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Update - Week 23, 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

New Japanese Guidelines for Familial Hypercholesterolemia (FH) management
The Japanese Atherosclerosis Society published update guidelines for the diagnosis and management of FH. For the diagnosis of FH a simple strategy is suggested; if two of the three following criteria are present, FH diagnosis is confirmed. 1.  LDL-C > 180 mg/dl. 2. Tendon/skin xanthomas. 3. History of FH or premature CAD in 2nd degree relatives. For Treatment the guidelines emphasize statins but in severe or drug resistant heterozygous FH, PCSK9ab or LDL-apheresis are suggested as alternatives for, or addon to statins.  Homozygous FH patient need LDL-apheresis plus PCSK9ab or MTP inhibitors. Specialized care is needed for homozygous FH, children with FH and as well as drug resistant heterozygous FH Patients or young FH women that have a desire to become pregnant. Cascade screening is the preferred approach for diagnosing new FH patients and in FH patients without CVD, regular checks for manifest CAD is recommended as well. 
Harada-Shiba M, Arai H, Ishigaki Y et al. Guidelines for Diagnosis and Treatment of Familial Hypercholesterolemia 2017. J Atheroscler Thromb 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29877295
Should elderly be treated differently?
The successes of statins in patients at risk for CVD has been firmly established, what remains a dilemma for many clinicians, are treatment strategies for the elderly and very elderly. In this retrospective analysis of a single Australian hospital, the authors evaluated 852 admitted patients aged ≥ 80 years (January 1st – June 30th, 2015). Statin use was recorded in in 359 (41%), approximately half were male and 34 (8.6%) were of Asian origin. Mean age was 85.6 years. Majority of patients were using a moderate intensity statin in line with guideline recommendations. Very few patients (<5%) used low potency statins. Due to physical characteristics, frailty and co-morbid conditions (70 % had impaired renal function) as well as reduced life expectancy and poly pharmacy the risk of statin related side effects is heightened. The use of ≥5 medications was observed in 96.1% of the patients with an average of 10 medications per patient. Drugs that could potentially interact with statins were used by 46% of the patients. Major interactions were observed in 7% of the patients with diltiazem as the most commonly prescribed drug in this category. During admission 16.2% stopped statins, approximately half because of a palliative setting. Muscle toxicity was recorded in 14 patients (3.9%), all using medium or high intensity statins, 9 of these were diagnosed as having rhabdomyolysis.  The authors suggest a comprehensive assessment of elderly patients that use statins and that hospital admissions would provide an excellent opportunity to conduct medication reviews in patients aged >75 years.
Chee WJ, Abdullahi H, Chan Y et al. Retrospective Evaluation of Statin Prescription in the Elderly. Internal medicine journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29869449
Atorvastatin vs Evolocumab; surprising differences on postprandial TRL’s
Remnant particles are the atherogenic left-offers of Chylomicrons, the lipoproteins responsible for transporting post prandial lipids. VLDL is taking care of lipid transport when fasting. Apo B48 is the characteristic apo-lipoprotein of Chylomicrons (remnants) vs Apo B100 in VLDL-(remnants). In this study the impact of atorvastatin and PCSK9ab (evolocumab) are compared, in a two by two factorial design, on postprandial triglyceride rich lipoprotein (TRL) metabolism. In this study 80 normolipidemic men were exposed to an oral fat-load after which curves were constructed for changes in triglycerides, apo B48, VLDL and apo B100 as well as apo CIII, ANGPTL3. The most remarkable difference when comparing the two treatment strategies, is that atorvastatin reduced apo B-48 concentrations, fasting and postprandial, while PCSK9ab had no effects. An increased catabolism of ApoB-48 TRL’s was the driving force of this observed outcome. The potential different intracellular, next to the extracellular effects, of these two treatment strategies are suggested as an explanation for these distinctive outcomes.
Chan DC, Watts GF, Somaratne R et al. Comparative Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) and Statins on Postprandial Triglyceride-Rich Lipoprotein Metabolism. Arterioscler Thromb Vasc Biol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29880491
How to overcome the non-adherence hurdle?
