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Update - Week 42, 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 High intensity Atorvastatin in Chinese ACS patients
Only limited data on long-term, high-dose high-intensity statin use in Chinese patients has been published to date. In this retrospective single center analysis of ACS patients scheduled for PCI. Group I patients (N=60) were randomized to a loading dose of atorvastatin 80 mg followed by 40 mg for 3 consecutive months post PCI. The control group (II) (N=60) was treated with 20 mg atorvastatin from date of admission and continued for 1-year post PCI.  Primary endpoint was LDL-C reduction from baseline to week 48 as well as percentage of patients achieving the LDL-C target of <1.81 mmol/L. Baseline LDL-c levels were higher in group I; 8.3% of group I patients had an LDL-C <1.81mmol/L versus 43.3% for group II. At week 24, 75.0% and 90.0% of group I and II patients, respectively, achieved the LDL-C target. At week 48, these percentages were 85.0% and 96.7%. LDL-c reductions at week 4 were -33.6% ±20.0% for group I versus -12.8% ±19.6% for group II, and at 48 weeks these percentages reached -47.0% ±25.5% and -36.4% ±20.2% respectively. Group I experienced marked improvement in cardiac function as well as a  significant reduction in plaque size. Atorvastatin was well tolerated over a period of 48 weeks. These observational findings re-affirm the benefits, safety and superiority of high intensity atorvastatin in Chinese ACS patients, Not only the expected superior LDL-c reduction but improved cardiac function as well as significant plaque size reduction as well.
Liu H, Dong A, Wang H. Long-term benefits of high-intensity atorvastatin therapy in Chinese acute coronary syndrome patients undergoing percutaneous coronary intervention: A retrospective study. Medicine (Baltimore) 2018; 97:e12687. http://www.ncbi.nlm.nih.gov/pubmed/?term=30334951
 
Review on lipid management in type 1 diabetics
In patients diagnosed with diabetes mellites type 2 (DM2), statins are considered standard therapy. The well characterized dyslipidemia associated with insulin resistance dictates the prescription of lipid lowering drugs such as statins. In patients with diabetes type 1 (DM1), the prescription of insulin generally normalizes the observed dyslipidemia of patients in whom glycemic control uncontrolled. Additionally, the young age of newly diagnosed DM1 patients and the lack of consistent recommendations by international guidelines contributes to the challenges physicians face when caring for DM1 patients. In this, case illustrated, vignet, the authors review the clinical features in a young female DM1 patient, highlighting CV risk factors that can be present as well as comparing guideline dictated recommendations. A reliable tool to calculate CVD risk in DM1 patients is lacking and the standard CV risk calculators are unsuited for DM1 patients. Evaluation of non-traditional risk markers such as calcium scoring, micro-albuminuria, Lp(a) and hs CRP are discussed. Lipid management in high risk patients primarily focusses on statins plus potential add-on therapies if targets are not reached.
Lan NSR, Fegan PG, Yeap BB et al. Dyslipidaemia in adults with type 1 diabetes - when to treat? Diabetes/metabolism research and reviews 2018:e3090. http://www.ncbi.nlm.nih.gov/pubmed/?term=30339719
 
Cumulative effects on LDL-c and hsCRP impacts stroke recurrence
The J-STARS study enrolled Japanese patients with history of non-cardiogenic ischemic stroke, and a total cholesterol of 180 – 240 mg/dl., between March 2004 – February 2009) Patients were randomly assigned to pravastatin 10 mg (N=545) and controls (N=550). In this post-hoc analysis 1077 participants were evaluated for LDL-c and hs-CRP changes, as well as recurrent events. During the 4.9-year follow-up 131 recurrent strokes/TIA’s were recorded. Patient reaching an LDL-c < 120 mg/dl had a 29% lower incidence of recurrent stroke and TIA compared to the patients with an LDL-c ≥120 mg/dL. The event rates were 2.20 vs. 3.11 per 100 person-years; HR 0.71 (0.50–0.99, p= 0.048). Patients with CRP <1 mg/L had 32% reduction compared to patients with CRP ≥ 1 mg/L. Event rate 2.26 vs. 3.40 per 100 person-years; HR 0.68 (0.48–0.96, p=0.031). Patients that achieved both targets had a 51% reduction of strokes/TIA’s, compared to patients with LDL-c ≥120 mg/d and CRP ≥ 1 mg/L. The observed event rates were 2.02 vs. 4.19 per 100 person-years; HR 0.49 (0.31–0.79). Based on these findings the dual control LDL-c and CRP decreased recurrent stroke and TIA risk in post ischemic stroke patients.
