMT inhibitors; HDAC inhibitors; HMG-CoA reductase inhibitors; epigenetics; histone acetylation
    DOI:  https://doi.org/10.3390/cancers11040516
  2. Liver Int. 2019 Apr 09.
    Prescription of statins in suspected non-alcoholic fatty liver disease and high cardiovascular risk, a population-based study.
    Eline H van den Berg, Alba A B Wolters, Robin P F Dullaart, Han Moshage, David Zurakowski, Vincent E de Meijer, Hans Blokzijl.
       BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, with concomitant high incidence of lipoprotein abnormalities. Cardiovascular disease (CVD) is the main cause of death in subjects with NAFLD and management of dyslipidemia is pivotal for prevention. We aimed to determine cardiovascular risk and indication for statin therapy in subjects with NAFLD.
    METHODS: Cross sectional analysis of the population-based Lifelines Cohort Study of 34,240 adult individuals. Subjects with reported use of lipid-lowering drugs were excluded. Suspected NAFLD was defined as Fatty Liver Index (FLI) ≥60 and advanced hepatic fibrosis as NAFLD fibrosis score (NFS) >0.676. Cardiovascular risk and indication for statin therapy were defined according to the European Society of Cardiology and European Atherosclerosis Society Guideline for the Management of Dyslipidemias.
    RESULTS: FLI≥60 was present in 7,067 (20.6%) participants and coincided with increased prevalence of type 2 diabetes mellitus, metabolic syndrome, CVD and impaired renal function (all P<0.001). 10-Year predicted cardiovascular risk was significantly increased in subjects with elevated FLI and NFS (both P<0.001). Indication for statin use was significantly increased in subjects with FLI≥60 (31.0% vs. 15.6%, P<0.001) and NFS>0.676 (73.2% vs. 30.6%, P<0.001). In multivariable analyses FLI≥60 (OR 1.26, 95%CI: 1.13-1.41%, P<0.001) and NFS>0.676 (OR 5.03, 95%CI: 2.76-9.17%, P<0.001) were independent predictors for indication regarding statin therapy.
    CONCLUSIONS: Because of increased cardiovascular risk, substantial proportions of subjects with suspected NAFLD and/or fibrosis have an indication for lipid-lowering treatment and could benefit from statin therapy. This article is protected by copyright. All rights reserved.
    Keywords:  Fatty Liver Index; NAFLD fibrosis score; Non-alcoholic fatty liver disease; dyslipidemia, cardiovascular risk; statin therapy
    DOI:  https://doi.org/10.1111/liv.14116
  3. Arh Hig Rada Toksikol. 2019 Mar 01. pii: /j/aiht.2019.70.issue-1/aiht-2019-70-3215/aiht-2019-70-3215.xml. [Epub ahead of print]70(1): 30-35
    Effects of simvastatin and fenofibrate on butyrylcholinesterase activity in the brain, plasma, and liver of normolipidemic and hyperlipidemic rats.
    Antonija Vukšić, Jasna Lovrić, Paško Konjevoda, Nina Blažević, Marinko Bilušić, Vlasta Bradamante.
      The study objective was to test the hypothesis that simvastatin and fenofibrate should cause an increase in butyrylcholinesterase (BuChE) activity not only in the plasma and liver but also in the brain of normolipidemic and hyperlipidemic rats. Catalytic enzyme activity was measured using acetylthiocholine (ATCh) and butyrylthiocholine (BTCh) as substrates. Normolipidemic and hyperlipidemic rats were divided in four groups receiving 50 mg/kg of simvastatin a day or 30 mg/kg of fenofibrate a day for three weeks and three control groups receiving saline. Simvastatin and fenofibrate caused an increase in brain BuChE activity in both normo- and hyperlipidemic rats regardless of the substrate. The increase with BTCh as substrate was significant and practically the same in normolipidemic and hyperlipidemic rats after simvastatin treatment (14-17% vs controls). Simvastatin and fenofibrate also increased liver and plasma BuChE activity in both normolipidemic and hyperlipidemic rats regardless of the substrate. In most cases the increase was significant. Considering the important role of BuChE in cholinergic transmission as well as its pharmacological function, it is necessary to continue investigations of the effects of lipid-lowering drugs on BuChE activity.
    Keywords:  Wistar rats; Zucker rats; acetylthiocoline; butyrylthiocholine; lipid-lowering drugs
    DOI:  https://doi.org/10.2478/aiht-2019-70-3215
  4. Am J Cardiovasc Drugs. 2019 Apr 10.
    Effects of Statins to Reduce All-Cause Mortality in Heart Failure Patients: Findings from the EPICAL2 Cohort Study.
    Muaamar Al-Gobari, Nelly Agrinier, Marc Soudant, Bernard Burnand, Nathalie Thilly.
       INTRODUCTION: The addition of statins to standard care in heart failure (HF) patients remains controversial in clinical practice. Large-scale clinical trials failed to show mortality benefits, but uncertainty persists in real-world settings.
    OBJECTIVE: We evaluated whether the prescription of statins at hospital discharge is associated with a reduction in all-cause mortality at up to 1 year of follow-up in HF patients.
