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Update - Week 33,  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

No reduced AKI risk in cardiac surgery patients using statins
Can patient that have cardiac surgery be protected from acute kidney injury (AKI) when using statins. That is the question the authors addressed in this meta-analysis. For this study 8 randomized controlled trials (RCT) with 3 204 patients were included. Primary endpoint was the incidence of post-operative AKI. Although all studies reported AKI, different definitions were used. Study size differed from 40 – 1 992 patients. Analyzed with a random-effects model, the pooled estimate of the 8 studies suggested that both statin and control groups had a comparable incidence of AKI, RR: 1.02 (0.82-1.28) Secondary outcomes were only reported in some of the studies, but no statin benefits were observed either. Renal replacement therapy – 3 studies -  RR=1.09 (0.45-2.66); mechanical ventilation duration – 2 studies - MD=24.84 min (-55.53-105.20); ICU length of stay – 7 studies - MD=0.04 days (-3.13-3.20); hospital length of stay – 6 studies - MD=-0.08 days (9-0.31-0.150; n=6); in-hospital mortality – 7 studies -  RR=3.76 (0.93-15.14). The authors concluded that based on their meta-analysis of RCT’s of perioperative statins in patients undergoing cardiac surgery, statins did not reduce the risk for AKI. Limitations in terms of the small number of trials, few participants and heterogeneity of patients as well as AKI definitions, larger RCT’s are needed to confirm or refute these findings as well as help to have a better understanding of the mechanisms involved.
Zhao BC, Shen P, Liu KX. Perioperative Statins Do Not Prevent Acute Kidney Injury After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials. Journal of cardiothoracic and vascular anesthesia 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28803772
 
Atorvastatin 80 mg for 3 months improved LVEF and NT ProBNP in Non-STEMI patients
The authors randomized 100 Egyptian patients, presenting with a non-STEMI, to 20 or 80 mg of atorvastatin daily. Patients were followed prospectively for 3 months. All patients received a loading dose of 80 mg Atorvastatin 24 and 12 hrs. before coronary angiography. Primary endpoints of the study were changes in NT ProBNP, left ventricular volume (LVEF) and major coronary events (MACE). Procedural data were comparable between the two treatment arms.
The patients treated with 80 mg had significantly lower NT ProBNP, post procedure and at 3 months (P < 0.001). Ejection fraction improved significantly as well (P<0.05). No difference in MACE was noted in the two treatment arms. The authors concluded that 3 months of atorvastatin 80 was superior compared to 20 mg in non-STEMI patients undergoing PTCA reflected by lower NT Pro BNP and improved LVEF.
Shehata M, Samir A, Dardiri M. Prognostic impact of intensive statin therapy on N-terminal pro-BNP level in non-ST-segment elevation acute myocardial infarction patients. J Interv Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28812321
 
Plasma PCSK9 a review on how to modify and the effects
In this review, the authors outline the effects of PCKS9 concentrations on LDL-cholesterol levels. Lipid lowering drugs like statins increase or sometimes decrease PCSK9 concentrations. Lower hepatic intracellular cholesterol concentrations activate SREB-2 and increase the production LDLr as well as PCSK9. After statin administration, the increase in PCSK9 occurs rapidly (<24hrs), is dose dependent and greater elevations have been reported with lipophilic statins as compared to hydrophilic statins. The observed increases are sustained over longer period of time. The PCSK9 gene response might be faster, more sensitive or more dose dependent than the LDLr gene. PCSK9 plasma concentrations reflect LDL-C levels but this correlation is extinguished when statins are used. Using the increase of PCSK9 to predict the LDL-C lowering response to statins shows conflicting evidence, most studies dispute this correlation. Other non-statin lipid lowering drugs influence PCSK9 plasma concentrations as well. Ezetimibe’s effects on PCSK9 are limited in mono therapy as well as in combination with statins. The effects of Fibrates have been conflicting with some studies showing decreases versus others that noted increases of plasma PCSK9. Data on Niacin is limited however a 13% decrease of PCSK9 has been described in patients using a combination of simvastatin 20 mg and Niacin. Directly reducing PCSK9 by blocking the binding of PCSK9 and the LDLr is the strategy used by giving patients PCSK9ab. Alternatives are now in tested in phase II - III studies, aiming to inhibit PCSK9 expression or interfering with PCSK9 secretion. Targeting this recently discovered key regulator of lipid metabolism seems promising and in combination with statins is the most effective approach to achieve very low LDL-C levels.
Nozue T. Lipid Lowering Therapy and Circulating PCSK9 Concentration. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28804094
 
What are the effects of statins on exercise performance or physical activity?
