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Update - Week 29, 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

Atorvastatin induced renal metabolic changes associated with CI-AKI protection 
The statin related protective effects for contrast induced acute kidney injury (CI-AKI) have been observed in numerous studies. The exact mechanisms or explanations for these effects remain puzzling. The aim of this study was to explore underlying metabolic changes, after an atorvastatin loading dose of 80 mg, by analyzing post-procedural renal hemodynamics and urinary renalase concentrations. For this prospective randomized single blinded study, 67 statin naïve patients, scheduled for CAG, were given Atorvastatin 80 mg, or placebo, 24 hours prior the procedure. CI-AKI was observed in 2 patients (6.1%) of the atorvastatin users vs 4 patients (11.8%) in the control group (P=0.351). The pre- and post-procedural values of intra-renal blood flow parameters were quite similar in both cohorts. However, in the patients using atorvastatin, the urinary excretion of reno-protective renalase was reduced. Atorvastatin interfered with intra-cellular signaling of the tubular cells via an up-regulation of heat-shock protein 27 (Hsp27) as well as downregulation of Rho/ROCK or JNK/P38 MAP kinase. These biomarker changes reflect a decreased contrast induced renal cell apoptosis. The authors concluded that the CI-AKI protective effects of atorvastatin in patients that undergo CAG seem not to be related to renal blood flow changes but metabolic changes of renalase, associated with preventing renal tubular cell apoptosis.
Wybraniec MT, Filipecki A, Chudek J, Mizia-Stec K. Atorvastatin facilitates protection against contrast-induced nephropathy in patients undergoing coronary angiography via humoral mediators rather than altered renal hemodynamics. Postepy w kardiologii interwencyjnej = Advances in interventional cardiology 2018; 14:191-194. http://www.ncbi.nlm.nih.gov/pubmed/?term=30008773
Adding Ezetimibe to Statins – what do we know?
The basis of lipid management remains the use (high dose high intensity) statins, and for the majority of patients this is effective safe and well tolerated. However in a significant number of patients statins are insufficient to optimally address elevated LDL-c. Add on treatment with alternative LDL-c reducing agents such as ezetimibe, bile acid sequestrants or PCSK9ab’s are needed in those individuals. In this systematic review the authors evaluate the benefits and potential harms of ezetimibe when combined with statins. They used PubMed, PubMed Central, and Cochrane to find randomized clinical trials, retrospective analyses, meta-analyses, and review articles on this topic. The effects of ezetimibe on LDL-c and Apo B translated in an additional 10-18% and 11-16% lowering, respectively, when used as monotherapy; when combined with statins LDL-c can be reduced by 25% and total cholesterol by 34-61%. Based on the IMPROVE-IT study ezetimibe was shown to reduce CHD events as well as well as cerebrovascular ischemic complications. Non-lipid lowering effects have been observed as well. The role of ezetimibe in managing NAFLD/NASH patients, and their postulated anti-inflammatory properties, contributed to the observed benefits. Of note is that, in contrast with statins, pro-diabetogenic effects were absent in patients treated with ezetimibe. improved insulin sensitivity a protective effect on pancreatic beta cells have been described in animal models. Improvement of glycemic parameters, when statins are combined with ezetimibe, are expected but solid clinical trial data to confirm this is still lacking. Based on currently available data the combinations of statin with ezetimibe are effective when additional LDL-c lowering is needed. The combination is well tolerated and is a viable alternative for patients that are unable to tolerate high dose, high intensity statins because of muscle problems. The potential beneficial effects on glycemic control warrant additional studies to confirm the observations from animal studies and observational registries.
Vavlukis M, Vavlukis A. Adding ezetimibe to statin therapy: latest evidence and clinical implications. Drugs in context 2018; 7:212534. http://www.ncbi.nlm.nih.gov/pubmed/?term=30023003
Is NAFLD/NASH a new indication for statins?
For gastroenterologists/hepatologists statins are gaining prominence in managing patients with NAFLD/NAHS. In the systematic review the authors evaluated the evidence of 12 clinical trials, that met the inclusion criteria for their analysis. Overall no harm was observed when statins were used in patients in whom NAFLD/NASH parameters were evaluated. Benefits were noted in a number of studies, but the collected data was insufficient for an in-depth analysis of benefits/harms. The number of participants was to small and the heterogeneity of the different studies made it impossible to combine the different data sets. The authors comment that statin use for the treatment of NAFLD remains controversial and off-label. The observed benefits in improving liver function tests as well as hepatic steatosis look promising and are explored in 6 ongoing trials (5 using atorvastatin and 1 pitavastatin). The pleiotropic anti-inflammatory, anti-oxidant effects of statins are postulated to contribute to the observed benefits. Since CVD is the most common cause of death in NAFLD patients, the benefits of statins in these patients far outweigh the potential harms. Statins are indicated to reduces to reduce elevated CVD risk observed in these patients and should not be stopped or withheld from those that present with NAFLD/NASH co-morbidities.  
Sigler MA, Congdon L, Edwards KL. An Evidence-Based Review of Statin Use in Patients With Nonalcoholic Fatty Liver Disease. Clinical medicine insights. Gastroenterology 2018; 11:1179552218787502. http://www.ncbi.nlm.nih.gov/pubmed/?term=30013416
Is atorvastatin 20 mg sufficient in Asian ACS patients?

