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Update - Week 36,  2017 
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

Twenty-year follow-up data of WOSCOP study show long term benefits
The WOSCOP investigators published their first results in 1997. The original cohort consisted of 6 595 men free of CVD, aged 45-64 years that were randomized to Pravastatin 40 mg vs placebo and clearly showed the benefits of Pravastatin 40 mg in this very high-risk male Scottish Population. In this follow up study selection of participants with an LDL cholesterol >190 mg/dl (N=2560) or <190mg/dl (N=2969) was evaluated. The mean LDL-c levels in both cohorts were 178±6 mg/dL and 206±12 mg/dL, respectively. Analyzing the data right after study completion CHD events and MACE were reduced by 27% (p=0.002) and 25% (p=0.004) respectively in all participants. For the participants with LDL-c >190 mg/dl these reductions amounted to a CHD event reduction of 27% (p=0.033) and a lower MACE incidence of 25% (p=0.037) during the initial trial phase. CHD deaths, cardiovascular deaths and all-cause mortality were reduced by 28% (p=0.020), 25% (p=0.009) and 18% (p=0.004), respectively over a total of 20 year follow up period. The authors concluded that this analysis provided robust evidence of the benefits on short term as well as long term use of Pravastatin in a cohort Scottish males with an LDL-C > 190 mg/dl. 
Vallejo-Vaz AJ, Robertson M, Catapano AL et al. LDL-Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men with Primary Elevations of LDL-Cholesterol Levels of 190 mg/dL or Above: Analyses from the WOSCOPS 5-year Randomised Trial and 20-year Observational Follow-Up. Circulation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28877913
Should patients with viral or alcohol related chronic liver disease start using statins?
In this week of the statin literature update two articles discussing the benefits and safety of statins in patients with advanced liver disease. An analysis of patients with alcohol related liver cirrhosis using a combination of the well-recognized Danish population registries (1995-2014). The second article a meta-analysis, evaluating the effects of statins on the risk of virus-related cirrhosis. The authors of the latter article combined data from 10 published observational studies up until May 7th, 2017; comprising 12 445 patients (8 cohort studies, n = 12,1823; 1 nested case-control, n = 1350; and 1 abstract, n = 272). In patients with virus related chromic liver disease, there was a significant 51% lower risk of developing virus-related cirrhosis; RR: 0.49 (0.30-0.80; P=0.004) and a comparable 51% reduced incidence of decompensation; RR: 0.49 (0.41-0.59; P<0.001). In the Danish analysis of alcohol linked cirrhosis, almost 25 000 patients were included and 5417 deemed suitable for matching. Statins were used in 15% of the cohort of those 744 were included in the matched group. The number of reported deaths: 88 (73-105) per 1000 years for statin users and 127 (114-141) for non-statin patients. This resulted in a HR of 0.57 (0.45-0.71). Patients with a more constant statin use exhibited an increased benefit; patients with cirrhotic manifestations showed a superior survival compared to the patients without. Both studies showed statin use was related to improved outcome in patients suffering from serious, and often fatal, complications of chronic liver disease either due to a viral infection or chronic alcohol abuse. In both analyses the data was based on retrospective registry data so that selection bias cannot be excluded. Despite the observed benefits more robust clinical trial data is needed to confirm the observations that statins should be recommended in patients with hepatic viral infections or chronic alcohol abuse.
Ma X, Sun D, Li C et al. Statin use and virus-related cirrhosis: A systemic review and meta-analysis. Clin Res Hepatol Gastroenterol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28866088
Bang UC, Benfield T, Bendtsen F. Reduced risk of decompensation and death associated with use of statins in patients with alcoholic cirrhosis. A nationwide case-cohort study. Alimentary pharmacology & therapeutics 2017; 46:673-680. http://www.ncbi.nlm.nih.gov/pubmed/?term=28880449
Korean algorithm for early detection of hepatotoxicity or ALT/AP increase in Statin users
The role of statin in liver disease has changed over the last 5-10 years with more studies, although most based on observational data, showing hepatic benefits and protection. The frequently observed rise in transaminases is considered not an expression of hepatic toxicity but altered liver metabolism. The Korean authors of this article are slightly more apprehensive and reflect on the Korean guideline recommendations to stop statins if transaminases reach a plasma level >3x ULN. Using available patient data from a single large hospital they developed a clinical algorithm, using electronic medical records (EMR) to detect patients were statins showed potential harm. Direct chart reviews were used to validate their electronically gathered data. This included laboratory information, underlying disease, diagnosis information, prescription information, and concomitant drugs. By using ALT and AP levels, patients were assigned the following status: adverse drug reaction(ADR)-free, little association, strong association, and weak association or indeterminable. Of the 9 241 patients included 126 (1.4%) were classified as a possible ADR event. Of these 33 patients were not using statins, this resulted in a ADR rate of 1% (93/9 241). No statistical differences between statins were noted, although fluvastatin showed a trend towards a higher incidence rate of ADR.  Based on the Korean recommendations this algorithm detects patients with ALT/AP increased related to statin use and, after chart review, patients with concomitant liver diseases e.g. viral causes and using medications that have (some) hepatotoxicity are excluded. It remains unclear in this review what the impact is on factual liver disease of the patients detected using their algorithm. The question if statins cause for liver damage beyond the infrequent case reports remains unanswered.  
