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Update - Week 38, 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

Despite statins, TG related residual risk is substantial
In this retrospective analysis of observational data collected in the Kaiser Permanente integrated medical care delivery service in the Northwest (KPNW) and Southern California (KPSC) regions. The initial selection included patients aged 45 and older with ASCVD or diabetes with at least one other risk factor; TG levels <500 mg/dL and LDL-C values between
40 and 100 mg/dL in 2010 while on statin treatment (N=170,590). For the final selection more, stringent criteria were used resulting in 65 469 participants. These were divided into two groups:  a high TG group (200-499 mg/dL, n=11,797) and a normal TG group (< 150mg/dL, n=42,320). Because a point estimate of TG has a wide range of inherent variability, we excluded 11,339. Patients with TG levels 150-199 mg/dL were excluded as well to ensure two clearly distinctive cohorts (N=11, 339). Over 1/3 (35.4%) of the statin treated patients with acceptable LDL-c levels Patient data was collected between from 2010 – December 2016.  Outcomes of the study were incidence rates of first non-fatal MI, non-fatal stroke, unstable angina, coronary revascularization. Statistical analysis was performed using a multivariable model. the incidence rate for non-fatal MI was 30% higher in the high TG group RR 1.30 (1.08-1.58, p=0.006). For non-fatal stroke a 23% increase was observed RR 1.23 (1.01-1.49, p=0.037); for coronary revascularization a RR 1.21 (1.02-1.43, p=0.027), and a non-significantly 33% increased risk for unstable angina; RR 1.33 (0.87-2.03, p=0.185). The authors concluded that despite adequate statin therapy, patients with moderately elevated TG were exposed to an excess of CVD risk. Using targeted treatments to optimize these aberrant TG levels could provide these very high-risk patients additional protection for ASCVD complications.
Nichols GA, Philip S, Reynolds K et al. Increased Residual Cardiovascular Risk in Patients with Diabetes and High vs. Normal Triglycerides Despite Statin-Controlled LDL Cholesterol. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30225881
Why do we continue to use low (atorva)statin dosages?  
Despite the guideline-recommended use of high dose – high-intensity statins, a large number of physicians prefer using lower dosages, possible out of fear of adverse events related to the intensive statin therapy. The dangers of exposing patients to an increased risk of (subsequent) ASCVD complications, when ignoring guidelines, is mostly overlooked. To evaluate if a low dose of atorvastatin would provide comparable protection in high-risk patients the authors conducted a prospective RCT trial in 256 Chinese patients that received a post-AMI primary PTCA. Participants were randomized to Atorvastatin 40 mg (N=133) or 20 mg (N-132). The follow-up period lasted 1 year, and all MACE’s were noted. The plasma LDL-c in patients using A-40 was significantly lower: 1.6 ± 0.6mmol/l vs. 1.8 ± 0.6 mmol/l, (P=0.041). Events were significantly lower in the A-40 group as well, 6.8 vs. 12.8%, P<0.03). Unplanned revascularization robustly decreased in patients using A40 than those on A 30; 5.2 vs. 8.3% (P=0.03). No differences were observed in the humbler or severity of statin-related adverse events. The results of this study re-affirms the importance of choosing the right statin in the right dosage so patients are optimally protected from (subsequent) ASCVD complications.
Liu Q, Wang Y, Cheng X. The functional effect of atorvastatin dose-dependent via inflammation factors on acute ST-segment elevation myocardial infarction after emergency percutaneous coronary intervention. Journal of cardiovascular medicine (Hagerstown, Md.) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30222665
Ca score in statin-treated patients depends on HDL changes
The relationship between statin therapy and the increase in Ca scores is confusing and the mechanisms responsible for these observed effects are poorly understood. The authors of this study used data collected in the Seoul Metabolic Syndrome registry (N=1370) and focused on the 2016 participants with complete follow-up (N=876). Their Aim was to study 5 statin-related metabolic changes and their relationship with increased CAC scores. The biochemical parameters were: LDL-c, HDL-c, triglyceride, glucose, and hsCRP. The main findings are that when adjusting for the covariates age, sex, SBP, and smoking, statin use was positively associated with CAC OR of 2.006 (1.383-2.851, P<0.001). Increases vascular calcium deposits remained even when the 5 mediation factors were excluded. Only HDL-C proved to be a significant mediator factor, with a mediation score of -0.011 (1.383 to 2.851, P< 0.001). This effect was independent of statin intensity. The authors concluded that HDL-c plasma levels predict Ca build up in the vascular wall and play an inhibitory mediating role in the potential causal pathway between statin and CAC development in patients using statins.
