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Update - Week 07, 2018
 
Curated by Peter Lansberg,
a Dutch lipidologist and educator, and
reviewed by prof. Philip Barter, Past President of the
International Atherosclerosis Society.

The IAS Statin Newsletter will keep you up-to-date with all recent statin publications, using a curated approach to select relevant articles.

Key publications

High dose vs low dose atorvastatin in high stroke risk patients
In this prospective observational study, conducted in a single Chinese center, 120 patients with symptomatic intra cranial arterial stenoses were randomized to 10, 20 and 40 mg atorvastatin. Follow up time was 12 months and assessed for clinical endpoints can cerebral blood flow changes. Treatment was completed by 112 patients. Cerebrovascular complications (TIA and stroke) at 1 month were equal in the three treatment groups (10%, 5% and 5% respectively). After 12 months the incidence increased to 26.3%, 13.5% and 5%. Patients using 40 mg atorvastatin had statistically significantly less events when compared to patients using 10 mg atorvastatin (P<0.05). no difference was discernable between patients using 10 vs 20 mg or  20 vs 40 mg of atorvastatin. Cerebral blood flow parameters improved in all three groups compared to baseline measurements (P<0.05). Patients using atorvastatin 40 mg showed improved relative time to peak flow compared to the individuals using lower dosages of atorvastatin (P<0.001). The authors concluded that using the highest atorvastatin dosage had important clinical advantages in patients with symptomatic intracranial stenosis.
Zhou P, Cao Z, Wang P et al. The Effect of Intensive Statin Therapy on Symptomatic Intracranial Arterial Stenosis. Iranian journal of public health 2018; 47:231-236. http://www.ncbi.nlm.nih.gov/pubmed/?term=29445633
 
Mirror, mirror on the wall which guideline is the best of all?
Despite the use of similar literature sources as well as rigorous evidentiary strategies, the major lipid treatment guidelines do differ in their recommendations. The authors of this review compared 5 major guidelines: American College of Cardiology/American Heart Association, Canadian Cardiovascular Society, European Society for Cardiology/European Atherosclerosis Society, U.S. Preventive Services Task Force, and the U.S. Veterans Affairs/Department of Defense recommendations. All guidelines shared similar advice for joined decision making based on clinician-patient discussion. As well as lifestyle improvements, prior or in conjunction to pharmacological interventions, and statins for first line treatment. However, recommendations regarding specific dosages and statin intensity were different. Another important distinction is the “treat to target approach” that is advocated in the ESC/AHA and CCS guidelines vs type and dosage of statin in the ACC/AHA, USPSTF and VA-DoD recommendations. Suggestions for add-on treatments, how to address co-morbidities and re-adjust statin dosage/intensity as well as the tools for calculating risk were different as well. New guidelines, based on recent hard clinical outcome trials, are in process and the authors expressed hope that incorporating this new high-quality data will enable guideline panels to resolve some of these hotly debated discrepancies in lipid lowering treatment recommendations.
Tibrewala A, Jivan A, Oetgen WJ, Stone NJ. A Comparative Analysis of Current Lipid Treatment Guidelines: Nothing Stands Still. J Am Coll Cardiol 2018; 71:794-799. http://www.ncbi.nlm.nih.gov/pubmed/?term=29447742
 