The continued media attention for muscle related side effects are creating confusion in patients and doctors alike. These messages also play an important role in the reported poor statin adherence. To examine the effects of statins on athletic/exercise performance and symptoms in active individuals the authors conducted systematic literature review. They identified 65 articles and include 32 in their analysis. Overall no correlation between statin uses and myalgia increase or exercise performance decrease was observed. Intensity of statins did not show a correlation with exercise parameters either. Myalgia was studied in 17/32 articles. An increase was reported in 47% (8/17). Muscle injury increases with CK elevations after exercise were reported in 35% (6/17). Aerobic exercise capacity was reduced in in 33% (3/10) studies. When examining muscle strength 25% (2/8) showed a decrease and 25% (2/8) showed an increase. Paradoxically, in 3 out of 5 studies patients increased their physical activity when statins were used compared to no statin use. The authors concluded that in some studies pointed an increase in exercise related muscle complaints and exercise induced rise in plasma CK levels was noted. However there is no consistent evidence that statins reduce muscle strength, endurance, overall exercise performance or physical activity.
Noyes AM, Thompson PD. The effects of statins on exercise and physical activity. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28807461
 
In Chinese patients, the SLCO1B1-521C SNP increases SAMS risk
Efficacy and safety of statins, especially in the higher dosage range, in East Asians have been, and still are, a hot debated issue. In this nested case control study, Chinese patients with CAD were evaluated for genetic variants associated with statins response and safety. Five SNP’s were tested in 148 patients with statin associated muscle symptoms (SAMS) as well as 255 controls, with muscle symptoms. Carriers of at least one SLCO1B1-521C allele had a significant increased risk for myotoxicity. OR:1.69 (1.07-2.67; P=0.024). When comparing the different statins, Rosuvastatin use was associated with an even a higher risk OR:3.67 (1.42-9.47; P=0.007). A non-significant association was observed for this particular variant in patients using simvastatin or atorvastatin. The other 4 SNP’s rs776746, rs2306283, rs7412, and rs429358, showed no association with SAMS (P>0.05). The SLCO1B1 (rs4149056, 521T > C) SNP is associated with a decreased OATP1B1 function and statin uptake. In Chinese patients, this increases the risk of rosuvastatin associated myotoxicity.
Liu JE, Liu XY, Chen S et al. SLCO1B1 521T > C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: a nested case-control study. Eur J Clin Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28812116
 
 Caveolin 3 deficiency produces myopathy and dyslipidemia
In this case report a patient presented with elevated cholesterol in combination with increased CK levels. A muscle biopsy confirmed the presence of a Caveolin 3 deficiency. Genetic testing revealed a missense mutation in the CAV3 gene. Caveolin’s (CAV’s) are cell membrane components seen as 60-80 ng wide pits unevenly distributed in plasma membranes. CAV’s have an important function in the formation of Caveolae that guard the shape, integrity, and molecular order at the membrane level. They are involved in endocytosis processes and modulation of intracellular signaling and play a role in glucose and lipid metabolism as well. In mammals three CAV’s have been described; CAV1 and CAV2 are expressed in hepatocytes, adipocytes and non-skeletal muscle cells. CAV3 is predominantly expressed in striated muscle but also in cardiomyocytes and smooth muscle cells. This patient presented with a total cholesterol of 291 mg/dl; HDL-C 38 mg/dl, LDL-C 210 mg/dl and triglycerides 291 mg/dl. His CK levels were high as well 1012 U/L. Mutations in LDLr, Apo B PCSK9 or LDL-Rap were ruled out. Patient has been treated with a combination of Cholestyramine (4 gram 2 x day) and Ezetimibe (10 mg every day) with this combination therapy he achieved an LDL-C reduction of 30% and his lipids were successfully managed for >10 years. For this patient PCSK9ab could be considered as an alternative or add on to the existing non-statin lipid lowering drugs he is using now.
