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Update - Week 38,  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

Using Statins showed impressive benefits in Chinese viral hepatitis patients
The role of statins in liver disease is gaining momentum fueled by accumulating studies showing the benefits in a broad spectrum of chronic liver disease populations. In this Hong Kong analysis data from Chinese chronic viral hepatitis patients were collected in a hospital based database from the Hong Kong Hospital Authority. Between 2000 and 2012 patient data was collected and 69 184 patients with chronic viral hepatitis identified. Using a retrospective propensity matching design 2 053 statin users and 67 131 non-statin users were followed for a 2-year land-mark analysis. A total of 23 baseline co-variates were used for the propensity score matching.  Statin users were allocated to this category if the cumulative daily dosage was >28. The primary outcome was a composite of portal hypertension related liver decompensation events, with adjustment for death as a competing risk. There were significant benefits of using statins vs no statins after an observation period of 2 years. Composite liver decompensation events HR: 0.55 (0.36-0.83; P = .005). Ascites HR: 0.57 (0.36-0.92; P = .02).  Dose dependent decrease in death HR: 0.87 (0.76-0.99; P = .035). The authors concluded that patients with viral hepatitis showed improved outcomes for chronic liver disease related complications. The need for additional prospective studies is self-evident.  Exploring the effects of the different statins and including patients with chronic liver diseases from other causes is of imminent importance.
Wong JC, Chan HL, Tse YK et al. Statins reduce the risk of liver decompensation and death in chronic viral hepatitis: a propensity score weighted landmark analysis. Alimentary pharmacology & therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28940673
Application of SAMS-CI in CoQ10 Study identified “Unlikely” SAMS patients
The recently developed SAMS Clinical Index (CI) was evaluated in the Coenzyme Q10 in Statin Myopathy (CoQ10) Study. In the CoQ10 study patients were randomized to simvastatin 20 mg or placebo for 8 weeks, using a cross-over design.  Only patients that experienced muscle symptoms on simvastatin only – 43/120 patients (36%) were confirmed as having SAMS. Data from the participants were retrospectively entered into the SAMS-CI score. The patients with confirmed SAMS had higher scores (6.7 ± 2.0 points) compared to patients reported muscle complaints in both treatment arms (5.7 ± 2.5 points); patients with complaints on placebo (2.4 ± 1.2 points) or patients that tolerated both simvastatin and placebo (2.2 ± 0.9 points). The SAMS-CI seems to be quite effective in identifying patients unlikely to have SAMS. A SAMS-CI score of 6-4 points (= unlikely SAMS) showed a negative predictive value of 90.6%. The authors concluded that the SAMS-CI can help physicians to encourage statin adherence in patients that perceive themselves to be statin intolerant.
Taylor BA, Sanchez RJ, Jacobson TA et al. Application of the Statin-Associated Muscle Symptoms-Clinical Index to a Randomized Trial on Statin Myopathy. J Am Coll Cardiol 2017; 70:1680-1681. http://www.ncbi.nlm.nih.gov/pubmed/?term=28935043
What impact does Evolocumab have on increasing the risk of developing new onset diabetes?
the increased risk of NODM by using statins has been confirmed in randomized controlled clinical trials, larger observational studies and Mendelian randomization analyses. For PCSK9 Mendelian randomization studies, analyzing genetic markers associated with reduced PCSK9 activity confirmed similar effects showing an increased NODM risk if PCSK9 activity was lower. The recently presented and published FOURIER outcome study, pre-specified endpoints included markers for glycemic status. The FOURIER study recruited a large number of diabetic and pre-diabetic patients. In this sub analysis efficacy and safety of Evolocumab in diabetic and pre-diabetic patients (HbA1c 5.7-6.4% or FPG 5.6-6.9 mmol/l) as well glycemic homeostasis were evaluated. At baseline 11 03 patients had DM (40%) and 10 344 had prediabetes (38%); only 6 189 were normoglycemic (22%)! Benefits of Evolocumab on the primary composite endpoints in patients with and without diabetes were respectively HR 0.83 (0.75-0.93; p=0.0008) and HR 0.87 (0.79-0.97; p=0.0052). Reduction of the secondary endpoints (CVD death, MI, and stroke) were respectively: HR 0.82 (0.72-0.93;0=0.0021) and 0.78 (0.69-0.89; p=0.0002). There was no increased risk for developing diabetes in patients without diabetes, HR: 1.05 (0.94-1.17) or with prediabetes HR 1.00 (0.89-1.13), at baseline. In the three patient groups levels of HbA1c and of FPG were not significantly different. Reported Adverse events were similar when comparing the Evolocumab cohort with the placebo group. In diabetics: 78.5% vs 78.3% in the patients without diabetes and 76.8% in both treatment arms in the diabetic cohort. Evolocumab treatment resulted in similar relative risk reductions in diabetics and non-diabetics. The absolute risk is roughly 50% higher in diabetics this translated in a NNT (over 3 years) of 37 for diabetic patients vs 62 for non-diabetic patients. The authors concluded that adding Evolocumab to maximal tolerated statins reduced CVD risk significantly in patients with or without diabetes. No tolerability or safety difference were observed in the diabetic, prediabetics or non-diabetic patients. No increased risk for developing NODM was detected during the 2.2-year median follow-up.
