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Update - Week 14, 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

The effects of atorvastatin on TRL and CHD risk in the TNT study
The triglyceride rich lipoproteins (TRL) have gained importance as a lipoprotein fractions associated with substantial risk. In this retrospective analysis, the effects of atorvastatin were evaluated in patients diagnosed with CAD that participated in the TNT trial. TRL-c was calculated as total cholesterol minus HDL-c minus LDL-c. Atorvastatin 10 mg reduced TRL-c -10.7%; atorvastatin 80 mg resulted in an 26.1% lower plasma concentration. Mace rates (5-years) correlated with TRL-c. For Q1=9.7%, Q5=13.8%; HR Q5-vs-Q1: 1.48 (1.15-1.92; p-trend<0.0001). atorvastatin 80 mg was not superior to atorvastatin 10 mg in Q1-Q2 but significantly reduce 5-year MACE risk in Q3-Q5; RR -29% – -41% (P=0.0053). Overall 1 SD percentage reduction of TRL-c with atorvastatin reduced MACE risk independently from LDL-c: HR 0.93 (0.86-1.0,p=0.0482) vs HR 0.89 (0.83-0.95; P=0.0008) for 1 SD percentage reduction of LDL-c. The authors concluded that TRL-c levels coincided with an increased 5-year MACE risk and that atorvastatin, in a dose dependent manner, reduced this risk by not only lowering LDL-c but also TRL-c. The observations put forward it this analysis could prompt further development of novel agents that aim to reduce TGL such as ANGPTL3 and APOC3 directed therapies.
Vallejo-Vaz AJ, Fayyad R, Boekholdt SM et al. Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the Treating to New Targets (TNT) Trial. Circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29618599
Personalized approach for use of statins in primary prevention
Statin eligibility should be determined by estimation of 10-year CVD risk combined with the expected risk reducing effects of statins, over a 10-year period. In this study a personalized approach was introduced by determining plaque burden (segment volume score, segment stenosis score, and segment involvement score) using CT-angio imaging. Overall 70 asymptomatic subjects were recruited (52% males and median age 56 years). Their Framingham CVD risk score (FRS): < 20%. The Calculated ARR10yrs of using statins was 2.7% (1.4%-4.6%) resulting in a NNT10years of 36 (22-63). Participants were divided using their expected ARR10yrs benefit of ≥2.3 % vs <2.3%.  Plaque burden was significantly greater in subjects with an ARR10yrs benefit of ≥2.3 % (P=0.02). The authors concluded that patients with a low-intermediate FRS had a substantial plaque burden. The greatest cardiovascular benefit of statins in asymptomatic low-intermediate CVD risk individuals, is expected in the ones with the higher coronary plaque burden.
Muniyappa R, Noureldin RA, Abd-Elmoniem KZ et al. Personalized Statin Therapy and Coronary Atherosclerotic Plaque Burden in Asymptomatic Low/Intermediate-Risk Individuals. Cardiorenal Med 2018; 8:140-150. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617001
Statins and NODM – latest meta-analysis
In this updated meta-analysis, the risk of new onset diabetes (NODM) was re-evaluated. Based on 11 studies and 236 864 participants (1180 811 controls vs 56 053 statin users)  the pooled OR for NODDM was 1.61 (1.55-188) – using a fixed model of statin use vs 1.92 (1.62-2.2) for the random-effects model. Despite the unequivocal detrimental effects of statins on NODM, the authors emphasize that this risk is favorably balanced by the observed cardiovascular benefits in the trials that were included in this meta-analysis and therefore should not influence clinical decision-making. Susceptible patients that start using statins deserve closer monitoring of blood glucose and HbA1C at baseline body mass index, liver fat content (presence of NAFLD/NASH), use of additional diabetogenic medications such as steroids, physical exercise capacity, statin potency + dosage, and baseline lipid fractions. Additional management approaches should include strategies that reduce the risk of NODM e.g. improving life style and choosing alternatives for pro-diabetogenic co-medications.