Diabetics respond favorably to statin-add on therapy with alirocumab

Lowering LDL-c is a major focus in managing patients with type 2 diabetes (T2DM). Statins, despite their pro-diabetogenic effects, are considered a first line and indispensable tool to reduce LDL-c and the associated CVD risk in diabetic patients. Non-statin add-on treatments are now being evaluated in phase 3 trials to determine their efficacy and safety in diabetics. The successful studies examining a PCSK9 antibodies-based add-on treatment in patients with coronary artery disease, catalyzed interest to examine their effects in this important, and difficult to treat, patient population. The ODYSSEY DM-DYSLIPIDEMIA study compared the effects of alirocumab vs usual care (UC) in T2DM and mixed dyslipidemia patients that were not optimally managed with (maximal tolerated) statin therapy. In this open label randomized trial patients (N=413) were allocated to 75 mg alirocumab bi-weekly or UC for 24 weeks. Patients in the Alirocumab arm were up-titrated to 150 mg bi-weekly at week 12, if at week 8, non -HDL-c >100 mg/dl (2.6 mmol/l).  Patients using alirocumab showed superior reductions of Non-HDL-c: -32,5%, LDL-c: -43.0%, Apo B: -32.2%, total -c: -24.6% and LDL-particle number:  -37.8% (all p<0.0001).  Overall 63.6% of Alirocumab allocated patients maintained their initial dosage of 75 mg/2 weeks. The drug was well tolerated with treatment associated adverse events observed in 68.4% of patients taking alirocumab vs 66.4% in patients allocated to usual care. An important observation was the noted absence of HbA1C increases and/or change in the number of glucose lowering agents. The authors concluded that alirocumab was a generally well-tolerated and very effective Non-HDL-c/LDL-c lowering agent in diabetic and mixed dyslipidemia patients, unable to reach treatment targets with maximally tolerated statins.
Ray KK, Leiter LA, Muller-Wieland D et al. Alirocumab versus usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29436756
 
Reviewing the evidence on statins in patients with liver disease
This review summarizes relevant published data on the potential role of statins in patients with liver diseases. Discussing the increased CVD risk in patients with NAFLD/NASH as well as the observed benefits in a broad spectrum of different types of liver disease. When statin were introduced the observed increase in transaminases were considered a signal to stop statins use in patients that participated in clinical trials. This approach was translated to patients in regular clinical care as well. However, in recent years severe liver damage was observed only sporadically, estimated to be a serious complication in 1 of the 1-2 million patients treated with statins. Retrospective analysis of subgroups in RCT’s of statins showed that statins not only reduced risk to a greater extend in patient with elevated transaminases but also improved biomarkers and imaging parameters, related to manifestations of liver disease. In this comprehensive review the authors assess current knowledge on statins and NAFLD/NASH, viral induced liver disease, progression of chronic liver disease, hepatocellular carcinoma as well as discussing the intrinsic properties of statins that can help to explain the observed benefits. They conclude that the circumstantial evidence pointing towards the benefits of statins in patients with liver disease is based on post-hoc analyses of three major prospective randomized controlled trials, observational data and animal studies. The CV benefits observed in NAFLD/NASH patients would indicate that stopping statins could potentially translate into harmful preventable CVD events. The intrinsic effects of statins to improve hepatic related outcomes needs to be more firmly established by well-designed studies; preferably liver biopsy-based evaluations to establish benefits unequivocally. Current guidelines do not recommend statins for NAFLD/NASH patients but encourage their use only for the management of dyslipidemia, if future recommendations will changes these directives remains to be seen.
Imprialos KP, Stavropoulos K, Doumas M et al. The potential role of statins in treating liver disease. Expert Rev Gastroenterol Hepatol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29431526
 
How to address postoperative cognitive dysfunction in elderly patients
Postoperative cognitive dysfunction (POCD) is a not uncommon post-surgery complication in elderly patients. in the first few months after surgery estimates of 10% - 38% have been reported. Risk factors for POCD are not firmly established, but age related potential predictors include elevated plasma levels of total cholesterol, LDL cholesterol, triglycerides and low HDL-cholesterol. Statins have repeatedly been linked do reduced PCOD risk. This meta-analysis aimed to explore the increase and decrease risk associated with dyslipidemia and statin use. Using PubMed, Ovid SP and the Cochrane databases, 17 of 205 articles were included. In total 2725 patients, mean age 67 years with a median follow up of 7 days (range 1 day – 4 years) were analyzed. Hypercholesterolemia and statins were the parameters studied in almost all trials. Based on the data collected in 12 studies no effect of hypercholesterolemia on PCOD risk was observed, RR 0.93 (0.80-1.08; P=0.34). If statin were used before surgery a reduced risk was observed, RR 0.81 (0.67-0.98; p=0.03). There were no studies that evaluated statin treatment duration. The authors concluded that, based on the trials included in this meta-analysis, elevated plasma cholesterol levels was not associated with increased PCOD risk. Statin users did have a reduced risk of PCOD. The paucity of trials and the limited study types as well as lack of high quality studies warrants additional trials to evaluate the benefits of statins in the prevention of PCOD.
Feinkohl I, Winterer G, Pischon T. Associations of dyslipidaemia and lipid-lowering treatment with risk of postoperative cognitive dysfunction: a systematic review and meta-analysis. Journal of epidemiology and community health 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29437865

