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Update - Week 19, 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

Delayed progression in patients using statins with mild cognitive impairment
In this retrospective analysis 686 American patients, identified with mild cognitive impairment (MCI), were grouped in 6 cohorts, according to their Apo E status, and statin use. In the follow-up phase of this study patients were assessed for cognitive decline using the Alzheimer’s Disease Assessment Scale 11 (ADAS 11). Less decline was observed in the patients using statins vs no statins use, 20.82 vs. 21.22, respectively. When patients were analyzed by Apo E type, Apo E4 absence showed on only a marginal effect on the ADAS 11 Score. The authors concluded. Because of the small sample size correction for potential confounders as well as a multi variate analysis was not possible. Although there was a trend towards delayed progression, the patients using statins were not worse when using a statin. The authors concluded “Because we show here that statins have no adverse effect on cognition in MCI and may have a slight positive benefit, a clinical trial should be considered with sample sizes large enough to detect significant differences with statin treatment”.
Smith KB, Kang P, Sabbagh MN. The Effect of Statins on Rate of Cognitive Decline in Mild Cognitive Impairment. Alzheimer's & dementia (New York, N. Y.) 2017; 3:149-156. http://www.ncbi.nlm.nih.gov/pubmed/?term=28480324
 
Implementing 2013 ACC/AHA guideline for statins can improve
By combining data from the NHANES survey 2007-2012 and the updated ACC/AHA lipid lowering guidelines, the authors were able to determine statin eligibility and actual statin use in Americans at increased risk for CVD. Of the > 42 million statins eligible, but untreated, adults, 52.6% were hypertensive and 71% <65 years. the number of, by statins use, preventable CVD events amounted to 232 000. Most of these individuals were <65 Years and a higher likelihood being Afro-Americans, Hispanics compared to Caucasians; 73.0%, 69.3% and 56.9 % (P<0.01) respectively. When calculating a ratio of statin eligibility but untreated to statin treated adults the ratios were higher in Hispanics (3.0) and Afro-Americans (2.9) compared to Caucasians (1.3) (P< 0.01). Intriguingly almost 2/3 of the statin eligible but untreated adults had 2 or more healthcare related visits per year providing ample opportunity to recognize and treat according to ACC/AHA Guideline rulings. This study recognizes opportunities to improve the use of statins in high risk individuals, by raising awareness in health care professionals, to do a proper evaluation of statin eligibility, in patients that present with a single or multiple CVD risk factor(s). Extra attention for patients that are non-Caucasians is warranted as well
Sarasua SM, Li J, Hernandez GT et al. Opportunities for improving cardiovascular health outcomes in adults younger than 65 years with guideline-recommended statin therapy. Journal of clinical hypertension (Greenwich, Conn.) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28480530
 
Open label vs randomized phase resulted in a 40% increase of muscle reported side effects in ASCOT
Evaluating statin tolerability is a daunting challenge for healthcare professionals managing patients with reported statin side effects. The so-called Nocebo effect is almost indistinguishable from genuine statin related muscle symptoms. In this sub-analysis of the ASCOT study, comparing atorvastatin 10 mg with placebo in hypertensive primary prevention patients, statin side effects and tolerability were evaluated. In total 11 181 patients were in included in the trial that was prematurely terminated due to the observed benefits in the treated patient. Patients were subsequently offered an open label 10 mg of Atorvastatin. For this analysis 9 899 patients were analyzed; 6409 (65%) used 10 mg atorvastatin and 3490 (35%) were in the placebo group.  The Median follow-up time was 2.3 years (2.2-2.4). the reported muscle related side-effects during the blinded study period amounted to 298 reported events (2·03%/yr.) vs 283 [2·00%/yr.]; HR 1·03 [95% CI 0·88–1·21]; p=0·72) in atorvastatin 10 mg and placebo users respectively. After starting open label atorvastatin 10 mg use, the reported muscle-related AEs increased significantly in the atorvastatin compared to those who were not.  161 (1·26%/yr.) vs 124 (1·00%/yr.); HR1·41 [1·10–1·79]; p=0·006). Tis amounts to a 40% increase in muscle reported AE’s after patients were aware that they were using atorvastatin 10 mg and not a placebo. This increase in reported AE’s was not observed for other monitored AS’s such as erectile dysfunction, sleep disturbances or cognitive impairment. The authors emphasize that the much higher incidence of muscle AE’s in observational studies and open label trials compared to RCT’s is most likely caused by the observed Nocebo effect in the ASCOT study.
Gupta A, Thompson D, Whitehouse A et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28476288
Pedro-Botet J, Rubies-Prat J. Statin-associated muscle symptoms: beware of the nocebo effect. Lancet 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28476289
 