Ibarretxe D, Pelleja J, Ortiz N, Masana L. Caveolin 3 deficiency myopathy associated with dyslipidemia: Treatment challenges and possible pathophysiological association. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28807458
Relevant publications
  1. Yudin ZM, Yaacob LH, Hassan NB et al. Achievement of LDL Cholesterol Goal and Adherence to Statin by Diabetes Patients in Kelantan. The Malaysian journal of medical sciences : MJMS 2017; 24:44-50. http://www.ncbi.nlm.nih.gov/pubmed/?term=28814932
  2. Xie G, Sun Y, Myint PK et al. Six-month adherence to Statin use and subsequent risk of major adverse cardiovascular events (MACE) in patients discharged with acute coronary syndromes. Lipids Health Dis 2017; 16:155. http://www.ncbi.nlm.nih.gov/pubmed/?term=28810873
  3. Vavuranakis M, Kariori M, Siasos G et al. Statins in acute coronary syndromes. Current pharmaceutical design 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28814233
  4. Stavroulakis K, Borowski M, Torsello G, Bisdas T. Association between statin therapy and amputation-free survival in patients with critical limb ischemia in the CRITISCH registry. Journal of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28807382
  5. Sawano M, Kohsaka S, Abe T et al. Patterns of statin non-prescription in patients with established coronary artery disease: A report from a contemporary multicenter Japanese PCI registry. PLoS One 2017; 12:e0182687. http://www.ncbi.nlm.nih.gov/pubmed/?term=28817616
  6. Norrington K, Androulakis E, Oikonomou E et al. Statins in Aortic Stenosis. Current pharmaceutical design 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28814237
  7. Lyubarova R, Robinson JG, Miller M et al. Metabolic syndrome cluster does not provide incremental prognostic information in patients with stable cardiovascular disease: A post hoc analysis of the AIM-HIGH trial. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28807460
  8. Lee JH, Kim SH, Choi DJ et al. Efficacy and tolerability of two different formulations of atorvastatin in Korean patients with hypercholesterolemia: a multicenter, prospective, randomized clinical trial. Drug design, development and therapy 2017; 11:2277-2285. http://www.ncbi.nlm.nih.gov/pubmed/?term=28814835
  9. Kim JS, Kim W, Park JY et al. Effects of statin therapy on clinical outcomes after acute myocardial infarction in patients with advanced renal dysfunction: A propensity score-matched analysis. PLoS One 2017; 12:e0183059. http://www.ncbi.nlm.nih.gov/pubmed/?term=28806769
  10. Chen Y, Li D, Jing J et al. Treatment Trends, Effectiveness, and Safety of Statins on Lipid Goal Attainment in Chinese Percutaneous Coronary Intervention Patients: a Multicenter, Retrospective Cohort Study. Clinical therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28807393
  11. Casagrande SS, Aviles-Santa L, Corsino L et al. Hemoglobin A1C, Blood Pressure, and LDL-Cholesterol Control among Hispanic/Latino Adults with Diabetes: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28816530
  12. Wang YB, Fu XH, Gu XS et al. Effects of intensive pitavastatin therapy on glucose control in patients with non-ST elevation acute coronary syndrome. American journal of cardiovascular disease 2017; 7:89-96. http://www.ncbi.nlm.nih.gov/pubmed/?term=28804682
  13. Stuart B, Hendrick F, Dougherty JS, Xu J. Does the offer of free prescriptions increase generic prescribing? The American journal of managed care 2017; 23:e193-e201. http://www.ncbi.nlm.nih.gov/pubmed/?term=28817295
  14. Shaitelman SF, Stauder MC, Allen P et al. Impact of Statin Use on Outcomes in Triple Negative Breast Cancer. Journal of Cancer 2017; 8:2026-2032. http://www.ncbi.nlm.nih.gov/pubmed/?term=28819403
  15. Serrano NA, Kalman NS, Anscher MS. Reducing rectal injury in men receiving prostate cancer radiation therapy: current perspectives. Cancer management and research 2017; 9:339-350. http://www.ncbi.nlm.nih.gov/pubmed/?term=28814898
  16. Min KL, Park MS, Jung J et al. Comparison of Pharmacokinetics and Safety of a Fixed-Dose Combination of Rosuvastatin and Ezetimibe Versus Separate Tablets in Healthy Subjects. Clinical therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28803122
  17. Merli GJ, Weitz HH. Annals Consult Guys - Is It Statin Myalgia? What a Pain! Annals of internal medicine 2017; 167:Cg1. http://www.ncbi.nlm.nih.gov/pubmed/?term=28806813
  18. Larsen SB, Dehlendorff C, Skriver C et al. Postdiagnosis Statin Use and Mortality in Danish Patients With Prostate Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017:Jco2016718981. http://www.ncbi.nlm.nih.gov/pubmed/?term=28806117