Sabatine MS, Leiter LA, Wiviott SD et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on
glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial.
The lancet. Diabetes & endocrinology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28927706
Starting statins < 6 months) after first stroke prevents atherothrombotic recurrences
The Japan Statin Treatment Against Recurrent Stroke (J-STARS) trial was conducted to evaluate the benefits of pravastatin 10 mg to prevent the recurrence of non-cardioembolic ischemic stroke. Although the incidence of total strokes and TIA’s were not different the patients using pravastatin compared to placebo, the incidence of atherothrombotic stroke was lower. Patients recruited for the J-STARS study were included for up to 3-years after the index stroke event. This is in contrast with the successful SPARCL trial were patients were randomized to 80 mg atorvastatin or placebo within 6 months of their qualifying event. In this sub analysis the investigators compared patients that started early (<6 months) to patients that started pravastatin 10 mg after 6 months. The number of participants in the J-STARS was 1578 (491 female; 66.2 ±8.5 years). There were 417 patients that started with pravastatin 10 mg < 6 months and 368 patients > 6 months. In the control group the number of patients were 417 and 368 respectively. During the follow-up time (4.9 ±1.4 years) the incidence of atherothrombotic strokes were significantly reduced in the patients using pravastatin; 0.24% vs 0.88%/year; p=0.01. The number of stroke sub-types did not differ between the early initiators and late initiators of pravastatin. The authors concluded that pravastatin is likely to reduce atherothrombotic stroke in patients when started early (<6 months) but his was not concusive for the prevention of recurrent stroke.
Hosomi N, Nagai Y, Kitagawa K et al. Pravastatin Reduces the Risk of Atherothrombotic Stroke when Administered within Six Months of an Initial Stroke Event. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28924103
Can we predict statin related muscle toxicity?
Statin related toxicity (SRM) is characterized by classical muscle symptoms, that resolve when medication is stopped and symptoms recur after re-challenge. SRM ranges from tolerable myalgia to intolerable muscle pain and weakness. SRM is a graded classification (0-6) according to symptom severity, CK elevations and end organ damage. SAMS is defined as musculoskeletal symptoms, in most cases without significant elevations of CPK levels. The focus of this study is to determine the impact of specific genetic and clinical factors on SRM (without CK elevations) as to provide clinicians with a better means to distinguish true statin intolerability from muscle complaints related to non-statins causes. For the study 606 patients were recruited (mean age 60.93 years); 125 cases and 481 controls (all European ancestry). All cases reported myalgia without CK elevations and were classified as SRM2. Cases were more often female vs controls (58.4% vs 44.1%) and were more likely to be treated with simvastatin than atorvastatin (85.6% vs 61.7%). Simvastatin 40 mg was the most frequently prescribed dosage and in the atorvastatin users 80 mg was the most common dosage. Contribution factors as BMI or co-morbidities and were evenly distributed between cases and controls, but cases had higher lipid levels. Exposure to drugs with statin pharmacokinetic interactions were observed 17-30 % in both cases and controls. There were fewer patients in the case group using warfarin (p=0.008) and fewer dihydroperidine calcium antagonist users in the control group (p=0.031). Genetic contributors to SRM were analyze by studying 12 SNP’s that are involved in statin pharmacokinetics and dynamics. Only the SNP in SLCO1B1 [rs4149056, (c.521T>C; V174A)] was associated with SRM (P=0.010). After multivariate logistic regression analysis only female gender and the SLCO1B1 SNP were significantly associated with SRM. The authors concluded that increased systemic exposure of simvastatin, and to a lesser extent atorvastatin, are implicated is SRM. In Simvastatin users, the presence of a C-allele had a diagnostic sensitivity/specificity of 70.4%/73.7%. The high frequency of the C-allele in statin tolerant patients makes a genetic test not clinical useful to identify patients at risk of SRM.