Meta-analysis of Statin benefits in patients with liver disease
The use of statins in patients at risk for CVD and manifest liver disease remains a challenge for health care professionals. Confusion started when transaminase increases were observed in RCT’s with statins and patients ended up being excluded from further participations if these measurements increased. Over the years the detrimental effects of an AST/ALT rise were questioned. Some studies showed that statins might protect the liver from (further) damage instead of causing harm. In this meta-analysis, the authors combined the data from 3 randomized and 10 cohort studies in adults with chronic liver disease (CLD), and that reported on the development of cirrhosis, decompensated cirrhosis, improvements in portal hypertension, or mortality in patients using statins. Evaluated were 121,058 patients with CLDs (84.5% with hepatitis C) of which 46% were exposed to statins. In cirrhotic patient’s statin use was associated with 46% lower risk of hepatic decompensation (4 studies; RR, 0.54; 95% CI, 0.46–0.62) and 46% lower mortality (5 studies; RR, 0.54; 95% CI, 0.47–0.61). Non-cirrhotic patients with CLD showed a, nonsignificant, 58% lower risk for cirrhosis or fibrosis progression (5 studies; RR, 0.42; 95% CI, 0.16–1.11). Data from 3 RCT’s showed a 27% reduced risk of variceal bleeding or progression of portal hypertension. HR, 0,73 (95% CI, 0.59-0.91). The quality of evidence was considered moderate in all evaluations except for the analysis of cirrhosis and fibrosis progression in non-cirrhotic patients this was based on very low-quality evidence. The authors concluded that based on this systematic review, statin use seemed to lower the risk of hepatic decompensation and mortality, and might reduce portal hypertension, in patients with CLD. However better designed prospective observational studies and RCT’s are needed to confirm these observations.
Kim RG, Loomba R, Prokop LJ, Singh S. Statin Use and Risk of Cirrhosis and Related Complications in Patients with Chronic Liver Diseases: a Systematic Review and Meta-analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28479502