    METHODS: We analyzed data from Epidémiologie et Pronostic de l'Insuffisance Cardiaque Aiguë en Lorraine (EPICAL2) cohort study of 2254 hospitalized acute HF patients who were admitted to 21 hospitals located in northeast France for acute HF between October 2011 and October 2012 and who received statins at discharge compared with patients who did not. We used propensity score matching and instrumental variable analyses to estimate the treatment effects of statins, and a multivariable Cox proportional-hazards model to examine survival with statin use, adjusting for patient demographics, HF characteristics, medical history, comorbidities, drug treatment and other known potential confounders. We plotted Kaplan-Meier survivor curves, and used log-rank test to determine the equality of survivor functions.
    RESULTS: We included 2032 patients in this investigation: 919 (45%) in the statin-treated group and 1113 (55%) in the control group. The estimated average statin-treatment effects for all-cause mortality in HF failed to demonstrate a significant effect on mortality [Z = - 1.73, 95% confidence interval (CI) - 0.11 to 0.007, p value = 0.083, and Z = - 0.95, 95% CI - 1.34 to 0.46, p value = 0.34] for propensity score matching and instrumental variable analyses, respectively. Moreover, the Cox proportional-hazards model showed that statin prescription was not significantly associated with the rate of death (hazard ratio = 0.85, 95% CI 0.66-1.11, p value = 0.26), adjusted for all confounders.
    CONCLUSION: In patients with HF (and reduced or preserved ejection fraction), the prescription of statins did not appear to be associated with better survival after 1 year of follow-up in the EPICAL2 cohort. We cannot exclude that a subpopulation of HF patients may have some benefits compared with the whole HF population or that there might be a lack of power to show such effect.
    CLINICAL TRIAL REGISTRATION: NCT02880358.
    DOI:  https://doi.org/10.1007/s40256-019-00346-4
  5. Cells. 2019 Apr 06. pii: E323. [Epub ahead of print]8(4):
    The Potential Use of Metformin, Dipyridamole, N-Acetylcysteine and Statins as Adjunctive Therapy for Systemic Lupus Erythematosus.
    Marcus Kai Xuan Tan, Thurston Yan Jia Heng, Anselm Mak.
      Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune condition that can potentially affect every single organ during the course of the disease, leading to increased morbidity and mortality, and reduced health-related quality of life. While curative treatment is currently non-existent for SLE, therapeutic agents such as glucocorticoids, mycophenolate, azathioprine, cyclosporine, cyclophosphamide and various biologics are the mainstay of treatment based on their immunomodulatory and immunosuppressive properties. As a result of global immunosuppression, the side-effect profile of the current therapeutic approach is unfavourable, with adverse effects including myelosuppression, infection and malignancies. Hydroxychloroquine, one of the very few Food and Drug Administration (FDA)-approved medications for the treatment of SLE, has been shown to offer a number of therapeutic benefits to SLE patients independent of its immunomodulatory effect. As such, it is worth exploring drugs similar to hydroxychloroquine that confer additional clinical benefits unrelated to immunosuppressive mechanisms. Indeed, apart from hydroxychloroquine, a number of studies have explored the use of a few conventionally non-immunosuppressive drugs that are potentially useful in the management of SLE. In this review, non-immunosuppressive therapeutic agents, namely metformin, dipyridamole, N-acetylcysteine and statins, will be critically discussed with regard to their mechanisms of action and efficacy pertaining to their potential therapeutic role in SLE.
    Keywords:  SLE; acetylcysteine; dipyridamole; immunosuppression; lupus; metformin; statin
    DOI:  https://doi.org/10.3390/cells8040323
  6. Diabetes Res Clin Pract. 2019 Apr 04. pii: S0168-8227(18)31191-4. [Epub ahead of print]151 96-105
    Evidence of heterogeneity in statin-associated type 2 diabetes mellitus risk: A meta-analysis of randomized controlled trials and observational studies.
    Joseph C Engeda, Ashlyn Stackhouse, Mary White, Wayne D Rosamond, Stefan K Lhachimi, Jennifer L Lund, Thomas C Keyserling, Christy L Avery.
       AIMS: To conduct a meta-analysis of statin-associated type 2 diabetes mellitus (T2D) risk among randomized controlled trials (RCTs) and observational studies (OBSs), excluding studies conducted among secondary prevention populations.
    METHODS: Studies were identified by searching PubMed (1994-present) and EMBASE (1994-present). Articles had to meet the following criteria: (1) follow-up >one year; (2) >50% of participants free of clinically diagnosed ASCVD; (3) adult participants ≥30 years old; (4) reported statin-associated T2D effect estimates; and (5) quantified precision using 95% confidence interval. Data were pooled using random-effects model.
    RESULTS: We identified 23 studies (35% RCTs) of n = 4,012,555 participants. OBS participants were on average younger (mean difference = 6.2 years) and had lower mean low-density lipoprotein cholesterol (LDL-C, mean difference = 20.6 mg/dL) and mean fasting plasma glucose (mean difference = 5.2 mg/dL) compared to RCT participants. There was little evidence for publication bias (P > 0.1). However, evidence of heterogeneity was observed overall and among OBSs and RCTs (PCochran = <0.05). OBS designs, younger baseline mean ages, lower LDL-C concentrations, and high proportions of never or former smokers were significantly associated with increased statin-associated T2D risk.
    CONCLUSIONS: Potentially elevated statin-associated T2D risk in younger populations with lower LDL-C merits further investigation in light of evolving statin guidelines targeting primary prevention populations.
    Keywords:  Guidelines; Low-density lipoprotein; Prevention; Statin; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.diabres.2019.04.005
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