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Update - Week 31, 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

Is a low dose atorvastatin on par with a high dose in Asians?
Are low dose high intensity statins just as protective and no need for higher dosages. In this study patients were randomized to atorvastatin 40-80 mg vs 20 mg. The 24 Chinese ACS / post PCI patients were followed for 9 months using OCT and lipoprotein + hs CRP measurement. Although both groups showed improved outcomes for all studied parameters including vulnerable plaque characteristics, patients allocated to the higher dosages of atorvastatin had significantly enhanced outcomes for all the studied parameters. The increase of the fibrous cap was more pronounced in the intensive-dose group vs the conventional-dose group 184.1±57.4 mm vs. 125.1± 28.6, P=.005). The lipid core arc was significantly decreased in both groups compared with baseline (72.9±29.3 vs. 127.6± 50.8, P<.01 and 74.6±32.9 vs. 132.6±51.3, P<.01, respectively). A inverse relationship between increased LDL-c plasma concentration and the thinnest fibrous cap as well as a direct correlation between hsCRP level and increased of the lipid core arc were observed as well. The, atorvastatin dose dependent, improvements of all studied parameters, is suggestive of the dual lipid lowering and anti-inflammatory effects of atorvastatin.
Ye H, Wang S, Hu Y et al. Therapeutic effects of different Atorvastatin doses on vulnerable plaques in coronary arteries assessed by intracoronary optical coherence tomography. Medicine (Baltimore) 2018; 97:e11718. http://www.ncbi.nlm.nih.gov/pubmed/?term=30075578
Low – lower - lowest is that right (or wrong)?
Should a patient with a low baseline LDL-c (< 70 mg/dl) be treated with lipid lowering drugs or is there no benefit or even harm to be expected?  To answer this question the authors of this study re-analyzed the Cholesterol Treatment Trialist Collaboration (CTT) data for statins and explored Medline databases for non-statin drugs (ezetimibe and PCSK9ab). Randomized double blind controlled CVD outcome trials of persons with LDL-c averaging 70 mg/dl, were included in this analysis. The risk ratio (RR) of major vascular events (a composite of coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization) per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was calculated. For both separate as well as the combined treatments approaches, the RR per 1 mmol/L of LDL-reductions were 0.78-0.79 with slightly different 95% CI’s; for statins:  0.65-0.94; the 3 non-statins trials: 0.70-0.88 and for the combined analysis: 0.71-0.87; P < .001. More importantly no increase of serious adverse events was observed in patients in whom LDL-c levels were reduced to very low levels, reaching sometimes LDL-c concentrations of 0.5 mmol/L (21mg/dL). These results re-affirm that reducing LDL-c to levels beyond what is dictated in current guidelines, continues to reduce CVD risk; updated guidelines are likely to incorporate these findings in upcoming releases.
Sabatine MS, Wiviott SD, Im K et al. Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels: A Meta-analysis. JAMA cardiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30073316
Diabetics, without CVD, remain healthier with lower LDL-c levels
In primary prevention the notion of achieving (very) low LDL-c is sometimes debated. For diabetic patients the impact of LDL-c levels on CVD risk is high-lighted in this retrospective Kaiser Permanente analysis (2006-2017) of 62 428 statin treated diabetic patients. Using a Cox multivariate data analyses to determine the HR’s for ASCVD events (myocardial infarction, ischemic stroke or coronary heart disease death. After a mean follow-up of 6 years, lower LDL-c or non-HDL-c levels consistently indicated a reduced CVD risk. A trend for LDL-c: p <0.0001 and for for non-HDL-c:  p <0.0001. When comparing achieved LDL-c levels of >130 mg/dl to <50 mg/dl a HR of 0.58 (0.49-0.69) was observed. Similar reductions for Non-HDL-c, of >160 vs < 80 mg/dl; HR 0.59 (0.51-0.68). Despite these optimistic findings, the challenge of reaching these lower targets remains formidable, a majority of patients included in meta-analyses of statin trials were unable to reach LDL-c levels of < 70 mg/dl (>60%). Convincing doctors as well as patients to actively pursue these lower LDL-c or Non HDL-c targets as standard diabetes management strategies, requires more efforts to reach and update/educate both.  