Kamran H, Kupferstein E, Sharma N et al. Statins and New-Onset Diabetes in Cardiovascular and Kidney Disease Cohorts: A Meta-Analysis. Cardiorenal Med 2018; 8:105-112. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617000
EMPATHY study results inconclusive
The standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) set out to examine whether intensive lipid lowering therapy, in Japanese patients, was superior to standard treatment. The included 5 995 patients had hyperlipidemia, diabetic retinopathy and no CVD. Participants were divided into two groups, targeting different LDL-C levels (<70 or ≥100 but <120 mg/dL), 2518 in the intensive arm vs 2 525 n the standard therapy group; the mean follow-up was 37 months. The primary endpoint was a range of atherosclerotic and renal complications. In the intensive group suffered 129 occurrences vs 153 in the standard treated patients. This translated in a non-significant reduction of the primary endpoint; HR:0.84 (0.67-1.07; P=0.15). the observed event rate was on par with observations in the primary prevention diabetes studies (CTT analysis. The authors suggested that the reasons for these disappointing results were the less than expected LDL-c difference of 40 mdl between the two treatment arms. Lower levels in the standard treated group resulted in a mean difference of 27.7 mg/dl and the duration of the trial was perhaps too short for this less than expected difference in LDL-c. Exploratory analysis of 4 subcategories:  <70 mg/dl.; 70-100 mg/dl.; 100-120 mg/dl. and > 120 mg/dl. did show significant improved outcomes in the patients that reached the lower targets. The authors concluded that the potential benefit of achieving LDL-C <70 mg/dl, in a treat-to-target strategy in high-risk patients deserves further investigation.
Itoh H, Komuro I, Takeuchi M et al. Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. Diabetes Care 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29626074
Meta-analysis of CCTA to evaluate plaque changes with statin therapy
The impact of cholesterol lowering on vessel wall plaque changes has been studied in numerous studies. This recent meta-analysis of coronary computed tomographic angiography (CCTA) trials reviews the effects of statins on vascular remodeling, plaque composition and plaque burden. The authors included 12 studies with a mean follow-up period of 14.5 ±9.5 months. Participants were intensive statin users (N=199) moderate statin users (N=404) and controls (n=189). The changes in total plaque volume (PV) were -20.87% (-31.17 - -10.56; P<0.001) mm3  -1.67 (-9.99, 6.65; P = 0.69) mm3 for intensive and moderate statin treatment.  Mean volume regression (percentage) -3.6% and -0.7% for the intensive and moderate statin users the controls showed progression of +5.8%. The non-calcified plaque volume decreased by -7.62 (-17.38-2.13; P = 0.124) mm3. Calcified plaque volumes increased by 11.83 (3.37-20.29; P = 0.006) mm3 and calcium signal intensity increased as well by 21.99 (9.2-34.8; P < 0.001) Hounsfield units. The authors concluded that there is now accumulating evidence that CCTA can be used monitor plaque changes resulting from lipid lowering treatments like statins.
Andelius L, Mortensen MB, Norgaard BL, Abdulla J. Impact of statin therapy on coronary plaque burden and composition assessed by coronary computed tomographic angiography: a systematic review and meta-analysis. European heart journal cardiovascular Imaging 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617981
Relevant publications
  1. Verdoodt A, Honore Pm Md PF, Jacobs R et al. Do Statins Induce or Protect from Acute Kidney Injury and Chronic Kidney Disease: An Update Review in 2018. Journal of translational internal medicine 2018; 6:21-25. http://www.ncbi.nlm.nih.gov/pubmed/?term=29607300
  2. Singh K, Crossan C, Laba TL et al. Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: Within-trial cost-effectiveness analysis of the UMPIRE trial. Int J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29622506
  3. Sessa M, Rafaniello C, Scavone C et al. Preventable statin adverse reactions and therapy discontinuation. What can we learn from the spontaneous reporting system? Expert opinion on drug safety 2018:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=29619841