Relevant publications
  1. Chen PH, Wang JS, Lin SY et al. Effects of statins on all-cause mortality at different low-density-lipoprotein cholesterol levels in Asian patients with type 2 diabetes. Current medical research and opinion 2018:1-20. https://www.ncbi.nlm.nih.gov/pubmed/29429368
  2. Ngo-Metzger Q, Gottfredson R. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults. American family physician 2017; 96:805-806. http://www.ncbi.nlm.nih.gov/pubmed/?term=29431375
  3. Mancano MA. ISMP Adverse Drug Reactions: Influenza Vaccine-Induced Stevens-Johnson Syndrome; Vilazodone-Induced Nightmares; Dabigatran-Induced Pustular Eruptions; Neurotoxic and Cardiotoxic Symptoms After Cannabis Concentrate Exposure; Rosuvastatin-Induced Skin Eruption. Hospital pharmacy 2018; 53:15-17. http://www.ncbi.nlm.nih.gov/pubmed/?term=29434381
  4. Liu Y, Sun L, Chen W et al. Combined treatment with simvastatin and rapamycin attenuates cardiac allograft rejection through the regulation of T helper 17 and regulatory T cells. Experimental and therapeutic medicine 2018; 15:1941-1949. http://www.ncbi.nlm.nih.gov/pubmed/?term=29434788
  5. Khan TJ, Ahmed YM, Zamzami MA et al. Atorvastatin Treatment Modulates the Gut Microbiota of the Hypercholesterolemic Patients. Omics : a journal of integrative biology 2018; 22:154-163. http://www.ncbi.nlm.nih.gov/pubmed/?term=29432061
  6. Disbrow D, Seelbach CL, Albright J et al. Statin medications are associated with decreased risk of sepsis and anastomotic leaks after rectal resections. American journal of surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29428155
  7. Cheng YY, Kao CL, Lin SY et al. Effect of an increased dosage of statins on spinal degenerative joint disease: a retrospective cohort study. BMJ Open 2018; 8:e017442. http://www.ncbi.nlm.nih.gov/pubmed/?term=29439066
  8. Carey W. Statin Use In Cirrhosis from Fatty Liver Disease. Hepatology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29443384
  9. Byrne P, Cullinan J, Murphy C, Smith SM. Cross-sectional analysis of the prevalence and predictors of statin utilisation in Ireland with a focus on primary prevention of cardiovascular disease. BMJ Open 2018; 8:e018524. http://www.ncbi.nlm.nih.gov/pubmed/?term=29439070
  10. Browndyke JN, Heflin MT. Cognition and brain changes associated with high-dose atorvastatin: A BOLD proposition? Am Heart J 2018; 197:163-165. http://www.ncbi.nlm.nih.gov/pubmed/?term=29447777
  11. Yoshimura S, Uchida K, Morimoto T. Response by Yoshimura et al to Letter Regarding Article, "Randomized Controlled Trial of Early Versus Delayed Statin Therapy in Patients With Acute Ischemic Stroke: ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient)". Stroke 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29438075
  12. Wang Y, Tian Y, Lv P et al. The effect of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Chinese people. Pharmazie 2017; 72:365-368. http://www.ncbi.nlm.nih.gov/pubmed/?term=29442027
  13. Taylor BA, Dager AD, Panza GA et al. The effect of high-dose atorvastatin on neural activity and cognitive function. Am Heart J 2018; 197:166-174. http://www.ncbi.nlm.nih.gov/pubmed/?term=29447778
  14. Setia N, Saxena R, Sawhney JPS, Verma IC. Familial Hypercholesterolemia: Cascade Screening in Children and Relatives of the Affected. Indian journal of pediatrics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29450819
  15. Scheitz JF, Lees KR, Endres M. Letter by Scheitz et al Regarding Article, "Randomized Controlled Trial of Early Versus Delayed Statin Therapy in Patients With Acute Ischemic Stroke: ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient)". Stroke 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29438082