The major hurdle to reduce cardiac threat in patients at risk for ASCVD is to ensure long term adherence to pharmacological interventions such as lowering blood pressure and reducing plasma cholesterol. In this review the authors share a practical synopsis of relevant topics that can help clinicians to evaluate and address issues surrounding statin compliance. Sharing recently published evidence of most commonly reported side effects, including appropriate definitions of Statin Associated Muscle Symptoms (SAMS), new-onset diabetes and hemorrhagic stroke. Intra-racial differences and the so-called Nocebo effects are explained. Simple pointers to help predict as well as proven strategies to measure and prevent non-adherence are discussed.  Intensifying efforts to address and overcome this formidable barrier to ensure that the benefits observed in large clinical outcome trials are ensured in patients that are prone to experience (renewed) cardiovascular complications.
Lansberg P, Lee A, Lee ZV et al. Nonadherence to statins: individualized intervention strategies outside the pill box. Vasc Health Risk Manag 2018; 14:91-102. http://www.ncbi.nlm.nih.gov/pubmed/?term=29872306
Using genetics to predict SAMS?
IN this systematic review the authors examine the evidence of predicting Statin Associated Muscle Symptoms (SAMS). The SLCO1B1 rs4149056 variant is the most robust genetic marker to predict SAMS. Despite the highly statistically significant association, the clinical relevance of using this test in daily practice remains limited. The sensitivity and specificity of one copy of this risk allele are 70.4% and 73.7% respectively. Translating in positive and negatively predictive values of 4.1% and 99.4%. The common finding of the rs4149056 variant in the western population (12.9%) vs the relative rare finding of statin intolerance explains the low positive predictive value. In contrast het high negative predictive value might be of value to exclude SAMS, particular in patients using simvastatin. Genetic testing did show an added advantage; it convinced patients of the benefits of statin use and decreased their apprehension that using HM-CoA reductase inhibitors would disrupt the life and daily activities. In a small study (58 patients and 59 controls) genotyped patients were more likely to get a new statin prescription as well as a lower LDL-cholesterol compared to the no genotyped patients. Studies are now exploring the values of combining a score of three candidate genes risk alleles, COQ2, ATP2B1, and DMPK. Including clinical factors that influence risk for SAMS, include advanced age, female sex, lower body mass index, and renal or hepatic dysfunction. The authors cite a study where a dosing algorithm, including SLCO1B1 and ABCG2 genotype as well as sex age body type and dosage timing predicted plasma drug levels of atorvastatin and rosuvastatin. The use of this model resulted in an improved adherence to atorvastatin 80 mg at 1 year compared to patients predicted not to tolerate this dosage, despite lacking statistical significance. The need of new models to predict SAMS are urgently needed and combining genetic markers as well as clinical parameters are self-evident.             
Brunham LR, Baker S, Mammen A et al. Role of Genetics in the Prediction of Statin-Associated Muscle Symptoms and Optimization of Statin Use and Adherence. Cardiovascular research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29878063
Relevant publications
  1. Zafrir B, Jubran A. Lipid-lowering Therapy with PCSK9-inhibitors in the Real World Setting: Two-year Experience of a Regional Lipid clinic. Cardiovasc Ther 2018:e12439. http://www.ncbi.nlm.nih.gov/pubmed/?term=29863817
  2. Tomilova DI, Karpov YA, Lopukhova VV. [Long-Term Statin Adherence in Patients with Stable Angina after Coronary Stenting]. Kardiologiia 2018:65-71. http://www.ncbi.nlm.nih.gov/pubmed/?term=29870326
  3. Shekar C, Budoff M. Calcification of the heart: mechanisms and therapeutic avenues. Expert Rev Cardiovasc Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29860888
  4. Rodriguez V, Newman JD, Schwartzbard AZ. Towards more specific treatment for diabetic dyslipidemia. Curr Opin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29878904
  5. Peng Y, Ou BQ, Li HH et al. Synergistic Effect of Atorvastatin and Folic Acid on Cardiac Function and Ventricular Remodeling in Chronic Heart Failure Patients with Hyperhomocysteinemia. Medical science monitor : international medical journal of experimental and clinical research 2018; 24:3744-3751. http://www.ncbi.nlm.nih.gov/pubmed/?term=29863106