Hong JY, Kim HS, Choi IY. Pilot Algorithm Designed to Help Early Detection of HMG-CoA Reductase Inhibitor-Induced Hepatotoxicity. Healthcare informatics research 2017; 23:199-207. http://www.ncbi.nlm.nih.gov/pubmed/?term=28875055
After a statin what is next?
The AHA/ACC guidelines were released in November 2016 and created some confusion due to the lack of treatment targets and the absence of “add on” LDL-c lowering recommendations. The April 2016 ACC expert consensus decision pathway (ECDP) addressed these issues, based on the just published trial data from the IMPROVE-IT study showing the benefits of ezetimibe as an addition to statin treatment. In this recent ECDP release data from the FOURIER and SPIRE I+II trials are added as well. Some revisions have been made for patients with ASCVD manifestations, with or without comorbidities on statin therapy. No changes in the decision algorithm for ezetimibe or PCSK9ab in a primary prevention setting have been added. Recommendations for bile-acid sequestrants were downgraded to an “optiona”l choice for patients intolerant for ezetimibe. Diagnostic clinical criteria (with or without genetic testing) for FH (heterozygous and homozygous) have been fine tuned as well. As to provide consistent guidance to healthcare professionals, most of the content of the original publication was kept intact. Based on these latest recommendations clinicians should be able to make well founded decisions on which add-on LDL-C lowering therapeutic regimen to use in their (very) high risk ASCVD patients.
Lloyd-Jones DM, Morris PB, Ballantyne CM et al. 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28886926
Relevant publications
  1. Acena A, Martin-Mariscal ML, Tarin N et al. Comparison of 3 Predictive Clinical Risk Scores in 603 Patients with Stable Coronary Artery Disease. Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 2017; 44:239-244. http://www.ncbi.nlm.nih.gov/pubmed/?term=28878576
  2. Tvaryanas AP, Wagner JH, Maupin GM, Schroeder VM. Statins and Musculoskeletal Conditions in U.S. Air Force Active Duty Service Members. Military medicine 2017; 182:e1938-e1945. http://www.ncbi.nlm.nih.gov/pubmed/?term=28885959
  3. Jansen ME, Rigter T, Rodenburg W et al. Review of the Reported Measures of Clinical Validity and Clinical Utility as Arguments for the Implementation of Pharmacogenetic Testing: A Case Study of Statin-Induced Muscle Toxicity. Frontiers in pharmacology 2017; 8:555. http://www.ncbi.nlm.nih.gov/pubmed/?term=28878673
  4. Purga SL, Sidhu M, Farkouh M, Schulman-Marcus J. Recent Insights into Pharmacologic Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus. Cardiovasc Drugs Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28871349
  5. Kim SM, Ko HK, Noh M et al. Factors Affecting Patency Following Successful Percutaneous Intervention for Dysfunctional Hemodialysis Vascular Access. Annals of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28887254
  6. Chun KH, Im E, Kim BK et al. Incidence, Predictors, and Clinical Outcomes of New-Onset Diabetes Mellitus after Percutaneous Coronary Intervention with Drug-Eluting Stent. J Korean Med Sci 2017; 32:1603-1609. http://www.ncbi.nlm.nih.gov/pubmed/?term=28875603
  7. Cariou B, Guerin P, Le May C et al. Circulating PCSK9 levels in acute coronary syndrome: Results from the PC-SCA-9 prospective study. Diabetes Metab 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28865748
  8. Wojcik C. Incorporation of PCSK9 inhibitors into prevention of atherosclerotic cardiovascular disease. Postgraduate medicine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28879791
  9. Wium-Andersen IK, Wium-Andersen MK, Jorgensen MB, Osler M. Anti-inflammatory treatment and risk of depression in 91,842 patients with acute coronary syndrome and 91,860 individuals without acute coronary syndrome in Denmark. Int J Cardiol 2017; 246:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28867006
  10. Polychronopoulos G, Tziomalos K. Novel treatment options for the management of heterozygous familial hypercholesterolemia. Expert Rev Clin Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28884604
  11. Noronha Oliveira M, Rau LH, Marodin A et al. Ridge Preservation After Maxillary Third Molar Extraction Using 30% Porosity PLGA/HA/beta-TCP Scaffolds With and Without Simvastatin: A Pilot Randomized Controlled Clinical Trial. Implant dentistry 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28885317