What remains a controversial challenge is the use of high dose, high intensity statins in Asian patients. The US and European guidelines emphasize the use of high dose, high intensity statin,  for patients at high or very high risk of ASCVD complications. In contrast, Asian studies, particular those that were conducted with Japanese patients, stress the observed sufficient LDL-C reductions, observed when using intermediate or even low dose, low intensity statins. In this prospective Korean study, 13 statin naïve, ACS patients that presented with non-calcified carotid plaques, were subjected to 18Ffluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) of their carotid arteries at baseline and after 1 month follow up. All patients were treated with atorvastatin 20 mg/day. The authors aimed to evaluated changes in plaque inflammation by measuring the FDG PET/CT target-to-background ratio of the carotid arteries reflecting the number as well as metabolic activity of macrophages. Atorvastatin 20 mg for 1 month was unable to reduce carotid plaque inflammation in one third of participating ACS patients. The TBR at baseline 1.6 (±0.20) vs 1.50 (±0.40) after 1 month. LDL cholesterol was effectively reduced to target in all 13 participants; baseline mean LDL-C 101.2 (± 21.1) mg/dL vs. 70.7 (± 12.4) mg/dL at completion (P<0.001). Changes in the TBR and serum LDL-C levels were not correlated (r = –0.27, p = 0.243). Based on this observation, plaque inflammation was not attenuated by using moderate intensity atorvastatin 20 mg despite an LDL-c 30% reduction and achieving an LDL-c target of 70 mg/dl. Notwithstanding the noted limitations of the study, the results show that one third of the Korean ACS patients had an insufficient response to intermediate dose atorvastatin, despite optimal LDL-c lowering. This highlights that Asian (as well as Caucasian patient, at high risk, are not sufficiently protected when guideline recommended high dose, high intensity statins are forsaken.
Kim CJ, Han EJ, Chu EH et al. Effect of moderate-intensity statin therapy on plaque inflammation in patients with acute coronary syndrome: A prospective interventional study evaluated by 18F-FDG PET/CT of the carotid artery. Cardiology journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30009378
Peri-procedural statin use associated with reduced risk in CEA patients
Carotid endarterectomy (CEA) is a procedure with substantial risk of peri-procedural cerebrovascular complications and even death. Using statins prior/during the procedure has been shown to attenuate this risk. In this systematic review/meta-analysis the authors evaluated 7 studies, including 21 387 patients, that analyzed perioperative stroke and/or survival outcomes following CEA in patients using statins (N=14 976 / 68.9%) or not (N=6 657 – 31.1%). Statin treated patients had significant more co-morbidities. Such as history of cardiac disease (23.6 vs. 12.2% in the statin-free group), diabetes (31.6 vs. 25.1% in the statin-free group), and hypertension (83.5 vs. 72.2% in the statin-free group). In the patients not using statin, symptomatic disease was more common. Periprocedural stroke incidence was reduce in all patients, OR 0.57 (0.34-0.95, P<0.03); In symptomatic patients OR 0.57 (0.35-0.93, P<0.03). A trend was observed for improved perioperative mortality, OR 0.54 (0.29-1.03). Overall survival was significantly better, HR 0.69 (0.59-0.81, P< 0.001). This was after a mean follow up of 62 months (27-76 months). Overall conclusions was that patients scheduled for CEA surgery would derive benefit from using periprocedural statins, however further investigations are needed to fully explore dosages, timing, type of statins and the specific benefits in all or subgroups of patients.
Ironside N, Brenner D, Heyer E et al. Systematic review and meta-analysis of perioperative and long-term outcomes in patients receiving statin therapy before carotid endarterectomy. Acta neurochirurgica 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30019211