Bakar NS, Neely D, Avery P et al. Genetic and clinical factors are associated with statin-related myotoxicity of moderate severity: A case-control study. Clinical pharmacology and therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28940218
Relevant publications
  1. Sissung TM, McKeeby JW, Patel J et al. Pharmacogenomics Implementation at the National Institutes of Health Clinical Center. Journal of clinical pharmacology 2017; 57 Suppl 10:S67-s77. http://www.ncbi.nlm.nih.gov/pubmed/?term=28921647
  2. Shirinsky IV, Biryukova AA, Shirinsky VS. Simvastatin as an Adjunct to Conventional Therapy of Non-infectious Uveitis: A Randomized, Open-Label Pilot Study. Current eye research 2017:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28937830
  3. Rajendran S, Kumar KS, Ramesh S, Rao SR. Thermoreversible in situ gel for subgingival delivery of simvastatin for treatment of periodontal disease. International journal of pharmaceutical investigation 2017; 7:101-106. http://www.ncbi.nlm.nih.gov/pubmed/?term=28929053
  4. Nishiguchi T, Kubo T, Tanimoto T et al. Effect of Early Pitavastatin Therapy on Coronary Fibrous-Cap Thickness Assessed by Optical Coherence Tomography in Patients With Acute Coronary Syndrome: The ESCORT Study. JACC. Cardiovascular imaging 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28917689
  5. Nicholls SJ, Puri R. Implications of GLAGOV study. Curr Opin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28937411
  6. Min JK, Chandrashekhar Y, Narula J. The Immediate Effects of Statins on Coronary Atherosclerosis: Can Phenotype Explain Outcome? JACC. Cardiovascular imaging 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28917681
  7. Li YH, Wang LH, Li Q et al. Effects of rosuvastatin on pentraxin 3 level and platelet aggregation rate in elderly patients with acute myocardial infarction undergoing elective interventional therapy: a double-blind controlled study. Eur Rev Med Pharmacol Sci 2017; 21:3730-3735. http://www.ncbi.nlm.nih.gov/pubmed/?term=28925467
  8. Hayward RA. When to Start a Statin Is a Preference-Sensitive Decision. Circulation 2017; 136:1099-1101. http://www.ncbi.nlm.nih.gov/pubmed/?term=28923904
  9. Deck BL, Rick J, Xie SX et al. Statins and Cognition in Parkinson's Disease. Journal of Parkinson's disease 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28922167
  10. Ayubi E, Safiri S. Risk of Colchicine-Associated Myopathy in Gout: Influence of Concomitant Use of Statin; Methodologic Issues. Am J Med 2017; 130:e467. http://www.ncbi.nlm.nih.gov/pubmed/?term=28927545
  11. Zhang MZ, Qian DH, Xu JC et al. Statins may be beneficial for patients with pulmonary hypertension secondary to lung diseases. J Thorac Dis 2017; 9:2437-2446. http://www.ncbi.nlm.nih.gov/pubmed/?term=28932549
  12. Waite LH, Phan YL, Spinler SA. Author's Reply to: Comment: Translating Guidelines Into Practice: Interpreting 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. The Annals of pharmacotherapy 2017:1060028017732359. http://www.ncbi.nlm.nih.gov/pubmed/?term=28922930
  13. Superko HR, Zhao XQ, Hodis HN, Guyton JR. Niacin and heart disease prevention: Engraving its tombstone is a mistake. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28927896
  14. Nestelberger T, Boeddinghaus J, Badertscher P et al. Effect of Definition on Incidence and Prognosis of Type 2 Myocardial Infarction. J Am Coll Cardiol 2017; 70:1558-1568. http://www.ncbi.nlm.nih.gov/pubmed/?term=28935032
  15. Li YR, Tsai SS, Lin YS et al. Moderate- to high-intensity statins for secondary prevention in patients with type 2 diabetes mellitus on dialysis after acute myocardial infarction. Diabetology & metabolic syndrome 2017; 9:71. http://www.ncbi.nlm.nih.gov/pubmed/?term=28932290
  16. Kozlowski S, Lipa M, Lipa J, Bomba-Opon D. An experimental administration of pravastatin in patient with previous, multiple pregnancy losses. Ginekologia polska 2017; 88:460-461. http://www.ncbi.nlm.nih.gov/pubmed/?term=28930366
  17. Koopal C, Marais AD, Westerink J et al. Effect of adding bezafibrate to standard lipid-lowering therapy on post-fat load lipid levels in patients with familial dysbetalipoproteinemia. A randomized, placebo-controlled, crossover trial. Journal of lipid research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28928170
  18. Kim DW, Kim HK, Bae EK. The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy. Epilepsy & behavior : E&B 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28927716
  19. Kato Y, Mukai Y, Rane A et al. Combined effect of telmisartan and fluvastatin on arachidonic acid metabolism in human liver microsomes. Xenobiotica 2017:1-25. http://www.ncbi.nlm.nih.gov/pubmed/?term=28933256