  12. Miyoshi T, Kohno K, Asonuma H et al. Effect of Intensive and Standard Pitavastatin Treatment With or Without Eicosapentaenoic Acid on Progression of Coronary Artery Calcification Over 12 Months- Prospective Multicenter Study. Circulation journal : official journal of the Japanese Circulation Society 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28867681
  13. Joo MK, Park JJ, Chun HJ. Additional Benefits of Routine Drugs on Gastrointestinal Cancer: Statins, Metformin, and Proton Pump Inhibitors. Dig Dis 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28881340
  14. Honda S, Sidharta SL, Shishikura D et al. High-density lipoprotein cholesterol associated with change in coronary plaque lipid burden assessed by near infrared spectroscopy. Atherosclerosis 2017; 265:110-116. http://www.ncbi.nlm.nih.gov/pubmed/?term=28881268
  15. Freitas Gouveia M, Trueb RM. Unsuccessful Treatment of Alopecia Areata with Simvastatin/Ezetimibe: Experience in 12 Patients. Skin appendage disorders 2017; 3:156-160. http://www.ncbi.nlm.nih.gov/pubmed/?term=28879192
  16. Ambrosio LMB, Rovai ES, Sendyk DI et al. Does the adjunctive use of statins provide additional benefits to nonsurgical periodontal treatment? A systematic review and meta-analysis. Journal of periodontal research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28872188
  17. Adua E, Roberts P, Sakyi SA et al. Profiling of cardio-metabolic risk factors and medication utilisation among Type II diabetes patients in Ghana: a prospective cohort study. Clinical and translational medicine 2017; 6:32. http://www.ncbi.nlm.nih.gov/pubmed/?term=28879491  
Miscellaneous publications
  1. Villarino N, Signaevskaia L, van Niekerk J et al. A screen for inducers of bHLH activity identifies pitavastatin as a regulator of p21, Rb phosphorylation and E2F target gene expression in pancreatic cancer. Oncotarget 2017; 8:53154-53167. http://www.ncbi.nlm.nih.gov/pubmed/?term=28881801
  2. Tanskanen A, Taipale H, Koponen M et al. Drug exposure in register-based research-An expert-opinion based evaluation of methods. PLoS One 2017; 12:e0184070. http://www.ncbi.nlm.nih.gov/pubmed/?term=28886089
  3. Swerts AA, Santos BFE, Bruzadelli SR et al. Treatment of experimental periodontal disease by laser therapy in simvastatin-modified rats. Journal of applied oral science : revista FOB 2017; 25:387-395. http://www.ncbi.nlm.nih.gov/pubmed/?term=28877277
  4. Simakova MN, Bisen S, Dopico AM, Bukiya AN. Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle. Biochem Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28865873
  5. Marques Dos Santos CH, Dourado DM, Kato da Silva BA et al. Atorvastatin Protect Kidney From Remote Reperfusion Injury. Annals of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28887239
  6. Leite GAA, Figueiredo TM, Pacheco TL et al. Vitamin C partially prevents reproductive damage in adult male rats exposed to rosuvastatin during prepuberty. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28887090
  7. Kim MH, Kim CE, Kim SW. Rosuvastatin inhibits high glucose-stimulated upregulation of VCAM-1 via the MAPK-signalling pathway in endothelial cells. Acta Cardiol 2017:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28885098
  8. Guirao V, Marti-Sistac O, DeGregorio-Rocasolano N et al. Specific rescue by ortho-hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB. Journal of neurochemistry 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28881028
  9. Atilano-Roque A, Joy MS. Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction. Toxicology in vitro : an international journal published in association with BIBRA 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28887287
  10. Maslanka A, Stolarczyk M, Apola A et al. Simultaneous Determination of Acetylsalicylic Acid, Hydrochlorothiazide, Enalapril, and Atorvastatin in a Polypill-Based Quaternary Mixture by TLC. J AOAC Int 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28882196
  11. Magan-Fernandez A, Fernandez-Barbero JE, F OV et al. Simvastatin exerts antiproliferative and differentiating effects on MG63 osteoblast-like cells: Morphological and immunocytochemical study. Journal of periodontal research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28868611
  12. Heringer de Souza F, Todeschini V, Sangoi MDS. Chemometric-Assisted Spectrophotometric Method for the Simultaneous Quantitative Determination of Ezetimibe and Simvastatin in Their Combined Dosage Forms. J AOAC Int 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28877782
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