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Update - Week 30,  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

Avoid highest dosage of (rosuva)statin in Chinese and Japanese patients
Do Asians respond differently to statins? An important question remains still unanswered after statins were first introduced exactly 30 years ago. In this letter to the editors the authors, based in Hong Kong, China and Taiwan, try to de-mystify this blind spot that is relevant for > 25% of the world population. Their discussion focusses on the pharmaco kinetics of rosuvastatin dosing and the differences in genetic back ground of Asians vs Caucasians. Polymorphisms in genes of the organic anion-transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) liver uptake transporter and the adenosine triphosphate (ATP)-binding cassette G2 (ABCG2) intestinal and liver efflux transporter play a significant role in statin pharmacokinetics. The ABCG2 SNP’s have shown to influence the LDL-C lowering effects of rosuvastatin in the Jupiter trial. The SNP’s associated with c.421C>A variant at rs 1481012 in ABCG2 showed an LDL-C reduction of 50.4%, 55% and 62.3% when respectively 0, 1 and 2 copies were present. This is the equivalent of doubling the dose or Rosuvastatin for each copy of the variant. The frequency of this variant is similar in in Chinese 28.9-29.3%) and Japanese (31.1-34.3%) and much higher compared to Caucasians (11.1-11.7%) and Indians (6.2%). The authors note that other genetic and or phenotypic factors affect the ethnic differences in rosuvastatin pharmacokinetics. The lower LDL-C in East Asians could be a reflection of reduced ABCG2 activity which in turn also causes increased rosuvastatin plasma concentrations. Avoiding the highest dose of statins, particular Rosuvastatin is recommended until better studies can provide a more detailed analysis on the causes of these ethnic differences.
Tomlinson B, Chan P, Liu ZM. Statin Responses in Chinese Patients. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28740057
 
If LDL-C is low, is there a better target for determining and reducing CVD risk
What lipid fractions or lipid related pathways detriment CVD risk when risk LDL-C is low (< 130 mg/dl)? In this study, using participants in the JUPTER study and CATHGEN study, CVD risk was determined using lipoprotein analysis of LDL and VLD particles as well as Apo B, non-HDL cholesterol and triglycerides. In patients allocated placebo in Jupiter CVD risk was associated with LDL (1.19 [1.02-1.38]) and VLDL (1.21 [1.04, 1.41]) Particles, as well as Apo B, non-HDL-C and triglycerides, but not LDL-C in the Jupiter study, participants were selected for this trial if LDL-C <130 mg/dl and hsCRP> 2 mg/dl. The uses of 20 mg Rosuvastatin reduced LDL-C but had variable effect on triglycerides and VLDL measures. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, the major impact on residual CVD risk increase (68% per SD (HR 1.68[128-2.22] was observed in the smallest VLDL subclasses. This was related to the VLDL cholesterol and not triglycerides or larger VLDL particles. These results were confirmed in independent prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN). The Authors concluded that in individuals    with low LDL-C the smallest subclasses of VLDL lipoproteins might be an attractive target for risk prediction as a well as therapeutic strategies to reduce residual risk.
Lawler PR, Akinkuolie AO, Chu AY et al. Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low-Density Lipoprotein Cholesterol. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28733430
 
How does negative media attention affect statin adherence?
The impact media attention on patients attitude and believes regarding medical treatment choices is the theme of this analysis. The effects of negative attention on statin adherence was studied in a Danish population where a tabloid newspaper “BT” published an article highlighting the side effects of satins on July 23, 2008. Statin discontinuations in all statin users in 2007 were compared to statin discontinuations after the article. Before the publication in 2007  343 438 Danish patients were treated with a statin, in 2008, 404 052 patients. Comparing 2007 with 2008 there was a 2.97 % percentage point (pp) increase in statin discontinuations. This increase was smallest in patients with a history of MI, 1.98 pp. In patients with high cholesterol or hypertension the pp changes were the largest 3.54. Patients that started a statin showed a higher discontinuation in 2008, 5.5 pp. the differences in MI patients (1.49 pp) was much smaller vs patients with potential atherosclerosis (7.05 pp) and hypercholesterolemia or primary hypertension patients (6.1 pp). The authors concluded that risk of statin discontinuation, after negative media attention, is greatest in new statin users and patients without CVD.
Kriegbaum M, Liisberg KB, Wallach-Kildemoes H. Pattern of statin use changes following media coverage of its side effects. Patient preference and adherence 2017; 11:1151-1157. http://www.ncbi.nlm.nih.gov/pubmed/?term=28744105
 