Relevant publications
  1. Yu Q, Wang F, Meng X et al. Shortterm use of atorvastatin affects glucose homeostasis and suppresses the expression of LDL receptors in the pancreas of mice. Mol Med Rep 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30015940
  2. Yamamoto H, Kihara Y, Kitagawa T et al. Coronary plaque characteristics in computed tomography and 2-year outcomes: The PREDICT study. Journal of cardiovascular computed tomography 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30017608
  3. Sayeed S, Hernandez AF. Review: In noncardiac surgery, amiodarone, beta-blocker, or statin prophylaxis reduces postoperative AF. Annals of internal medicine 2018; 169:Jc7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30014096
  4. Marzal D, Rodriguez Padial L, Arnaiz JA et al. Use of the cardiovascular polypill 40mg in secondary cardiovascular prevention. Clin Investig Arterioscler 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30017176
  5. Kosmas CE, Munoz Estrella A, Sourlas A et al. Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases (Basel, Switzerland) 2018; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=30011788
  6. Kereiakes DJ, Lepor NE, Gerber R et al. Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: Pooled analysis of eight ODYSSEY phase 3 trials. Atherosclerosis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30025648
  7. Ibanez B, Castellano JM, Fuster V. Polypill strategy at the heart of cardiovascular secondary prevention. Heart 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30030331
  8. Ho K, Jamsen KM, Bell JS et al. Demographic, clinical and lifestyle factors associated with high-intensity statin therapy in Australia: the AusDiab study. Eur J Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30027413
  9. Baris G, Mach F. Lipid management in ACS: Should we go lower faster? Atherosclerosis 2018; 275:368-375. http://www.ncbi.nlm.nih.gov/pubmed/?term=30015301
  10. Asleh R, Briasoulis A, Pereira NL et al. Timing of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor initiation and allograft vasculopathy progression and outcomes in heart transplant recipients. ESC heart failure 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30019530
  11. Rej S, Schulte SW, Rajji TK et al. Statins and cognition in late-life bipolar disorder. International journal of geriatric psychiatry 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30022520
  12. Liu N, Yang G, Hu M et al. Association of ABCC2 polymorphism and gender with high-density lipoprotein cholesterol response to simvastatin. Pharmacogenomics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30024814
  13. Leporowski A, Godman B, Kurdi A et al. Ongoing activities to optimize the quality and efficiency of lipid-lowering agents in the Scottish National Health System: influence and implications. Expert review of pharmacoeconomics & outcomes research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30014725
  14. Green DM, Wang M, Krasin MJ et al. Serum ALT elevations in survivors of childhood cancer. A report from the St. Jude Lifetime Cohort Study. Hepatology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30016547
  15. Dixit A, Abrudescu A. A Case of Atorvastatin-Associated Necrotizing Autoimmune Myopathy, Mimicking Idiopathic Polymyositis. Case Rep Rheumatol 2018; 2018:5931046. http://www.ncbi.nlm.nih.gov/pubmed/?term=30026996
  16. Bougarne N, Weyers B, Desmet SJ et al. Molecular actions of PPARalpha in lipid metabolism and inflammation. Endocrine reviews 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30020428
  17. Balke M, Brunn A, Claeys KG et al. Late onset necrotizing autoimmune myopathy 1 year after cessation of statin treatment. Acta neurologica Belgica 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30008064

Miscellaneous publications
  1. Yang MY, Diao ZY, Wang ZY et al. Pravastatin alleviates lipopolysaccharide-induced placental TLR4 over-activation and promotes uterine arteriole remodeling without impairing fetal development of rats. Journal of biomedical research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30008464
  2. Xie Y, Liu C, Huang H et al. Bone-targeted delivery of simvastatin-loaded PEG-PLGA micelles conjugated with tetracycline for osteoporosis treatment. Drug delivery and translational research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30027372
  3. Wang C, Li T, Yan F et al. Effect of simvastatin and microRNA-21 inhibitor on metastasis and progression of human salivary adenoid cystic carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 105:1054-1061. http://www.ncbi.nlm.nih.gov/pubmed/?term=30021341
  4. Tissier F, Farhat F, Philouze C et al. Long-term atorvastatin treatment decreases heart maximal oxygen consumption and its vulnerability to in vitro oxidative stress in WHHL rabbit. Canadian journal of physiology and pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30011375
  5. Ruan H, Yu Y, Guo X et al. The possibility of healing alveolar bone defects with simvastatin thermosensitive gel: in vitro/in vivo evaluation. Drug design, development and therapy 2018; 12:1997-2003. http://www.ncbi.nlm.nih.gov/pubmed/?term=30013319
  6. Li J, Feng X, Shi J et al. Porous Polylactide Film Plus Atorvastatin-Loaded Thermogel as an Efficient Device for Peritoneal Adhesion Prevention. ACS omega 2018; 3:2715-2723. http://www.ncbi.nlm.nih.gov/pubmed/?term=30023849
  7. Li H, Chen C, Wang D. Lowfrequency ultrasound and microbubbles combined with simvastatin promote the apoptosis of MCF7 cells by affecting the LATS1/YAP/RHAMM pathway. Mol Med Rep 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30015955
  8. Hamzeh M, Hosseinimehr SJ, Mohammadi HR et al. Atorvastatin attenuates the ovarian damage induced by cyclophosphamide in rat: An experimental study. International journal of reproductive biomedicine (Yazd, Iran) 2018; 16:323-334. http://www.ncbi.nlm.nih.gov/pubmed/?term=30027148
  9. Zhang H, Moriyama Y, Ayukawa Y et al. Generation and histomorphometric evaluation of a novel fluvastatin-containing poly(lactic-co-glycolic acid) membrane for guided bone regeneration. Odontology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30022371
  10. Han Y, Kim SJ. Simvastatin-dependent actin cytoskeleton rearrangement regulates differentiation via the extracellular signal-regulated kinase-1/2 and p38 kinase pathways in rabbit articular chondrocytes. Eur J Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30009811
  11. Chen B, Kang C, Yu D et al. [Different effects of simvastatin on keloid fibroblasts under hypoxia and TGF-beta1 treatment]. Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery 2016; 32:130-135. http://www.ncbi.nlm.nih.gov/pubmed/?term=30024693

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