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Update - Week 18, 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

Bleeding risk of statins evaluated in acute ischemic stroke patients
One of the reasons doctors refrain from prescribing statins, is the fear of an increased bleeding risk. This was observed in the SPARCL study, where the use of atorvastatin in post-acute ischemic stroke (AIS) patients was assessed. Data collected in the Enhanced Control of Hypertension And Thrombolysis stroke study (ENCHANTED), a study designed to evaluate alteplase dosing in acute ischemic stroke patients, was re-tested by mean of a post-hoc sub group analysis. Of the total group of 3284 patients; 614 (19%) patients used lipid lowering medication. The primary endpoint was death or disability (modified Rankin Scale scores 2–6) at 90 days. Statin users were significantly different when compared to the no-statin users; they were older, non-Asian and more likely to have vascular co-morbidities. After propensity matching and adjustments for baseline variables, no significant differences in mortality, OR 0.85 (0.58–1.25, p = 0.42), or overall 90-day death and disability, OR 0.85 (0.67–1.09, p = 0.19) were noted. A significant reduced risk for symptomatic ischemic stroke was observed in patients that used statins, OR 0.49 (0.28–0.83, p = 0.009). Other key safety and efficacy parameters were not different between the two groups. The authors concluded that lipid lowering pre-treatment was not associated with an increased bleeding risk in post AIS patients.
Minhas JS, Wang X, Arima H et al. Lipid-Lowering Pretreatment and Outcome Following Intravenous Thrombolysis for Acute Ischaemic Stroke: A Post Hoc Analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study Trial. Cerebrovasc Dis 2018; 45:213-220. http://www.ncbi.nlm.nih.gov/pubmed/?term=29705803
 
EAS update on relevant statin adverse effects
The EAS consensus panel released a clinical update, on the adverse effects of statin therapy: perception vs. the evidence – focus on glucose homeostasis, cognitive, renal and hepatic function, hemorrhagic stroke and cataract. The authors review current updated literature (2000 – 2017) on these topics and provide a simple comprehensive overview on the most common reported adverse events of statins. This is a easily accessible resource for practicing clinicians that need to be updated on new developments regarding statin side effects overall or that seek information on a specific problem that confronted them in clinical practice. For each separate topic: muscle related, new onset diabetes, Renal function, liver function, cognitive adverse effects, hemorrhagic stroke and cataracts, literature and relevant clinical trials are discussed, and 3-5 take-home message are added to summarize the current evidence. Overall the recommendations of the EAS consensus panel re-affirm the long-term safety of statins and underlines the importance of following the recently published European Guidelines for lipid management of patients at risk for CVD.
Mach F, Ray KK, Wiklund O et al. Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29718253
 
CTO Patient without revasc. have a greater chance of surviving when on statins
In this retrospective analysis of data collected in a single Korean medical center, between March 2003 and February 2012, patients with at least one chronic total occlusion (CTO) of their coronary arteries were evaluated. In total 2024 patients were included in the CTO registry and 664 were managed conservatively, without a revascularization procedure. After exclusion criteria 551 patients were eligible, 369 used a statin and 182 did not. After a median follow-up time of 45.7 months (inter quartile range: 19.9 -70.5 months), 22 patients (6.0%) in the statin group died vs 24 (13.2%) patients did not survive in the non-statin group (P<0.001). After propensity score matching, statin use was associated a reduced risk of cardiac death, HR: 0.39 (0.18-0.85, P=0.022) and major cardiovascular events, HR: 0.66 (0.43-0.98, P= 0043). After a multivariate analysis, mortality predictors were age >70 years, renal insufficiency, prior MI, VEF < 40%, proximal to mid CTO location and statin use. The authors concluded that statin therapy seems to benefit CTO patients in who no re-vascularization is possible.
Kim BS, Yang JH, Jang WJ et al. Long-term Survival Benefit of Statin in Patients with Coronary Chronic Total Occlusion without Revascularization. J Korean Med Sci 2018; 33:e134. http://www.ncbi.nlm.nih.gov/pubmed/?term=29713254
 