Relevant publications
  1. Wang S, Yao H, Yu H et al. Effect of perioperative statin therapy on renal outcome in patients undergoing cardiac surgery: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2017; 96:e6883. http://www.ncbi.nlm.nih.gov/pubmed/?term=28489791
  2. Sarfo FS, Ovbiagele B. Stroke minimization through additive anti-atherosclerotic agents in routine treatment (SMAART): A pilot trial concept for improving stroke outcomes in sub-Saharan Africa. J Neurol Sci 2017; 377:167-173. http://www.ncbi.nlm.nih.gov/pubmed/?term=28477689
  3. Ohta A, Kato H, Ishii S et al. Effect of Ezetimibe Monotherapy on Low-Density Lipoprotein Cholesterol and on Markers of Cholesterol Synthesis and Absorption in Japanese Patients With Hypercholesterolemia. Journal of clinical medicine research 2017; 9:476-481. http://www.ncbi.nlm.nih.gov/pubmed/?term=28496547
  4. Nobre MRC, Domingues RZL. Patient adherence to ischemic heart disease treatment. Rev Assoc Med Bras (1992) 2017; 63:252-260. http://www.ncbi.nlm.nih.gov/pubmed/?term=28489132
  5. Giacoppo D, Gargiulo G, Buccheri S et al. Preventive Strategies for Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Procedures: Evidence From a Hierarchical Bayesian Network Meta-Analysis of 124 Trials and 28 240 Patients. Circulation. Cardiovascular interventions 2017; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=28487354
  6. Ehelepola NDB, Sathkumara S, Bandara H, Kalupahana KLR. Atorvastatin-Diltiazem Combination Induced Rhabdomyolysis Leading to Diagnosis of Hypothyroidism. Case reports in medicine 2017; 2017:8383251. http://www.ncbi.nlm.nih.gov/pubmed/?term=28487744
  7. Caldwell S. NASH Therapy: omega 3 supplementation, vitamin E, insulin sensitizers and statin drugs. Clinical and molecular hepatology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28494529
  8. Xie W, Ning L, Huang Y et al. Statin use and survival outcomes in endocrine-related gynecologic cancers: A systematic review and meta-analysis. Oncotarget 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28489569
  9. Teramoto T, Daida H, Ikewaki K et al. Lipid-modifying efficacy and tolerability of anacetrapib added to ongoing statin therapy in Japanese patients with dyslipidemia. Atherosclerosis 2017; 261:69-77. http://www.ncbi.nlm.nih.gov/pubmed/?term=28478132
  10. Sugiyama Y, Kazuya M, Toshimoto K. Is ethnic variability in the exposure to rosuvastatin explained only by genetic polymorphisms in OATP1B1 and BCRP or should the contribution of intrinsic ethnic differences in OATP1B1 be considered? Journal of pharmaceutical sciences 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28479351
  11. Su VY, Su WJ, Yen YF et al. Statin Use is Associated with a Lower Risk of Tuberculosis. Chest 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28479115
  12. Qureshi WT, Kaplan RC, Swett K et al. American College of Cardiology/American Heart Association (ACC/AHA) Class I Guidelines for the Treatment of Cholesterol to Reduce Atherosclerotic Cardiovascular Risk: Implications for US Hispanics/Latinos Based on Findings From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28495699
  13. Phillips KP. Role of Inflammation in Initiation and Perpetuation of Atrial Fibrillation: A Systematic Review of the Published Data. Journal of atrial fibrillation 2013; 6:935. http://www.ncbi.nlm.nih.gov/pubmed/?term=28496901
  14. Paturi A, Shukla A, Ebra G et al. Do Statins Reduce Atrial Fibrillation After Coronary Artery Bypass Grafting? Journal of atrial fibrillation 2011; 4:347. http://www.ncbi.nlm.nih.gov/pubmed/?term=28496694
  15. Lu VM, McDonald KL. The current evidence of statin use affecting glioblastoma prognosis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28495423
  16. Kitzmiller JP, Luzum JA, Dauki A et al. Candidate-Gene Study of Functional Polymorphisms in SLCO1B1 and CYP3A4/5 and the Cholesterol-Lowering Response to Simvastatin. Clinical and translational science 2017; 10:172-177. http://www.ncbi.nlm.nih.gov/pubmed/?term=28482130
  17. Gamboa CM, Colantonio LD, Brown TM et al. Race-Sex Differences in Statin Use and Low-Density Lipoprotein Cholesterol Control Among People With Diabetes Mellitus in the Reasons for Geographic and Racial Differences in Stroke Study. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28490523
  18. Fauchier L, Clementy N, Pierre B, Babuty D. Statin and Atrial Fibrilation: When does it work? Journal of atrial fibrillation 2012; 5:443. http://www.ncbi.nlm.nih.gov/pubmed/?term=28496754
  19. Corrado A, Raviele A. Antiarrhythmic Effect of Statin Therapy and Atrial Fibrillation A Meta-Analysis of Randomized Controlled Trials. Journal of atrial fibrillation 2008; 1:50. http://www.ncbi.nlm.nih.gov/pubmed/?term=28496573
  20. Cardwell CR, Spence AD, Hughes CM, Murray LJ. Statin use after esophageal cancer diagnosis and survival: A population based cohort study. Cancer epidemiology 2017; 48:124-130. http://www.ncbi.nlm.nih.gov/pubmed/?term=28486205
  21. Barnes BJ, Solomon S, Howard PA et al. Preoperative Statin use is not Associated with a Reduced Risk of Atrial Fibrillation After Cardiac Surgery. Journal of atrial fibrillation 2011; 4:325. http://www.ncbi.nlm.nih.gov/pubmed/?term=28496690
  22. Allott EH, Howard LE, Vidal AC et al. Statin Use, Serum Lipids, and Prostate Inflammation in Men with a Negative Prostate Biopsy: Results from the REDUCE Trial. Cancer prevention research (Philadelphia, Pa.) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28487295