  6. Mason RP, Dawoud H, Jacob RF et al. Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 103:1231-1237. http://www.ncbi.nlm.nih.gov/pubmed/?term=29864903
  7. Jurisic A, Jurisic Z, Lefkou E et al. Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect. Vascul Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29879462
  8. Jayalath VH, Nayan M, Finelli A et al. Statin use and time to progression in men on active surveillance for prostate cancer. Prostate Cancer Prostatic Dis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29875433
  9. Firnhaber JM. Newer cholesterol-lowering agents: What you must know. The Journal of family practice 2018; 67:339;341;344;345. http://www.ncbi.nlm.nih.gov/pubmed/?term=29879234
  10. Epure AM, Leyvraz M, Mivelaz Y et al. Risk factors and determinants of carotid intima-media thickness in children: protocol for a systematic review and meta-analysis. BMJ Open 2018; 8:e019644. http://www.ncbi.nlm.nih.gov/pubmed/?term=29866720
  11. Cholan RA, Weiskopf NG, Rhoton D et al. From Concepts and Codes to Healthcare Quality Measurement: Understanding Variations in Value Set Vocabularies for a Statin Therapy Clinical Quality Measure. EGEMS (Washington, DC) 2017; 5:19. http://www.ncbi.nlm.nih.gov/pubmed/?term=29881739
  12. Athyros VG, Katsiki N, Mikhailidis DP. Statins and substantially increased ALT values at baseline. Cardiovasc Ther 2018:e12444. http://www.ncbi.nlm.nih.gov/pubmed/?term=29883041
  13. Uthman OA, Nduka C, Watson SI et al. Statin use and all-cause mortality in people living with HIV: a systematic review and meta-analysis. BMC infectious diseases 2018; 18:258. http://www.ncbi.nlm.nih.gov/pubmed/?term=29866059
  14. Lin CY. Immortal Time Bias Can Occur in the Analysis of Dose-Dependent Effect of Statin. Chest 2018; 153:1508-1509. http://www.ncbi.nlm.nih.gov/pubmed/?term=29884263
  15. Feng Y. Efficacy of statin therapy in patients with acute respiratory distress syndrome/acute lung injury: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 2018; 22:3190-3198. http://www.ncbi.nlm.nih.gov/pubmed/?term=29863265
  16. Burkard T, Huegle T, Layton JB et al. The risk of incident osteoarthritis of the hand in statin initiators:A sequential cohort study. Arthritis care & research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29885074
Miscellaneous publications
  1. Wegner A, Pavlovic D, Haussmann-Vopel S, Lehmann C. Impact of lipid modulation on the intestinal microcirculation in experimental sepsis. Microvascular research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29859746
  2. Tong H, Zhang X, Meng X et al. Simvastatin Inhibits Activation of NADPH Oxidase/p38 MAPK Pathway and Enhances Expression of Antioxidant Protein in Parkinson Disease Models. Frontiers in molecular neuroscience 2018; 11:165. http://www.ncbi.nlm.nih.gov/pubmed/?term=29872377
  3. Rezazadeh M, Parandeh M, Akbari V et al. Incorporation of rosuvastatin-loaded chitosan/chondroitin sulfate nanoparticles into a thermosensitive hydrogel for bone tissue engineering: preparation, characterization, and cellular behavior. Pharmaceutical development and technology 2018:1-23. http://www.ncbi.nlm.nih.gov/pubmed/?term=29863957
  4. Gao WY, Chen PY, Chen SF et al. Pinostrobin inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression through the modulation of FoxO3a protein in HepG2 cells. Journal of agricultural and food chemistry 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29862818
  5. Deloughery EP, Prasad V. If the IMPROVE-IT Trial Was Positive, as Reported, Why Did the FDA Denied Expanded Approval for Ezetimibe and Simvastatin? An Explanation of the Tipping Point Analysis. Journal of general internal medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29869138
  6. Blanka SS, Gabor O, Hajnal K. Pharaceutical chemical characterization of ezetimibe. Acta pharmaceutica Hungarica 2016; 86:133-139. http://www.ncbi.nlm.nih.gov/pubmed/?term=29870599
  7. Barros S, Montes R, Quintana JB et al. Chronic environmentally relevant levels of simvastatin disrupt embryonic development, biochemical and molecular responses in zebrafish (Danio rerio). Aquatic toxicology (Amsterdam, Netherlands) 2018; 201:47-57. http://www.ncbi.nlm.nih.gov/pubmed/?term=29879595
  8. Zhao Y, Gao H, He J et al. Co-delivery of LOX-1 siRNA and statin to endothelial cells and macrophages in the atherosclerotic lesions by a dual-targeting core-shell nanoplatform: A dual cell therapy to regress plaques. J Control Release 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29885417
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