Rana JS, Liu JY, Moffet HH et al. Risk of Incident Atherosclerotic Cardiovascular Disease Events by Achieved Atherogenic Lipid Levels Among 62,428 Statin-Treated Individuals With Diabetes Mellitus. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30057224
RCT Study in Chinese CSDH patients, re-affirms benefits of atorvastatin
The CVD benefits of (atorva)statin for post ischemic stroke patients has been substantiated in the SPARCL trial. The benefits (or harms) associated with a potential for increased bleeding risk remain controversial. Despite the increase of hemorrhagic strokes in the SPRACL study, accumulation observational studies show benefits of (atorva)statin in patients at risk for cerebral hemorrhagic complications. In this the Effect of Atorvastatin on Chronic Subdural Hematoma (ATOCH) study the use of atorvastatin showed improved outcomes as well This was a randomized, placebo-controlled, double-blind phase II clinical trial conducted in multiple centers in China from February 2014 to November 2015. The investigators invited 254 patients with Chronic Subdural Hematoma (CSDH), diagnosed with a CT scan; of these, 200 (78.7%) were enrolled in the trial. Patients were randomized to atorvastatin 20 mg or placebo for 8 weeks and followed for an additional 16 weeks. The primary outcome: change in hematoma volume (HV) measured (CT scan) after 8 weeks of treatment. The secondary outcomes were HV at 4th, 12th, and 24th weeks as well as neurological function that was evaluated using the Markwalder grading scale/Glasgow Coma Scale and the Barthel Index at 8th weeks. Baseline HV measurements were comparable between the two treatment arms. At 8 weeks HV reduction in the statin users (n=98) improved significantly (-12.55 mL) compared to the placebo group (N=98); -12,55 mL (-0.9 - -23.9 mL; p= 0.003). Neurological tests improved in 45 45.9%) statins users vs 28 (28.6%) of the placebo group, this translated into an OR of 1.957 (1.07-3.58; P=0.03) for neurological improvements associated with atorvastatin use. Post event complications, surgery for enlarging of hematoma or deteriorating clinical conditions were more frequent in the no statin users as well 11 (11.2%) vs 23 (23.5%); HR 0.47 (0.24-0.92; p=0.03). Patients using atorvastatin 20 mg for 8 weeks did not report an increased number of adverse events. The authors suggest that atorvastatin reduces hematomas, primarily by suppressing local Inflammation and reducing inflammation-induced vascular leakage as well as promoting angiogenesis. Atorvastatin could thus prevent the formation as well as accelerate the absorption of hematomas and quicken neurological improvements in CSDH patients. Using statins as an alternative to surgical management of CSDH patients, warrants a larger properly designed randomized placebo-controlled trial.
Jiang R, Zhao S, Wang R et al. Safety and Efficacy of Atorvastatin for Chronic Subdural Hematoma in Chinese Patients: A Randomized ClinicalTrial. JAMA neurology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30073290
Heightened awareness needed for statin associated necrotizing myositis
Insights into the nature of the elusive statin associated myopathy is examined with the Australian Myositis Databases. Although most of reported the muscle related problems are benign and resolve when statins are stopped, Immune mediated idiopathic inflammatory myositis (IIM) and more specifically, the auto-antibody mediated necrotizing myositis is a serious complication, necessitating immunosuppressant medication for prolonged periods. Using a population-based case-control design of data collected in the South Australian Myositis database of histological confirmed cases of IIm diagnosed between 1990 – 2014 (N=221) and population-based controls form the North West Adelaide Health Study (N=662), matched by age and sex in a 3:1 ratio. The mean age of IIm cases was 62,2 and 59.7% were female. Statins were used by 68 (30.8%) of the IIM cases and 142 (21.5%) of the controls P=0.005). The likelihood of statin use in IIM patients was double the rate of what was observed in the control group. This resulted in an adjusted odds ratio, 1.79 (1.23-2.60; P = .001). When patients with necrotizing myositis were compared to controls an adjusted odds ratio of 1.92 (1.29-2.86; P = 0.001) was observed. Based on this analysis statin exposure significantly increased the risk of histologically established IIM. The wide spread use of statins warrants alertness and recognition of this rare adverse event associated with statin exposure.