  19. Kullgren JT, Segel JE, Peterson TA et al. Availability and variation of publicly reported prescription drug prices. The American journal of managed care 2017; 23:444-448. http://www.ncbi.nlm.nih.gov/pubmed/?term=28817781
  20. Jankovic J. Statin-related musculoskeletal pain in Parkinson's disease. Pain 2017; 158:1840. http://www.ncbi.nlm.nih.gov/pubmed/?term=28816887
  21. Giugliano RP, Mach F, Zavitz K et al. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med 2017; 377:633-643. http://www.ncbi.nlm.nih.gov/pubmed/?term=28813214
  22. Ghanem F, Vodnala D, J KK et al. Cholesterol crystal embolization following plaque rupture: a systemic disease with unusual features. Journal of biomedical research 2017; 31:82-94. http://www.ncbi.nlm.nih.gov/pubmed/?term=28808190
  23. Edwards JE, Eliot L, Parkinson A et al. Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects. Adv Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28808886
  24. Cheng SF, Brown MM. Contemporary medical therapies of atherosclerotic carotid artery disease. Seminars in vascular surgery 2017; 30:8-16. http://www.ncbi.nlm.nih.gov/pubmed/?term=28818261
  25. Batais MA, Almigbal TH, Bin Abdulhak AA et al. Assessment of physicians' awareness and knowledge of familial hypercholesterolemia in Saudi Arabia: Is there a gap? PLoS One 2017; 12:e0183494. http://www.ncbi.nlm.nih.gov/pubmed/?term=28817709
Miscellaneous publications
  1. Yue R, Zuo C, Zeng J et al. Atorvastatin attenuates experimental contrast-induced acute kidney injury: a role for TLR4/MyD88 signaling pathway. Ren Fail 2017; 39:643-651. http://www.ncbi.nlm.nih.gov/pubmed/?term=28805489
  2. Ying L, Yan F, Zhao Y et al. (-)-Epigallocatechin-3-gallate and atorvastatin treatment down-regulates liver fibrosis related genes in non-alcoholic fatty liver disease. Clin Exp Pharmacol Physiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28815679
  3. Park J, Hwang I, Kim SJ et al. Atorvastatin prevents endothelial dysfunction in high glucose condition through Skp2-mediated degradation of FOXO1 and ICAM-1. Biochem Biophys Res Commun 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28802579
  4. Melendez QM, Wooten CJ, Lopez D. Atorvastatin and lovastatin, but not pravastatin, increased cellular complex formation between PCSK9 and the LDL receptor in human hepatocyte-like C3A cells. Biochem Biophys Res Commun 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28802576
  5. Mancano MA. ISMP Adverse Drug Reactions: Levofloxacin-Induced Neuroexcitation and Hallucinations; Statin-Induced Muscle Rupture; Mefloquine-Induced Rhabdomyolysis; Methimazole-Induced Cholestatic Hepatitis; Decitabine-Induced Hand and Foot Syndrome. Hospital pharmacy 2017; 52:330-333. http://www.ncbi.nlm.nih.gov/pubmed/?term=28804147
  6. Liu MW, Liu R, Wu HY et al. Atorvastatin has a protective effect in a mouse model of bronchial asthma through regulating tissue transglutaminase and triggering receptor expressed on myeloid cells-1 expression. Experimental and therapeutic medicine 2017; 14:917-930. http://www.ncbi.nlm.nih.gov/pubmed/?term=28810543
  7. Lin HP, Tu HP, Hsieh YP, Lee BS. Controlled release of lovastatin from poly(lactic-co-glycolic acid) nanoparticles for direct pulp capping in rat teeth. International journal of nanomedicine 2017; 12:5473-5485. http://www.ncbi.nlm.nih.gov/pubmed/?term=28814864
  8. Korybalska K, Kawka E, Breborowicz A, Witowski J. The role of mTOR inhibitors and HMG-CoA reductase inhibitors on young and old endothelial cell functions, critical for re-endothelialisation after percutaneous coronary intervention: an in vitro study. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 2017; 68:397-405. http://www.ncbi.nlm.nih.gov/pubmed/?term=28820396
  9. Jung EJ, Chung KH, Kim CW. Identification of simvastatin-regulated targets associated with JNK activation in DU145 human prostate cancer cell death signaling. BMB reports 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28803608
  10. Chen X, Cobbs A, George J et al. Endocytosis of Albumin Induces Matrix Metalloproteinase-9 by Activating the ERK Signaling Pathway in Renal Tubule Epithelial Cells. Int J Mol Sci 2017; 18. http://www.ncbi.nlm.nih.gov/pubmed/?term=28805677
  11. Ayothiraman S, Gummadi SN, Panda T. Comparison of the elution characteristics of individual forms of lovastatin in both isocratic and gradient modes and HPLC-PDA method development for pure and fermentation derived lovastatin. Preparative biochemistry & biotechnology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28816626
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