  4. Saeed A, Ballantyne CM. Bempedoic Acid (ETC-1002): A Current Review. Cardiol Clin 2018; 36:257-264. http://www.ncbi.nlm.nih.gov/pubmed/?term=29609755
  5. Rozenbaum Z, Ravid D, Margolis G et al. Association of Pre-Admission Statin Therapy and the Inflammatory Response in ST Elevation Myocardial Infarction patients. Biomarkers 2018:1-19. http://www.ncbi.nlm.nih.gov/pubmed/?term=29620476
  6. Patel SS, Guzman L, Lin FP et al. Utilization of Aspirin and Statin in Management of Coronary Artery Disease in Patients with Cirrhosis Undergoing Liver Transplant Evaluation. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29624871
  7. Pang J, Martin AC, Bates TR et al. Parent-child genetic testing for familial hypercholesterolaemia in an Australian context. Journal of paediatrics and child health 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29626384
  8. Cesena FHY, Laurinavicius AG, Valente VA et al. Statin Eligibility in Primary Prevention: From a Risk-Based Strategy to a Personalized Approach Based on the Predicted Benefit. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29605080
  9. Banach M, Mikhailidis DP. Statin Intolerance: Some Practical Hints. Cardiol Clin 2018; 36:225-231. http://www.ncbi.nlm.nih.gov/pubmed/?term=29609752
  10. Ako J, Hibi K, Kozuma K et al. Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design. J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29606415
  11. Aday AW, Everett BM. Statins in Peripheral Artery Disease: What Are We Waiting For? Circulation 2018; 137:1447-1449. http://www.ncbi.nlm.nih.gov/pubmed/?term=29610126
  12. Smit J, Schonheyder HC, Nielsen H et al. In Reply-Statin Use Associated With a Decreased Risk of Community-Acquired Staphylococcus aureus Bacteremia. Mayo Clinic proceedings 2018; 93:542. http://www.ncbi.nlm.nih.gov/pubmed/?term=29622103
  13. Sadeeqa S, Maqsood M, Ahmad M. Prevalence of statin induced myopathy in Lahore, Pakistan. Pak J Pharm Sci 2018; 31:617-622. http://www.ncbi.nlm.nih.gov/pubmed/?term=29625933
  14. Pontes HBD, Pontes J, Azevedo Neto E et al. Evaluation of the Effects of Atorvastatin and Ischemic Postconditioning Preventing on the Ischemia and Reperfusion Injury: Experimental Study in Rats. Brazilian journal of cardiovascular surgery 2018; 33:72-81. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617505
  15. Nguyen S, Chuah SY, Fontas E et al. Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo: A Randomized Clinical Trial. JAMA dermatology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617528
  16. Nelson AJ, Nicholls SJ. Treating Dyslipidemia in Type 2 Diabetes. Cardiol Clin 2018; 36:233-239. http://www.ncbi.nlm.nih.gov/pubmed/?term=29609753
  17. Masaki N, Kumagai K, Sasaki K et al. Suppressive effect of pitavastatin on aortic arch dilatation in acute stanford type B aortic dissection: analysis of STANP trial. General thoracic and cardiovascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29626287
  18. Liu Y, Song X, Zhou H et al. Gut Microbiome Associates With Lipid-Lowering Effect of Rosuvastatin in Vivo. Frontiers in microbiology 2018; 9:530. http://www.ncbi.nlm.nih.gov/pubmed/?term=29623075
  19. Lin FJ, Lin HW, Ho YF. Effect of Statin Intensity on the Risk of Epilepsy After Ischaemic Stroke: Real-World Evidence from Population-Based Health Claims. CNS drugs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29619760
  20. Lee TC, Kaouache M, Grover SA. Evaluation of the cost-effectiveness of evolocumab in the FOURIER study: a Canadian analysis. CMAJ open 2018; 6:E162-e167. http://www.ncbi.nlm.nih.gov/pubmed/?term=29622685
  21. Ko HHT, Lareu RR, Dix BR, Hughes JD. Statin Use Associated With a Decreased Risk of Community-Acquired Staphylococcus aureus Bacteremia. Mayo Clinic proceedings 2018; 93:541-542. http://www.ncbi.nlm.nih.gov/pubmed/?term=29622101
  22. Khokhar B, Simoni-Wastila L, Slejko JF et al. In-Hospital Mortality Following Traumatic Brain Injury Among Older Medicare Beneficiaries, Comparing Statin Users With Nonusers. The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians 2017; 33:225-236. http://www.ncbi.nlm.nih.gov/pubmed/?term=29607441
  23. Kaasenbrood L, Ray KK, Boekholdt SM et al. Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease. Heart 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29622600