  16. Schairer C, Freedman DM, Gadalla SM, Pfeiffer RM. Lipid-lowering drugs, dyslipidemia, and breast cancer risk in a Medicare population. Breast Cancer Res Treat 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29450675
  17. Samardzic I, Benkovic I, Vrca VB. Incidence of statin-drug interactions in Croatian community pharmacy. Pharmazie 2017; 72:187-191. http://www.ncbi.nlm.nih.gov/pubmed/?term=29442055
  18. Peringat J, Manappallil RG, Karadan U. Rhabdomyolysis: a rare complication of Hashimoto's thyroiditis precipitated by statin therapy. BMJ case reports 2018; 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29440138
  19. Parish S, Hopewell JC, Hill MR et al. Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study. Circulation. Genomic and precision medicine 2018; 11:e001696. http://www.ncbi.nlm.nih.gov/pubmed/?term=29449329
  20. Noaman S, Al-Mukhtar O, Abramovic S et al. Changes in Statin Prescription Patterns in Patients Admitted to an Australian Geriatric Subacute Unit. Heart, lung & circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29433992
  21. Mladenovska K, Grapci AD, Vavlukis M et al. Influence of SLCO1B1 polymorphisms on atorvastatin efficacy and safety in Macedonian subjects. Pharmazie 2017; 72:288-295. http://www.ncbi.nlm.nih.gov/pubmed/?term=29441875
  22. Li X, Zhou J. Impact of post-diagnostic statin use on ovarian cancer mortality: a systematic review and meta-analysis of observational studies. Br J Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29453799
  23. Li R, Wang TJ, Lyu PY et al. Effects of Plasma Lipids and Statins on Cognitive Function. Chinese medical journal 2018; 131:471-476. http://www.ncbi.nlm.nih.gov/pubmed/?term=29451153
  24. Kusters DM, Braamskamp M, Langslet G et al. Response by Kusters et al to Letter Regarding Article, "Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label)". Circulation 2018; 137:641-642. http://www.ncbi.nlm.nih.gov/pubmed/?term=29431667
  25. Koh KK. Letter by Koh Regarding Article, "Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label)". Circulation 2018; 137:639-640. http://www.ncbi.nlm.nih.gov/pubmed/?term=29431666
  26. Karunaratne K, Amiras D, Pickering MC et al. Autoimmune necrotising myopathy and HMGCR antibodies. Practical neurology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29439058
  27. Izurieta HS, Chillarige Y, Kelman JA et al. Statin use and risks of influenza-related outcomes among older adults receiving standard-dose or high-dose influenza vaccines through Medicare during 2010-2015. Clin Infect Dis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29438483
  28. Futatsugi A, Toshimoto K, Yoshikado T et al. Evaluation of alteration in hepatic and intestinal BCRP function in vivo due to ABCG2 c.421C>A polymorphism based on PBPK analysis of rosuvastatin. Drug metabolism and disposition: the biological fate of chemicals 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29440178
  29. Franklin JM, Gopalakrishnan C, Krumme AA et al. The relative benefits of claims and electronic health record data for predicting medication adherence trajectory. Am Heart J 2018; 197:153-162. http://www.ncbi.nlm.nih.gov/pubmed/?term=29447776
  30. Ekinci A, Koc S, Erdogan AS, Kesici H. Profilactic role of simvastatin and mitomycin C in tracheal stenosis after tracheal damage: Study in rats. International journal of pediatric otorhinolaryngology 2018; 105:79-84. http://www.ncbi.nlm.nih.gov/pubmed/?term=29447825