Caughey GE, Gabb GM, Ronson S et al. Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population. JAMA Intern Med 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30073275
Curfman G. Statin-Associated Myopathy-An Elusive Clinical Problem. JAMA Intern Med 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30073289
Relevant publications
  1. Teramoto T, Usami M, Takagi Y, Baccara-Dinet MT. Efficacy and Safety of Alirocumab in Japanese Patients with Diabetes Mellitus: Post-hoc Subanalysis of ODYSSEY Japan. J Atheroscler Thromb 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30068817
  2. Singh A, Davidson M. Update on PCSK9 therapies for the treatment of dyslipidemia. Expert review of endocrinology & metabolism 2016; 11:87-95. http://www.ncbi.nlm.nih.gov/pubmed/?term=30063452
  3. Rymer JA, Newby LK. Failure to Launch: Targeting Inflammation in Acute Coronary Syndromes. JACC. Basic to translational science 2017; 2:484-497. http://www.ncbi.nlm.nih.gov/pubmed/?term=30062164
  4. Rodriguez F, Knowles JW, Maron DJ et al. Frequency of Statin Use in Patients With Low-Density Lipoprotein Cholesterol >/=190 mg/dl from the Veterans Affairs Health System. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30055758
  5. Reynolds AL, Del Monte MA, Archer SM. The effect of oral statin therapy on strabismus in patients with thyroid eye disease. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30075294
  6. Pose E, Trebicka J, Mookerjee RP et al. Statins: old drugs as new therapy for liver diseases? J Hepatol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30075229
  7. Mefford MT, Tajeu GS, Tanner RM et al. Willingness to be Reinitiated on a Statin (from the REasons for Geographic and Racial Differences in Stroke Study). Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30057227
  8. Kosmeri C, Siomou E, Vlahos AP, Milionis H. Review shows that lipid disorders are associated with endothelial but not renal dysfunction in children. Acta paediatrica (Oslo, Norway : 1992) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30066344
  9. Harrison TN, Scott RD, Cheetham TC et al. Trends in Statin Use 2009-2015 in a Large Integrated Health System: Pre- and Post-2013 ACC/AHA Guideline on Treatment of Blood Cholesterol. Cardiovasc Drugs Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30062465
  10. Hackam DG, Vyas MV. Utilization of Vasculoprotective Therapy for Peripheral Artery Disease: A Systematic Review and Meta-analysis. Am J Med 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30056102
  11. Cybulska B, Klosiewicz-Latoszek L. How do we know that statins are diabetogenic and why? Is it an important issue in the clinical practice? Kardiol Pol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30067279
  12. Cho L, Dent R, Stroes ESG et al. Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies. Cardiovasc Drugs Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30073585
  13. Chandra Ghosh G, Bandyopadhyay D, Ghosh RK et al. Effectiveness and Safety of Inclisiran, A Novel Long-Acting RNA Therapeutic Inhibitor of Proprotein Convertase Subtilisin/Kexin 9. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30075894
  14. Bagheri B, Alikhani A, Mokhtari H, Rasouli M. Esterification of HDL-cholesterol is Decreased in Diabetes Mellitus and CAD and Enhanced Following Treatment with Statins. Medical archives (Sarajevo, Bosnia and Herzegovina) 2018; 72:197-201. http://www.ncbi.nlm.nih.gov/pubmed/?term=30061766
  15. von Buedingen F, Hammer MS, Meid AD et al. Changes in prescribed medicines in older patients with multimorbidity and polypharmacy in general practice. BMC family practice 2018; 19:131. http://www.ncbi.nlm.nih.gov/pubmed/?term=30055583
  16. Urpilainen E, Marttila M, Hautakoski A et al. Prognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins: a retrospective cohort study. BMC Cancer 2018; 18:767. http://www.ncbi.nlm.nih.gov/pubmed/?term=30055585