Is atorvastatin 20 mg sufficient to prevent CI-AKI Chinese patients
The risk of contrast induced acute kidney injury (CI-AKI) can be reduced by pre-procedural use of atorvastatin. In this Chinese prospective non-randomized study, the aim was to compare the benefits of using 40 mg (n=334) vs 20 mg (n=985), 1-3 days before the procedure until 2-3 days after the procedure. Primary endpoint was CI-AKDI, secondary endpoints were renal, cardiac complications and death. Patients were re-evaluated after 1, 6, 12 and 24 months. The mean follow-up time was 2.52±0.85 years (1.84-3.24). Overall 76 patients (5.8%) developed CI-AKI). Atorvastatin 40 mg had no significant impact on a additional risk reduction OR:2.28 (0.92-5.62; P=4.24). Effects on mortality were equal in the two dosage arms as well HR: 0.47 (0.10-2.18; p=0.339). The authors compared patients with the highest tertile of hsCRP with the lowest and again no significant difference could be discerned. There was an increased risk of CI-AKI in patients on atorvastatin 40 mg + creatinine clearance <60ml/min, anemia, contrast volume >200 ml and >2 stents (p=0.046, 0.009, 0.024, and 0.026 respectively). There was no CI-AKI benefit observed in Chinese patients using 40 mg vs 20 mg of Atorvastatin and even an increased risk if patients were at higher risk due to reduced renal function or high contrast volume. Generalizability of this results need careful consideration. All participants were of Chinese/Asian ethnic background and this study was not randomized. Choice of dosage was at the discretion the physician, resulting in only 1:3 patients receiving atorvastatin 40mg.  
Bei WJ, Chen SQ, Li HL et al. Comparing common doses (double-dose vs usual-dose) of atorvastatin for preventing contrast-induced acute kidney injury and mortality after coronary angiography. Medicine (Baltimore) 2017; 96:e7501. http://www.ncbi.nlm.nih.gov/pubmed/?term=28746193
 