Miscellaneous publications
  1. Sekine Y, Nakayama H, Miyazawa Y et al. Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC-3 cells via an AKR1C3 mechanism. Oncology letters 2018; 15:3167-3172. http://www.ncbi.nlm.nih.gov/pubmed/?term=29435052
  2. Richter CP, Young H, Richter SV et al. Fluvastatin protects cochleae from damage by high-level noise. Scientific reports 2018; 8:3033. http://www.ncbi.nlm.nih.gov/pubmed/?term=29445111
  3. Pan S, Wu Z, Liu X et al. Simvastatin Ameliorates PAK4 Inhibitor-Induced Gut and Lung Injury. BioMed research international 2017; 2017:8314276. http://www.ncbi.nlm.nih.gov/pubmed/?term=29445744
  4. Li Y, Liu Q, Sun J et al. Mitochondrial protective mechanism of simvastatin protects against amyloid beta peptide-induced injury in SH-SY5Y cells. International journal of molecular medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29436584
  5. Jang YO, Kim SH, Cho MY et al. Synergistic effects of simvastatin and bone marrow-derived mesenchymal stem cells on hepatic fibrosis. Biochem Biophys Res Commun 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29428718
  6. Huai J, Yang Z, Yi YH, Wang GJ. Different Effects of Pravastatin on Preeclampsia-like Symptoms in Different Mouse Models. Chinese medical journal 2018; 131:461-470. http://www.ncbi.nlm.nih.gov/pubmed/?term=29451152
  7. Hu X, Song C, Fang M, Li C. Simvastatin inhibits the apoptosis of hippocampal cells in a mouse model of Alzheimer's disease. Experimental and therapeutic medicine 2018; 15:1795-1802. http://www.ncbi.nlm.nih.gov/pubmed/?term=29434767
  8. Honda K, Matoba T, Antoku Y et al. Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols. Arterioscler Thromb Vasc Biol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29449331
  9. Gottschall H, Schmoecker C, Hartmann D et al. Aspirin alone and combined with a statin suppresses eicosanoid formation in human colon tissue. Journal of lipid research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29444936
  10. De Wolf E, De Wolf C, Richardson A. ABT-737 and pictilisib synergistically enhance pitavastatin-induced apoptosis in ovarian cancer cells. Oncology letters 2018; 15:1979-1984. http://www.ncbi.nlm.nih.gov/pubmed/?term=29434898
  11. Chiorescu S, Andercou OA, Grad NO, Mironiuc IA. Intraperitoneal administration of rosuvastatin prevents postoperative peritoneal adhesions by decreasing the release of tumor necrosis factor. Clujul medical (1957) 2018; 91:79-84. http://www.ncbi.nlm.nih.gov/pubmed/?term=29440955
  12. Abdel-Daim MM, Abdeen A. Protective effects of rosuvastatin and vitamin E against fipronil-mediated oxidative damage and apoptosis in rat liver and kidney. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2018; 114:69-77. http://www.ncbi.nlm.nih.gov/pubmed/?term=29432839
  13. Zidan MF, Ibrahim HM, Afouna MI, Ibrahim EA. In vitro and in vivo evaluation of cyclodextrin-based nanosponges for enhancing oral bioavailability of atorvastatin calcium. Drug development and industrial pharmacy 2018:1-34. http://www.ncbi.nlm.nih.gov/pubmed/?term=29452493
  14. Castellanos-Esparza YC, Wu S, Huang L et al. Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells. International journal of oncology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29436616

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