Lee D, Joo HJ, Jung HW, Lim DS. Investigating potential mediator between statin and coronary artery calcification. PLoS One 2018; 13:e0203702. http://www.ncbi.nlm.nih.gov/pubmed/?term=30226851
Patients with advanced renal disease and using statin reduced their risk for developing sepsis
The Taiwanese National Health Insurance Research database (N=23 million!)  was used to study the benefits or harms of statin use in patients with impaired renal function. Non-diabetic patient with advanced renal disease (eGFR < <15 mL/min/1.73 m2) were evaluated. Statin users and non-statin-users were matched using a propensity score, as well as a Cox proportional hazard model. Advanced renal disease was present in 14,452 patients; 2 551 statin users and 7 653 patients not using statins. Statin use was not related to an increased risk for developing NODM or decreasing the risk for MACE. Statin use reduced total mortality, HR 0.59 (0.42–0.84, p = 0.004) and sepsis-related mortality, HR = 0.53 (0.32–0.87, p = 0.012) in patients with severely impaired renal function. This new and surprising finding, in a very large national observational registry, is provocative but will need to be confirmed in a large RCT.
Huang TM, Wu VC, Lin YF et al. Effects of Statin Use in Advanced Chronic Kidney Disease Patients. Journal of clinical medicine 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30227675
To stop or not to stop statins after a hemorrhagic stroke?
From the same Taiwanese National Health Insurance Research database (N=23 million!) An analysis was conducted to study the effects of continuing or stopping statins after an intracerebral hemorrhage (ICH) overall the registry collected data of 114,101 ICH patients. Endpoints, all-cause mortality, and cardiovascular complications were evaluated after 3 years. Ultimately 2 468 post-ICH and dyslipidemic patients were enrolled. Statin users who continued their medication were matched, using a propensity score model, with statin users that stopped. Mortality was significantly reduced in the participants that continued using their lipid-lowering medication 4.9% vs.12.3% at 1 year; HR 0.38 (0.26–0.57). After 3 years total mortality in the statin-users vs statin-stoppers:  12.9% vs. 25.3% respectively; HR 0.45 (0.35–0.58). The authors noted a significant difference in mortality when they compared patients using hydrophilic statins (rosuvastatin-pravastatin) vs lipophilic statins (atorvastatin – simvastatin); HR 0.65 (0.43–0.99). There were no clear benefits for stroke and all-cause mortality when comparing patients that used moderate intensity vs high-intensity statins; HR 0.76 (0.40-1.46). Despite the expected harm of using statins in post-ICH patients, as was observed in the SPARCL study, statin uses was associated with improved survival and less cardiovascular complications. No clear differences of ischemic strokes and ICH recurrence between the patients who continued and discontinued their statins. Also, no difference between high intensity vs low intensity was discerned, but hydrophilic statins seemed superior to lipophilic statins in this analysis. These findings suggest that continuing statin therapy may be safe and result in less serious adverse outcomes.
Chung CM, Lin MS, Liu CH et al. Discontinuing or continuing statin following intracerebral hemorrhage from the view of a national cohort study. Atherosclerosis 2018; 278:15-22. http://www.ncbi.nlm.nih.gov/pubmed/?term=30236866
Relevant publications
  1. Wang H, Wang S, Tao Y, Sun Y. Further insight into 10-year CVD risk evaluation and recommended eligibility for statin therapy in Chinese population: Comparison of cardiovascular risk prediction models and their guidelines. Int J Cardiol 2018; 271:343. http://www.ncbi.nlm.nih.gov/pubmed/?term=30223366
  2. Range JT, LaFontaine PR, Ryder PT, Polston M. Factors Associated With Adherence to Statin Medications of Patients Enrolled in a Self-insured University Health Plan. Clinical therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30231972
  3. Oh TK, Park HY, Shin HJ et al. The Role of Perioperative Statin Use in the Prevention of Delirium After Total Knee Replacement Under Spinal Anesthesia. The Journal of arthroplasty 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30236494
  4. Mickiewicz A, Borowiec-Wolna J, Bachorski W et al. Long-term lipoprotein apheresis in the treatment of severe familial hypercholesterolemia refractory to high intensity statin therapy: Three year experience at a lipoprotein apheresis centre. Cardiology journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30234904
  5. Lee J, Lee S. Comparative Effectiveness of Combination Therapy with Statins and Angiotensin-Converting Enzyme Inhibitors versus Angiotensin II Receptor Blockers in Patients with Coronary Heart Disease: A Nationwide Population-Based Cohort Study in Korea. Pharmacotherapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30225928
  6. Katsiki N, Mikhailidis DP. Lipids: a personal view of the past decade. Hormones (Athens, Greece) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30229482
  7. Jubran A, Zetser A, Zafrir B. Lipoprotein(a) screening in young and middle-aged patients presenting with acute coronary syndrome. Cardiology journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30234895
  8. Davidson ER, Snider MJ, Bartsch K et al. Tolerance of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) Inhibitors in Patients With Self-Reported Statin Intolerance. Journal of pharmacy practice 2018:897190018799218. http://www.ncbi.nlm.nih.gov/pubmed/?term=30222031
  9. Colussi G, Zuttion F, Bais B et al. Pre-Procedural Statin Use Is Associated with Improved Long-Term Survival and Reduced Major Cardiovascular Events in Patients Undergoing Carotid Artery Stenting: A Retrospective Study. Journal of clinical medicine 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30227674
  10. Cicero AFG, Fogacci F, Bove M et al. Optimizing Lipid Pattern by Adding a Combined Nutraceutical or Pravastatin to Fenofibrate Treatment in Hypertriglyceridemic Subjects: Single Site, Randomized, Open-Label, Post-Market Clinical Investigation. High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30229462
  11. Braun LR, Feldpausch MN, Czerwonka N et al. Effects of Pitavastatin on Insulin Sensitivity and Liver Fat: A Randomized Clinical Trial. J Clin Endocrinol Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30239757
  12. Alkhalil M, Biasiolli L, Akbar N et al. T2 mapping MRI technique quantifies carotid plaque lipid, and its depletion after statin initiation, following acute myocardial infarction. Atherosclerosis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30227984
  13. Pawar AM, LaPlante KL, Timbrook TT, Caffrey AR. Optimal duration for continuation of statin therapy in bacteremic patients. Therapeutic advances in infectious disease 2018; 5:83-90. http://www.ncbi.nlm.nih.gov/pubmed/?term=30224951
  14. Lin JS, Evans CV, Johnson E et al. U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews. In: Nontraditional Risk Factors in Cardiovascular Disease Risk Assessment: A Systematic Evidence Report for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality (US); 2018.