Do English language websites drive statin nocebo effects?
Perceived issues regarding safety and tolerability, remain a significant hurdle in (long term) statin adherence. The scientific evidence of safety, efficacy, as well as low costs of statins, are overshadowed by the harms touted by semi scientific claims based on individual case reports, and over-emphasis of observational data vs RCT data. In this article the authors evaluate the impact of web based information on statin tolerability and show that psychological, not pharmacological factors, are likely to play a dominant role. By performing a single day Google search in 13 countries they observed a predominance of English language vs local language websites on statin intolerance. English language websites were significantly more prolific with a ratio of approximately 4-5:1 When correlating this with reported rates of statin intolerance in English language countries (Canada, UK, USA and Australia) vs the remaining 9 countries, a similar ratio was observed. Countries with similar healthcare systems and ethnic composition e.g. UK vs Sweden, Spain and Italy reported incidences of statin tolerability of 11% vs 2% respectively. The authors concluded that on-line information on statin intolerance may be an important contributing factor to the statin nocebo effect.
Khan S, Holbrook A, Shah BR. Does Googling lead to statin intolerance? Int J Cardiol 2018; 262:25-27. http://www.ncbi.nlm.nih.gov/pubmed/?term=29706390
Tobert JA. Statins - Good drugs, not so good reputation. Int J Cardiol 2018; 262:28-29. http://www.ncbi.nlm.nih.gov/pubmed/?term=29706391
 
Can Statins improve portal hypertension in cirrhotic patients?
The use of statin in patients with liver disease is changing. In the past statins were not prescribed, or stopped in patients with liver problems, recently several studies highlighted the surprising benefits of statin in patients with even advanced chronic liver disease. In this single center Egyptian study 40 patients with advance liver cirrhosis and associated portal hypertension were randomized to simvastatin 20 mg for 2 weeks followed by 40 mg for an additional two weeks. The control group did not get simvastatin, so an open label design. Patient underwent doppler ultrasound as well as laboratory and clinical examinations at the start and at the end of this 30-day study. Parameters related to portal hypertension improved significantly in the patient using simvastatin; including hepatic artery resistance index 0.785 ± 0.088 to 0.717 ± 0.086 (P < 0.001), portal hypertension index 3.915 ± 0.973 m/sec to 3.605 ± 1.168 m/sec (P = 0.024) and modified liver vascular index 11.540 ± 3.266 cm/sec to 13.305 ± 3.222 cm/sec, an increase of 15.3% from baseline (P = 0.009). No difference in adverse events were observed between the two groups. Based on this small PROBE randomized controlled trial, simvastatin was shown to improve portal hypertension related parameter. The reported results should serve as a strong impetus to conduct larger well-designed placebo controlled randomized trials to confirm the observed benefits.
Elwan N, Salah R, Hamisa M et al. Evaluation of portal pressure by doppler ultrasound in patients with cirrhosis before and after simvastatin administration - a randomized controlled trial. F1000Research 2018; 7:256. http://www.ncbi.nlm.nih.gov/pubmed/?term=29707200
 