Miscellaneous publications
  1. Li R, Gan YH. Inhibiting HDAC1 Enhances the Anti-Cancer Effects of Statins through Downregulation of GGTase-Ibeta Expression. Int J Mol Sci 2017; 18. http://www.ncbi.nlm.nih.gov/pubmed/?term=28481295
  2. Kassem AM, Ibrahim HM, Samy AM. Development and Optimization of Atorvastatin Calcium loaded Self-nanoemulsifying Drug Delivery System (SNEDDS) for Enhancing Oral Bioavailability: in vitro and in vivo Evaluation. Journal of microencapsulation 2017:1-41. http://www.ncbi.nlm.nih.gov/pubmed/?term=28481663
  3. Kapelouzou A, Giaglis S, Peroulis M et al. Overexpression of Toll-Like Receptors 2, 3, 4, and 8 Is Correlated to the Vascular Atherosclerotic Process in the Hyperlipidemic Rabbit Model: The Effect of Statin Treatment. Journal of vascular research 2017; 54:156-169. http://www.ncbi.nlm.nih.gov/pubmed/?term=28478461
  4. El-Nabarawi N, El-Wakd M, Salem M. Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study. Drug design, development and therapy 2017; 11:1383-1391. http://www.ncbi.nlm.nih.gov/pubmed/?term=28496308
  5. Chin LH, Hsu SP, Zhong WB, Liang YC. Correction: Combined Treatment with Troglitazone and Lovastatin Inhibited Epidermal Growth Factor-Induced Migration through the Downregulation of Cysteine-Rich Protein 61 in Human Anaplastic Thyroid Cancer Cells. PLoS One 2017; 12:e0177545. http://www.ncbi.nlm.nih.gov/pubmed/?term=28481927
  6. Bayatmakoo R, Rashtchizadeh N, Yaghmaei P et al. Atorvastatin inhibits cholesterol-induced caspase-3 cleavage through down-regulation of p38 and up-regulation of Bcl-2 in the rat carotid artery. Cardiovascular journal of Africa 2017; 28:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28498386
  7. Bayat N, Izadpanah R, Ebrahimi-Barough S et al. Erratum to: Anti-inflammatory Effects of Atorvastatin in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment. Mol Neurobiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28478505
  8. Rageh AH, Atia NN, Abdel-Rahman HM. Lipophilicity estimation of statins as a decisive physicochemical parameter for their hepato-selectivity using reversed-phase thin layer chromatography. Journal of pharmaceutical and biomedical analysis 2017; 142:7-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=28477451
  9. J BV, Ramakrishna S, Madhusudhan B. Preparation and characterisation of atorvastatin and curcumin-loaded chitosan nanoformulations for oral delivery in atherosclerosis. IET nanobiotechnology 2017; 11:96-103. http://www.ncbi.nlm.nih.gov/pubmed/?term=28476969
  10. Gum SI, Nguyen PA, Lee JR et al. The physico-chemical alteration of lovastatin and enhanced antioxidant effect of Bacillus subtilis fermented-red yeast rice product. Food chemistry 2017; 232:203-209. http://www.ncbi.nlm.nih.gov/pubmed/?term=28490066
  11. Gabr MM, Mortada SM, Sallam MA. Hexagonal liquid crystalline nanodispersions proven superiority for enhanced oral delivery of rosuvastatin: in-vitro characterization and in-vivo pharmacokinetic study. Journal of pharmaceutical sciences 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28479357

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