  15. Korpela T, Cardenas-Jaen K, Archibugi L et al. Chronic use of statins and risk of post-ERCP acute pancreatitis (STARK): Study protocol for an international multicenter prospective cohort study. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30224317
  16. Aburuz S, Al-Bekairy A, Alqahtani AA et al. Comparison of the application of treatment Panel III and American College of Cardiology/American heart Association guidelines for blood cholesterol treatment in Saudi Arabia. J Saudi Heart Assoc 2018; 30:349-355. http://www.ncbi.nlm.nih.gov/pubmed/?term=30228788
Miscellaneous publications
  1. Yao D, Jing T, Niu L et al. Amyloidogenesis Induced by Diet Cholesterol and Copper in a Model Mouse for Alzheimer's Disease and Protection Effects of Zinc and Fluvastatin. Brain research bulletin 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30227236
  2. Wu H, Lv W, Pan Q et al. Simvastatin therapy in adolescent mice attenuates HFD-induced depression-like behavior by reducing hippocampal neuroinflammation. Journal of affective disorders 2018; 243:83-95. http://www.ncbi.nlm.nih.gov/pubmed/?term=30236762
  3. Woodcock J, Khan MA. FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities. Therapeutic innovation & regulatory science 2014; 48:554-556. http://www.ncbi.nlm.nih.gov/pubmed/?term=30231449
  4. Wang H, Li J, Fu X et al. Effect of simvastatin on expression of VEGF and TGF-beta1 in atherosclerotic animal model of type 2 diabetes mellitus. Experimental and therapeutic medicine 2018; 16:2889-2894. http://www.ncbi.nlm.nih.gov/pubmed/?term=30233664
  5. Seliger C, Hau P. Drug Repurposing of Metabolic Agents in Malignant Glioma. Int J Mol Sci 2018; 19. http://www.ncbi.nlm.nih.gov/pubmed/?term=30223473
  6. Rizvi F, Siddiqui R, DeFranco A et al. Simvastatin reduces TGF-beta1-induced SMAD2/3-dependent human ventricular fibroblasts differentiation: Role of protein phosphatase activation. Int J Cardiol 2018; 270:228-236. http://www.ncbi.nlm.nih.gov/pubmed/?term=30220377
  7. Mao Z, Wang P, Pan Q et al. Pravastatin alleviates interleukin 1beta-induced cartilage degradation by restoring impaired autophagy associated with MAPK pathway inhibition. Int Immunopharmacol 2018; 64:308-318. http://www.ncbi.nlm.nih.gov/pubmed/?term=30243066
  8. Leite GAA, de Barros JWF, Martins ADC, Jr. et al. Ascorbic acid supplementation ameliorates testicular hormonal signaling, sperm production and oxidative stress in male rats exposed to rosuvastatin during pre-puberty. Journal of applied toxicology : JAT 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30240002
  9. Adeli S, Zahmatkesh M, Ansari Dezfouli M. Simvastatin Attenuates Hippocampal MMP-9 Expression in the Streptozotocin-Induced Cognitive Impairment. Iranian biomedical journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30218997
  10. Wang C, Ku P, Nie X et al. Effects of simvastatin on the PXR signaling pathway and the liver histology in Mugilogobius abei. The Science of the total environment 2018; 651:399-409. http://www.ncbi.nlm.nih.gov/pubmed/?term=30240922
  11. Minas da Piedade ME, Simoes RG, Bernardes CES et al. Polymorphism in Simvastatin: Twinning, Disorder and Enantiotropic Phase Transitions. Molecular pharmaceutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30230340
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