  17. Shih HJ, Tsai PS, Wen YC et al. Hyperlipidemia patients with long-term statin treatment are associated with a reduced risk of progression of benign prostatic enlargement. The aging male : the official journal of the International Society for the Study of the Aging Male 2018:1-8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30058422
  18. Nikolic Turnic TR, Jakovljevic VP, Djuric D et al. EFFICENCY OF ATORVASTATIN AND SIMVASTATIN IN IMPROVING OF CARDIAC FUNCTION DURING THE DIFFERENT DEGREE OF HYPERHOMOCYSTEINEMIA. Canadian journal of physiology and pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30067069
  19. Moriarty F, Bennett K, Fahey T. Fixed-dose combination antihypertensives and risk of medication errors. Heart 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30072364
  20. Dougherty JA. Atorvastatin-Associated Macroglossia in a Cardioembolic Stroke Patient. The Annals of pharmacotherapy 2018:1060028018793111. http://www.ncbi.nlm.nih.gov/pubmed/?term=30058342
  21. Chen Z, Xiang Y, Bao B et al. Simvastatin improves cerebrovascular injury caused by ischemiareperfusion through NFkappaBmediated apoptosis via MyD88/TRIF signaling. Mol Med Rep 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30066928
  22. Chen M, Ji M, Si X. The effects of statin therapy on mortality in patients with sepsis: A meta-analysis of randomized trials. Medicine (Baltimore) 2018; 97:e11578. http://www.ncbi.nlm.nih.gov/pubmed/?term=30075526
Miscellaneous publications
  1. Zhang X, Xiao S, Li Q. Pravastatin polarizes the phenotype of macrophages toward M2 and elevates serum cholesterol levels in apolipoprotein E knockout mice. J Int Med Res 2018:300060518787671. http://www.ncbi.nlm.nih.gov/pubmed/?term=30058421
  2. Wang HM, Gao JH, Lu JL. Pravastatin improves atherosclerosis in mice with hyp aerlipidemia by inhibiting TREM-1/DAP12. Eur Rev Med Pharmacol Sci 2018; 22:4995-5003. http://www.ncbi.nlm.nih.gov/pubmed/?term=30070336
  3. Ren J, Liu W, Li GC et al. Atorvastatin Attenuates Myocardial Hypertrophy Induced by Chronic Intermittent Hypoxia In Vitro Partly through miR-31/PKCepsilon Pathway. Current medical science 2018; 38:405-412. http://www.ncbi.nlm.nih.gov/pubmed/?term=30074205
  4. Huang J, Lin C, Fang J et al. The pH-sensitive nanocarrier mediated codelivery of simvastatin and noggin siRNA for synergistic enhancement of osteogenesis. ACS applied materials & interfaces 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30067011
  5. Dworacka M, Iskakova S, Wesolowska A et al. Simvastatin attenuates the aberrant expression of angiogenic factors induced by glucose variability. Diabetes Res Clin Pract 2018; 143:245-253. http://www.ncbi.nlm.nih.gov/pubmed/?term=30056191
  6. Choi NY, Kim JY, Hwang M et al. Atorvastatin Rejuvenates Neural Stem Cells Injured by Oxygen-Glucose Deprivation and Induces Neuronal Differentiation Through Activating the PI3K/Akt and ERK Pathways. Mol Neurobiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30073508
  7. Pohlen M, Pirker L, Lustrik M, Dreu R. A redispersible dry emulsion system with simvastatin prepared via fluid bed layering as a means of dissolution enhancement of a lipophilic drug. Int J Pharm 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30075251
  8. Moid M, Afzal S, Rahim N et al. High performance liquid chromatographic method validation for determination of rosuvastatin calcium in tablet dosage forms. Pak J Pharm Sci 2018; 31:1577-1582. http://www.ncbi.nlm.nih.gov/pubmed/?term=30058551
  9. Mathur M, Vemula KD. Investigation of different types of nano drug delivery systems of Atorvastatin for the treatment of Hyperlipidemia. Drug development and industrial pharmacy 2018:1-36. http://www.ncbi.nlm.nih.gov/pubmed/?term=30073852
  10. Kamal S, Akhter N, Khan SG et al. Enhanced production of Lovastatin by filamentous fungi through solid state fermentation. Pak J Pharm Sci 2018; 31:1583-1589. http://www.ncbi.nlm.nih.gov/pubmed/?term=30058552
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