Kitagawa K, Hosomi N, Nagai Y et al. Cumulative Effects of LDL Cholesterol and CRP Levels on Recurrent Stroke and TIA. J Atheroscler Thromb 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30318492
 
Two novel genetic targets associated with SAMS
Statin associated muscle symptoms (SAMS) remain poorly understood and a diagnostic challenge. In this study 76 severely statin intolerant patients were compared to 50 statin tolerant controls. Next generation exome and whole genome sequencing determined twelve potential variants of two novel genes, RYR1 and CACNA1S. Pathogenetic variants of the two genes were associated with CK increases 5X – 400X of the upper limit of normal and symptomatic muscle complaints. Probable pathogenic variants in the RYR1 and CACNA1S gene were present in 16% of the patients with severe SAMS, a four-fold increase compared to statin tolerant controls. The authors concluded that Genetic variants within the RYR1 and CACNA1S genes are likely to be major contributors to SAMS susceptibility.
Isackson PJ, Wang J, Zia M et al. RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms. Pharmacogenomics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30325262
 
DYSIS – II: lipid management in European CHD patients is sub-par
The observational Dyslipidemia International Study II (DYSIS II) aimed to evaluate how effective LDL-c was managed in very high CVD risk patients. It was set up as a multi-center trial, conducted in 7 European countries between December 2012 and November 2014. Overall   4344 patients; 1298 ACS patients and 2946 stable CHD patients, were enrolled. Entry mean LDL-c plasma levels were 89.5 and 112.5 mg/dl, respectively. The recommended European Guideline goal (<70 mg/dl) was observed in 29.6% and 8.3% of ACS and stable CHD patients. Majority of patients (79.8%) were using statin mono-therapy the most commonly used add on dug was ezetimibe, this combination was used by 11.6% of patients.  Atorvastatin was the most commonly used statin (56.6%) followed by rosuvastatin (22.6%) and simvastatin (22.25).  Average dosage prescribed was the equivalent of 27 ± 20 mg atorvastatin for CHD, and 22 ± 17 mg for ACS patients. After a 4-month follow-up period 95.0% of ACS patients were using statins, with more than half on atorvastatin. Dosage prescribed after hospitalization increased to atorvastatin 35 ±25 mg; goal attainment was light increased slightly; 30.9% in patients using lipid lowering treatment at baseline and 41.5% in patients that did not have lipid lowering therapy when admitted for ACS. Simvastatin usage decreased from 37.9% to 27.8% after 4 months. The addition of non-statin lipid lowering drugs increased as well from 8.8% to 11.6%, with a relatively small number of patients 5.7% using ezetimibe. In the ACS group 1.2% died during follow-up, majority of cardiovascular causes (71.4%). Less hospitalizations were needed in patients that used lipid lowering treatment vs those that did not, 20.6% vs 26.2% respectively (P<0.05). The authors concluded that despite the widespread use of statins a large number of ACS and stable CHD patients are not adequately treated as reflected by off target LDL-c levels. There remains a significant treatment gap that urgently needs to be addressed.