  24. Ham SY, Song SW, Nam SB et al. Effects of chronic statin use on 30-day major adverse cardiac and cerebrovascular events after thoracic endovascular aortic repair. J Cardiovasc Surg (Torino) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29616526
  25. Desai P, Wallace R, Anderson ML et al. An analysis of the effect of statins on the risk of Non-Hodgkin's Lymphoma in the Women's Health Initiative cohort. Cancer medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29608241
  26. Chen YA, Lin YJ, Lin CL et al. Simvastatin Therapy for Drug Repositioning to Reduce the Risk of Prostate Cancer Mortality in Patients With Hyperlipidemia. Frontiers in pharmacology 2018; 9:225. http://www.ncbi.nlm.nih.gov/pubmed/?term=29623039
  27. Can A, Castro VM, Dligach D et al. Lipid-Lowering Agents and High HDL (High-Density Lipoprotein) Are Inversely Associated With Intracranial Aneurysm Rupture. Stroke 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29622625
  28. Bin Abdulhak AA, Robinson JG. Optimizing Statins and Ezetimibe in Guideline-Focused Management. Cardiol Clin 2018; 36:221-223. http://www.ncbi.nlm.nih.gov/pubmed/?term=29609751
  29. Barter PJ, Rye KA. Cholesteryl Ester Transfer Protein Inhibitors as Agents to Reduce Coronary Heart Disease Risk. Cardiol Clin 2018; 36:299-310. http://www.ncbi.nlm.nih.gov/pubmed/?term=29609759
Miscellaneous publications
  1. Yoon SJ, Kim EC, Noh K, Lee DW. Supramolecular Hydrogels Based on MPEG-Grafted Hyaluronic Acid and alpha-CD Containing HP-beta-CD/Simvastatin Enhance Osteogenesis In Vivo. Journal of nanoscience and nanotechnology 2017; 17:217-223. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617547
  2. Snarska A, Gonkowski S, Rytel L et al. Influence of simvastatin on red blood cell line in porcine bone marrow. Polish journal of veterinary sciences 2017; 20:811-814. http://www.ncbi.nlm.nih.gov/pubmed/?term=29611640
  3. Shahid N, Adnan S, Farooq M et al. DEVELOPMENT OF COMPRESSED COATED POLYPILL WITH MUCOADHESIVE CORE COMPRISING OF ATORVASTATIN/CLOPIDOGREL/ASPIRIN USING COMPRESSION COATING TECHNIQUE. Acta poloniae pharmaceutica 2017; 74:477-487. http://www.ncbi.nlm.nih.gov/pubmed/?term=29624252
  4. Lettiero B, Inasu M, Kimbung S, Borgquist S. Insensitivity to atorvastatin is associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism in breast cancer cells. Scientific reports 2018; 8:5462. http://www.ncbi.nlm.nih.gov/pubmed/?term=29615666
  5. Huai J, Yang Z, Yi YH et al. [Regulation of pravastatin on long-chain fatty acid oxidative enzyme in pre-eclampsia-like mouse model]. Zhonghua fu chan ke za zhi 2018; 53:183-189. http://www.ncbi.nlm.nih.gov/pubmed/?term=29609233
  6. Fowke JH, Motley SS. Statin Use Linked with a Decrease in the Conversion from High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) to Prostate Cancer. Carcinogenesis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617729
  7. Bech AP, Wetzels JFM, Nijenhuis T. Effects of sildenafil, metformin, and simvastatin on ADH-independent urine concentration in healthy volunteers. Physiological reports 2018; 6:e13665. http://www.ncbi.nlm.nih.gov/pubmed/?term=29611351
  8. Ahmadi Y, Haghjoo AG, Dastmalchi S et al. Effects of Rosuvastatin on the expression of the genes involved in cholesterol metabolism in rat: Adaptive responses by extrahepatic tissues. Gene 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29605604
  9. Wang N, Lu Y, Wang K et al. Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2018; 46:618-632. http://www.ncbi.nlm.nih.gov/pubmed/?term=29617679
  10. Cruz P, Reyes F, Torres CG. Simvastatin modulates beta-catenin/MDR1 expression on spheres derived from CF41.Mg canine mammary carcinoma cells. Polish journal of veterinary sciences 2018; 21:95-99. http://www.ncbi.nlm.nih.gov/pubmed/?term=29624022
  11. Clementino A, Sonvico F. Development and validation of a RP-HPLC method for the simultaneous detection and quantification of simvastatin's isoforms and coenzyme Q10 in lecithin/chitosan nanoparticles. Journal of pharmaceutical and biomedical analysis 2018; 155:33-41. http://www.ncbi.nlm.nih.gov/pubmed/?term=29605683
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