Is alternate day dosing a viable alternative for SAMS patients?
For patients that are suffering from statin associated muscle symptoms (SAMS), alternate day dosing could be an attractive therapeutic option. The authors conducted a meta-analysis of RCT’s to evaluate safety and efficacy of such lipid corrective regimens. computerized literature search of PubMed, SCOPUS, Web of Science, and Embase was conducted from inception until January 2, 2017. The meta-analysis was designed using the preferred reporting items for systematic reviews and meta-analyses (PRISMA), and in accordance with the “Cochrane handbook for systematic reviews interventions”. The primary endpoints were reductions in LDL-C, TC and TG’s. Secondary endpoints: adverse events and adherence. Twelve RCT’s and 1 quasi-RCT (n=1023) were included in the analysis, with a treatment duration of 6-24 weeks. No significant differences were discernable between daily and alternate day dosing of atorvastatin and rosuvastatin for the primary endpoints: LDL-C and TG. Mean difference (MD) 6.79 mg/dL (-1.59-15.17; p = 0.11) and 10.51 mg/dL( −0.23-21.26; p = 0.06), respectively. For total cholesterol, daily dosing of atorvastatin and rosuvastatin were superior compared to alternate day dosing. Mean difference 12.45 mg/dL (8.14-16.76; p < 0.00001) and 15.80 mg/dL (5.66-25.95; p = 0.002) respectively. The authors concluded that alternate day dosing of atorvastatin and rosuvastatin is efficacious and compares favorably with a daily dosing regimen, making this a reasonable treatment option for patients with statin intolerance.  However larger well designed RCT’s are recommend confirming and extending the findings of this relatively small and limited meta-analysis.
Awad K, Mikhailidis DP, Toth PP et al. Efficacy and Safety of Alternate-Day Versus Daily Dosing of Statins: a Systematic Review and Meta-Analysis. Cardiovasc Drugs Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28741244
Relevant Publications
  1. Nissen SE. Statin Denial: An Internet-Driven Cult With Deadly Consequences. Annals of internal medicine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28738422
  2. Zheng F, Guo Y, Krischek B. Statin Use in Patients with Aneurysmal Subarachnoid Hemorrhage May not Significantly Reduce the Occurrence of Delayed Ischemic Neurological Deficit. World neurosurgery 2017; 104:1032-1033. http://www.ncbi.nlm.nih.gov/pubmed/?term=28732423
  3. Serban MC, Muntner P, Rosenson RS. Reply: Statin Intolerance and Risk for Recurrent Myocardial Infarction, Coronary Heart Disease Events, and All-Cause Mortality. J Am Coll Cardiol 2017; 70:685-686. http://www.ncbi.nlm.nih.gov/pubmed/?term=28750708
  4. Tentzeris I, Farhan S, Freynhofer MK et al. Usefulness of Elevated Levels of Growth Differentiation Factor-15 to Classify Patients With Acute Coronary Syndrome Having Percutaneous Coronary Intervention Who Would Benefit from High-Dose Statin Therapy. Am J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28734463
  5. Parkin L, Sharples KJ, Barson DJ, Blank ML. Simvastatin dose and acute kidney injury without concurrent serious muscle injury: A nationwide nested case-control study. PLoS One 2017; 12:e0182066. http://www.ncbi.nlm.nih.gov/pubmed/?term=28753656
  6. Mascitelli L, Goldstein MR. Statin Intolerance and the Obsession With Aggressive Cholesterol Lowering to Prevent Coronary Heart Disease. J Am Coll Cardiol 2017; 70:684. http://www.ncbi.nlm.nih.gov/pubmed/?term=28750707
  7. Gulizia MM, Colivicchi F, Arca M et al. ANMCO Position Paper: diagnostic-therapeutic pathway in patients with hypercholesterolaemia and statin intolerance. European heart journal supplements : journal of the European Society of Cardiology 2017; 19:D55-d63. http://www.ncbi.nlm.nih.gov/pubmed/?term=28751834
  8. Sharma N, Cooper R, Kuh D. Associations of statin use with motor performance and myalgia may be modified by 25-hydroxyvitamin D: findings from a British birth cohort. Scientific reports 2017; 7:6578. http://www.ncbi.nlm.nih.gov/pubmed/?term=28747665
  9. Raebel MA, Dyer W, Nichols GA et al. Relationships Between Medication Adherence and Cardiovascular Disease Risk Factor Control in Elderly Patients With Diabetes. Pharmacotherapy 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28752555
  10. Peng D, Fong A, Pelt AV. Original Research: The Effects of Red Yeast Rice Supplementation on Cholesterol Levels in Adults. The American journal of nursing 2017; 117:46-54. http://www.ncbi.nlm.nih.gov/pubmed/?term=28749884
  11. Page MM, Watts GF. PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease. Diabetes Obes Metab 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28736830
  12. Jetty V, Glueck CJ, Lee K et al. Eligibility for alirocumab or evolocumab treatment in 1090 hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol >/=70 mg/dL despite maximal-tolerated LDL-cholesterol-lowering therapy. Vasc Health Risk Manag 2017; 13:247-253. http://www.ncbi.nlm.nih.gov/pubmed/?term=28740397
  13. Huesch MD. Commercial Online Social Network Data and Statin Side-Effect Surveillance: A Pilot Observational Study of Aggregate Mentions on Facebook. Drug Saf 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28748367
  14. Ennezat PV, Guerbaai RA. Real Clinical Significance of Statin Cessation After Adjustment for Smoking Persistence and Antiplatelet Treatment Discontinuation. J Am Coll Cardiol 2017; 70:684-685. http://www.ncbi.nlm.nih.gov/pubmed/?term=28750706
  15. El Shahawy M, Cannon CP, Blom DJ et al. Efficacy and Safety of Alirocumab Versus Ezetimibe Over 2 Years (from ODYSSEY COMBO II). Am J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28750828
  16. Dixon DL, Buckley LF, Trankle CR et al. Clinical utility of evolocumab in the management of hyperlipidemia: patient selection and follow-up. Drug design, development and therapy 2017; 11:2121-2129. http://www.ncbi.nlm.nih.gov/pubmed/?term=28744103
  17. Choi J, Khan AM, Jarmin M et al. Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a post-commercialization study. Lipids Health Dis 2017; 16:141. http://www.ncbi.nlm.nih.gov/pubmed/?term=28738813
Basic Science Publications
  1. Shin SK, Cho JH, Kim EJ et al. Anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium-induced colitis model. World J Gastroenterol 2017; 23:4559-4568. http://www.ncbi.nlm.nih.gov/pubmed/?term=28740344
  2. Sequetto PL, Goncalves RV, Pinto AS et al. Low Doses of Simvastatin Potentiate the Effect of Sodium Alendronate in Inhibiting Bone Resorption and Restore Microstructural and Mechanical Bone Properties in Glucocorticoid-Induced Osteoporosis. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada 2017:1-13. http://www.ncbi.nlm.nih.gov/pubmed/?term=28743325
  3. Navratilova L, Mandikova JR, Pavek P et al. Honey flavonoids inhibit hOATP2B1 and hOATP1A2 transporters and hOATP-mediated rosuvastatin cell uptake in vitro. Xenobiotica 2017:1-34. http://www.ncbi.nlm.nih.gov/pubmed/?term=28745105
  4. Kaviani E, Rahmani M, Kaeidi A et al. Protective Effect of Atorvastatin on D-galactose-Induced Aging Model in Mice. Behavioural brain research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28750834
  5. Jia S, Xie P, Hong SJ et al. Local Application of Statins Significantly Reduced Hypertrophic Scarring in a Rabbit Ear Model. Plastic and reconstructive surgery. Global open 2017; 5:e1294. http://www.ncbi.nlm.nih.gov/pubmed/?term=28740761
  6. Aouba A. KRASG12D, pulmonary LCH, and atorvastatin. Blood 2017; 130:391-392. http://www.ncbi.nlm.nih.gov/pubmed/?term=28751357
  7. Pu H, Zhang Q, Zhao C et al. VEGFA Involves in the Use of Fluvastatin and Zoledronate Against Breast Cancer. Pathology oncology research : POR 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28744693
  8. Perini M, Carbone G, Camin F. Stable isotope ratio analysis for authentication of red yeast rice. Talanta 2017; 174:228-233. http://www.ncbi.nlm.nih.gov/pubmed/?term=28738573
  9. El-Zaher AA, Elkady EF, Elwy HM, Saleh M. A Versatile Liquid Chromatographic Method for the Simultaneous Determination of Metformin, Sitagliptin, Simvastatin, and Ezetimibe in Different Dosage Forms. J AOAC Int 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28748781
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