Ferrieres J, De Ferrari GM, Hermans MP et al. Predictors of LDL-cholesterol target value attainment differ in acute and chronic coronary heart disease patients: Results from DYSIS II Europe. Eur J Prev Cardiol 2018:2047487318806359. http://www.ncbi.nlm.nih.gov/pubmed/?term=30335504
 
 
Relevant publications
  1. Yousufuddin M, Young N, Shultz J et al. Predictors of Recurrent Hospitalizations and the Importance of These Hospitalizations for Subsequent Mortality After Incident Transient Ischemic Attack. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30340936
  2. Yang Q, Yin RX, Cao XL et al. ANGPTL4 variants and their haplotypes are associated with serum lipid levels, the risk of coronary artery disease and ischemic stroke and atorvastatin cholesterol-lowering responses. Nutrition & metabolism 2018; 15:70. http://www.ncbi.nlm.nih.gov/pubmed/?term=30323852
  3. Han KH. Functional Implications of HMG-CoA Reductase Inhibition on Glucose Metabolism. Korean Circ J 2018; 48:951-963. http://www.ncbi.nlm.nih.gov/pubmed/?term=30334382
  4. Wu X, Gong C, Weinstock J et al. Associations of the SLCO1B1 Polymorphisms With Hepatic Function, Baseline Lipid Levels, and Lipid-lowering Response to Simvastatin in Patients With Hyperlipidemia. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 2018:1076029618805863. http://www.ncbi.nlm.nih.gov/pubmed/?term=30336686
  5. Wander GS, Hukkeri MYK, Yalagudri S et al. Rosuvastatin: Role in Secondary Prevention of Cardiovascular Disease. The Journal of the Association of Physicians of India 2018; 66:65-69. http://www.ncbi.nlm.nih.gov/pubmed/?term=30341873
  6. Sreenivasan J, Khan MS, Li H et al. Statins and incidence of contrast-induced acute kidney injury following coronary angiography - Five year experience at a tertiary care center. Cardiovascular revascularization medicine : including molecular interventions 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30318173
  7. Silbernagel G, Steiner LK, Hollstein T et al. The Interrelations between PCSK9-Metabolism and Cholesterol Synthesis and Absorption. Journal of lipid research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30323110
  8. Ridker PM. Should Aspirin Be Used for Primary Prevention in the Post-Statin Era? N Engl J Med 2018; 379:1572-1574. http://www.ncbi.nlm.nih.gov/pubmed/?term=30332575
  9. Pradhan AD, Paynter NP, Everett BM et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018; 206:80-93. http://www.ncbi.nlm.nih.gov/pubmed/?term=30342298
  10. Nicholls SJ, Puri R, Anderson T et al. Effect of Evolocumab on Coronary Plaque Composition. J Am Coll Cardiol 2018; 72:2012-2021. http://www.ncbi.nlm.nih.gov/pubmed/?term=30336824
  11. Nerild HH, Christensen MB, Knop FK, Bronden A. Preclinical discovery and development of colesevelam for the treatment of type 2 diabetes. Expert opinion on drug discovery 2018:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30336707
  12. Mirzaee S, Thein PM, Nogic J et al. The effect of combined ezetimibe and statin therapy versus statin therapy alone on coronary plaque volume assessed by intravascular ultrasound: A systematic review and meta-analysis. J Clin Lipidol 2018; 12:1133-1140.e1115. http://www.ncbi.nlm.nih.gov/pubmed/?term=30318063
  13. McGrath ER, Doughty CT, Amato AA. Autoimmune Myopathies: Updates on Evaluation and Treatment. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30341597
  14. Liu A, Wu Q, Guo J et al. Statins: adverse reactions, oxidative stress and metabolic interactions. Pharmacology & therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30321555
  15. Joseph P, Pais P, Dans AL et al. The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct. Am Heart J 2018; 206:72-79. http://www.ncbi.nlm.nih.gov/pubmed/?term=30342297
  16. Grigoropoulou P, Tentolouris A, Eleftheriadou I et al. Effect of 12-month intervention with low-dose atorvastatin on pulse wave velocity in subjects with type 2 diabetes and dyslipidaemia. Diabetes & vascular disease research 2018:1479164118805320. http://www.ncbi.nlm.nih.gov/pubmed/?term=30328360
  17. Desai NK, Mendelson MM, Baker A et al. Hepatotoxicity of Statins as determined by Serum Alanine Aminotransferase in a Pediatric Cohort with Dyslipidemia. Journal of pediatric gastroenterology and nutrition 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30334928
  18. de Knegt MC, Linde JJ, Fuchs A et al. Relationship between patient presentation and morphology of coronary atherosclerosis by quantitative multidetector computed tomography. European heart journal cardiovascular Imaging 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30325406
  19. Unlu S, Nurkoc SG, Sezenoz B et al. Impact of statin use on high sensitive troponin T levels with moderate exercise. Acta Cardiol 2018:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=30328783