  20. Islam MM, Yang HC, Nguyen PA et al. Exploring association between statin use and breast cancer risk: an updated meta-analysis. Archives of gynecology and obstetrics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28940025
  21. Guimaraes ES, Cerda A, Dorea EL et al. Effects of short term add-on ezetimibe to statin treatment on expression of adipokines and inflammatory markers in diabetic and dyslipidemic patients. Cardiovasc Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28940978
  22. Gao X, Nan Y, Zhao Y et al. Atorvastatin reduces lipid accumulation in the liver by activating protein kinase A-mediated phosphorylation of perilipin 5. Biochim Biophys Acta 2017; 1862:1512-1519. http://www.ncbi.nlm.nih.gov/pubmed/?term=28919478
  23. Cicero AFG, Colletti A, Bajraktari G et al. Lipid-lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel. Nutrition reviews 2017; 75:731-767. http://www.ncbi.nlm.nih.gov/pubmed/?term=28938795
  24. Bove M, Fogacci F, Cicero A. Pharmacokinetic drug evaluation of ezetimibe + simvastatin for the treatment of hypercholesterolemia. Expert Opin Drug Metab Toxicol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28922021
  25. Zhong P, Wu D, Ye X et al. Secondary prevention of major cerebrovascular events with seven different statins: a multi-treatment meta-analysis. Drug design, development and therapy 2017; 11:2517-2526. http://www.ncbi.nlm.nih.gov/pubmed/?term=28919704
Miscellaneous publications
  1. Zhao SP, Li R, Dai W et al. Xuezhikang contributes to greater triglyceride reduction than simvastatin in hypertriglyceridemia rats by up-regulating apolipoprotein A5 via the PPARalpha signaling pathway. PLoS One 2017; 12:e0184949. http://www.ncbi.nlm.nih.gov/pubmed/?term=28934253
  2. Zhang N, Song C, Zhao B et al. Neovascularization and Synaptic Function Regulation with Memantine and Rosuvastatin in a Rat Model of Chronic Cerebral Hypoperfusion. Journal of molecular neuroscience : MN 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28920182
  3. Zanoni C, Aiello G, Arnoldi A, Lammi C. Hempseed Peptides Exert Hypocholesterolemic Effects with a Statin-Like Mechanism. Journal of agricultural and food chemistry 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28931275
  4. Vieira G, Cavalli J, Goncalves ECD et al. Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I. Frontiers in pharmacology 2017; 8:584. http://www.ncbi.nlm.nih.gov/pubmed/?term=28928655
  5. Urbano F, Bugliani M, Filippello A et al. Atorvastatin but Not Pravastatin Impairs Mitochondrial Function in Human Pancreatic Islets and Rat beta-Cells. Direct Effect of Oxidative Stress. Scientific reports 2017; 7:11863. http://www.ncbi.nlm.nih.gov/pubmed/?term=28928397
  6. Ungaro F, Catanzano O, d'Angelo I et al. Microparticle-embedded fibroin/alginate beads for prolonged local release of simvastatin hydroxyacid to mesenchymal stem cells. Carbohydrate polymers 2017; 175:645-653. http://www.ncbi.nlm.nih.gov/pubmed/?term=28917913
  7. Tricarico PM, Gratton R, Braga L et al. 25-Hydroxycholesterol and inflammation in Lovastatin-deregulated mevalonate pathway. The international journal of biochemistry & cell biology 2017; 92:26-33. http://www.ncbi.nlm.nih.gov/pubmed/?term=28918367
  8. Showande SJ, Adegbolagun OM, Igbinoba SI, Fakeye TO. In vivo pharmacodynamic and pharmacokinetic interactions of Hibiscus sabdariffa calyces extracts with simvastatin. Journal of clinical pharmacy and therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28925046
  9. Kanno M, Nakayama M, Zhu WJ et al. Rosuvastatin pretreatment suppresses distant organ injury following unilateral renal ischemia-reperfusion in hypertensive Dahl salt-sensitive rats. Nephrology (Carlton) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28940950
  10. Janjic M, Pappa F, Karagkiozaki V et al. Surface modification of endovascular stents with rosuvastatin and heparin-loaded biodegradable nanofibers by electrospinning. International journal of nanomedicine 2017; 12:6343-6355. http://www.ncbi.nlm.nih.gov/pubmed/?term=28919738
  11. Bhuyan AAM, Nussle S, Cao H et al. Simvastatin, a Novel Stimulator of Eryptosis, the Suicidal Erythrocyte Death. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2017; 43:492-506. http://www.ncbi.nlm.nih.gov/pubmed/?term=28930754
  12. Al-Habsi AA, Massarsky A, Moon TW. Atorvastatin alters gene expression and cholesterol synthesis in primary rainbow trout (Oncorhynchus mykiss) hepatocytes. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28919473
  13. Gabr MM, Mortada SM, Sallam MA. Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for enhancement of rosuvastatin oral bioavailability. Eur J Pharm Sci 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=
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