 
Relevant publications
  1. Shrivastava-Ranjan P, Flint M, Bergeron E et al. Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing. mBio 2018; 9. http://www.ncbi.nlm.nih.gov/pubmed/?term=29717011
  2. Pradhan AD, Aday AW, Rose LM, Ridker PM. Residual Inflammatory Risk On Treatment with PCSK9 Inhibition and Statin Therapy. Circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29716940
  3. Lin HW, Ho YF, Lin FJ. Statin Use Associated with Lower Risk of Epilepsy after Intracranial Hemorrhage: A Population-Based Cohort Study. Br J Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29714813
  4. Leppien E, Mulcahy K, Demler TL et al. Effects of Statins and Cholesterol on Patient Aggression: Is There a Connection? Innovations in clinical neuroscience 2018; 15:24-27. http://www.ncbi.nlm.nih.gov/pubmed/?term=29707423
  5. Karlson BW, Nicholls SJ, Lundman P et al. Modeling Statin-Induced Reductions of Cardiovascular Events in Primary Prevention: A VOYAGER Meta-Analysis. Cardiology 2018; 140:30-34. http://www.ncbi.nlm.nih.gov/pubmed/?term=29705799
  6. Clarke R, Valdes-Marquez E, Hill M et al. Plasma cytokines and risk of coronary heart disease in the PROCARDIS study. Open heart 2018; 5:e000807. http://www.ncbi.nlm.nih.gov/pubmed/?term=29713486
  7. Benesic A, Rotter I, Dragoi D et al. Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-induced Liver Injury. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29723689
  8. Zheng W, Yang W, Zhang QE et al. Meta-analysis of the Efficacy and Safety of Adjunctive Rosuvastatin for Dyslipidemia in Patients with Schizophrenia. Shanghai archives of psychiatry 2018; 30:4-11. http://www.ncbi.nlm.nih.gov/pubmed/?term=29719353
  9. Yamazaki S. Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug-Drug Interactions on Metabolizing Enzymes and Transporters. Journal of clinical pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29723430
  10. Quon J, Parkin L, Sharples K, Barson D. Co-prescribing of contraindicated and use-with-caution drugs in a national cohort of new users of simvastatin: how well are prescribing guidelines followed? The New Zealand medical journal 2018; 131:35-44. http://www.ncbi.nlm.nih.gov/pubmed/?term=29723177
  11. Lin TK, Chou P, Lin CH et al. Long-term effect of statins on the risk of new-onset osteoporosis: A nationwide population-based cohort study. PLoS One 2018; 13:e0196713. http://www.ncbi.nlm.nih.gov/pubmed/?term=29723231
  12. Kaleem Z, Khan JA, Mushtaq Z et al. Assessment of potential interaction between simvastatin and clarithromycin in healthy adult male subjects. Pak J Pharm Sci 2018; 31:801-806. http://www.ncbi.nlm.nih.gov/pubmed/?term=29716858
  13. Ayesha SM, Meena AK, Vangala N et al. Necrotizing Autoimmune Myopathy: Clinicopathologic Study from a Single Tertiary Care Centre. Annals of Indian Academy of Neurology 2018; 21:62-67. http://www.ncbi.nlm.nih.gov/pubmed/?term=29720800
  14. Allott EH, Farnan L, Steck SE et al. Statin use, high cholesterol and prostate cancer progression; results from HCaP-NC. Prostate 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29717502
Miscellaneous publications
 
 
  1. Thompson JM, Alvarez A, Singha MK et al. Targeting the mevalonate pathway suppresses VHL-deficient CC-RCC through a HIF-dependent mechanism. Molecular cancer therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29720560
  2. Kubo Y, Akanuma SI, Hosoya KI. Recent advances in drug and nutrient transport across the blood-retinal barrier. Expert Opin Drug Metab Toxicol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29719158
  3. de Bruyn T, Ufuk A, Cantrill C et al. Predicting Human Clearance of OATP substrates using Cynomolgus monkey: In vitro-in vivo scaling of hepatic uptake clearance. Drug metabolism and disposition: the biological fate of chemicals 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29720472
  4. Chen T, Wang Y, Zhang T et al. Simvastatin Enhances Activity and Trafficking of alpha7 Nicotinic Acetylcholine Receptor in Hippocampal Neurons Through PKC and CaMKII Signaling Pathways. Frontiers in pharmacology 2018; 9:362. http://www.ncbi.nlm.nih.gov/pubmed/?term=29706890
  5. Yao Y, Toshimoto K, Kim SJ et al. Quantitative analysis of complex drug-drug interactions (DDIs) between cerivastatin and inhibitors using physiologically based pharmacokinetic (PBPK) modeling. Drug metabolism and disposition: the biological fate of chemicals 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29712725
  6. Jin Z, Jung Y, Yi CO et al. Atorvastatin pretreatment attenuates kainic acid-induced hippocampal neuronal death via regulation of lipocalin-2-associated neuroinflammation. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 2018; 22:301-309. http://www.ncbi.nlm.nih.gov/pubmed/?term=29719452
  7. Bae SH, Park WS, Han S et al. Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 2018; 22:321-329. http://www.ncbi.nlm.nih.gov/pubmed/?term=29719454
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This activity is supported by an educational grant from Pfizer.