  20. Uchiyama H, Tsujimoto M, Kimura A et al. Effects of Uremic Serum Residue on OATP1B1- and OATP1B3-Mediated Pravastatin Uptake in OATP-Expressing HEK293 Cells and Human Hepatocytes. Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30318712
  21. Thompson PL, Nidorf SM. Colchicine: an affordable anti-inflammatory agent for atherosclerosis. Curr Opin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30320614
  22. Theocharidou E, Papademetriou M, Reklou A et al. The role of PCSK9 in the pathogenesis of non-alcoholic fatty liver disease and the effect of PCSK9 inhibitors. Current pharmaceutical design 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30317984
  23. Sharma A, Mohan N. Role of niacin in current clinical practice: a review. Minerva medica 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30334440
  24. Nelson CP, Erridge C. Are toll-like receptors potential drug targets for atherosclerosis? Evidence from genetic studies to date. Immunogenetics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30327825
  25. Mondul AM, Joshu CE, Barber JR et al. Longer-term lipid-lowering drug use and risk of incident and fatal prostate cancer in black and white men in the ARIC Study. Cancer prevention research (Philadelphia, Pa.) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30327368
  26. Liu JM, Chen TH, Chuang HC et al. Statin reduces the risk of dementia in diabetic patients receiving androgen deprivation therapy for prostate cancer. Prostate Cancer Prostatic Dis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30337635
  27. Kuang H, Zhou X, Li L et al. Early severe coronary heart disease and ischemic heart failure in homozygous familial hypercholesterolemia: A case report. Medicine (Baltimore) 2018; 97:e12869. http://www.ncbi.nlm.nih.gov/pubmed/?term=30335000
  28. Gaudet D, Langslet G, Gidding SS et al. Efficacy, safety, and tolerability of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia: Rationale and design of the HAUSER-RCT study. J Clin Lipidol 2018; 12:1199-1207. http://www.ncbi.nlm.nih.gov/pubmed/?term=30318065
  29. Chen WC, Boursi B, Mamtani R, Yang YX. Total Serum Cholesterol and Pancreatic Cancer: A Nested Case-Control Study. Cancer Epidemiol Biomarkers Prev 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30333217
  30. Banegas MP, Emerson MA, Adams AS et al. Patterns of medication adherence in a multi-ethnic cohort of prevalent statin users diagnosed with breast, prostate, or colorectal cancer. Journal of cancer survivorship : research and practice 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30338462
  31. Ai C, Zhang S, He Q, Shi J. Comparing the combination therapy of ezetimibe and atorvastatin with atorvastatin monotherapy for regulating blood lipids: a systematic review and meta-analyse. Lipids Health Dis 2018; 17:239. http://www.ncbi.nlm.nih.gov/pubmed/?term=30326894
Miscellaneous publications
 
 
  1. Zhou TY, Zhou YL, Qian MJ et al. Interleukin-6 induced by YAP in hepatocellular carcinoma cells recruits tumor-associated macrophages. Journal of pharmacological sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30340922
  2. Zhang H, Lu X, Liu Z, Du K. Rosuvastatin reduces the pro-inflammatory effects of adriamycin on the expression of HMGB1 and RAGE in rats. International journal of molecular medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30320373
  3. Wang XL, Sun W, Zhou YL, Li L. Rosuvastatin stabilizes atherosclerotic plaques by reducing CD40L overexpression-induced downregulation of P4Halpha1 in ApoE(-/-) mice. The international journal of biochemistry & cell biology 2018; 105:70-77. http://www.ncbi.nlm.nih.gov/pubmed/?term=30336263
  4. Ruiz-DeDiego I, Fasano S, Solis O et al. Genetic enhancement of Ras-ERK pathway does not aggravate L-DOPA-induced dyskinesia in mice but prevents the decrease induced by lovastatin. Scientific reports 2018; 8:15381. http://www.ncbi.nlm.nih.gov/pubmed/?term=30337665
  5. Du J, Zhu Y, Meng X et al. Atorvastatin attenuates paraquat poisoning-induced epithelial-mesenchymal transition via downregulating hypoxia-inducible factor-1 alpha. Life sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30336147
  6. Chimini JS, Possomato-Vieira JS, Silva M, Dias-Junior CA. Placental nitric oxide formation and endothelium-dependent vasodilation underlie pravastatin effects against angiogenic imbalance, hypertension in pregnancy and intrauterine growth restriction. Basic & clinical pharmacology & toxicology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30318719
  7. Chen Y, Zhu R, Ma F et al. Assessment of OATP Transporter-Mediated Drug-Drug Interaction using Physiologically-Based Pharmacokinetic (PBPK) Modeling - A Case Example. Biopharmaceutics & drug disposition 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30335192
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