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Update - Week 06, 2019
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

Meta-analysis comparing statins ezetimibe and PCSK9ab
To compare the different lipid lowering strategies using data of published clinical trials is and remains a challenge. The result of a network meta-analysis approach was shared in this recent publication. The authors included 84 randomized controlled trials (N=246 706), published between 2001 and 2018 in which statins, ezetimibe and PCSK9ab were evaluated for efficacy and safety. Due to the absence of comparative head to head studies, a hierarchy of evidence was used to compare different treatment strategies. Single strategies vs placebo and vs a comparable treatment strategy were calculated for CVD events and common adverse events e.g. New onset diabetes, neurocognitive events etc. Analyses were based on trial outcomes not individual events. Lipid lowering efficacy was most effective with PCSK9ab. CV event reductions were similar in for statins and PCSK9ab, OR: 0.98 (0.87–1.11). Statins had a higher probability ranking of 60.6% vs 37.1% for the latter. For all-cause mortality and CVD mortality statins were superior compared to placebo; OR: 0.90 (0.85–0.96) and 0.83 (0.75–0.91) respectively. No mortality benefits were noted for PCSK9ab and ezetimibe. Adverse events were neutral for all agents, except statins that had a negative impact on ALT (OR 0.81 [1.42-2.51]), CK (OR 1.45, [1.09–1.93]) and NODM. (OR 1.89 [1.02–1.26]). The authors conclude that PCSK9ab showed the best results in terms of lipid lowering efficacy, reduction of CV events but lacking the observed harms associated with statins. Ezetimibe monotherapy showed no significant benefits on CV events underlining the need to combine this lipid lowering agent with statins or PCSK9ab. Although no harms were observed in patients treated with PCSK9ab, they were unable to show mortality benefits. Limitations of the available published trials available for newer agents such a18s PCSK9ab will need to be taken into account as well.
Zhao Z, Du S, Shen S et al. Comparative efficacy and safety of lipid-lowering agents in patients with hypercholesterolemia: A frequentist network meta-analysis. Medicine (Baltimore) 2019; 98:e14400. http://www.ncbi.nlm.nih.gov/pubmed/?term=30732185
Statins in primary prevention, class/individual benefits and harms
Comparing different classes of lipid lowering agents is challenging; comparing the different statins in a primary prevention setting is an even greater controversial matter. The aim of this network meta-analysis was to review available evidence of all published RCT’s up until January 1st, 2018. A random-effect pairwise meta-analysis of all statins as a class and a network meta-analysis for the specific statins on different benefit and harm outcomes, was employed. Overall a solid and statistically significant effect on CVD and all-cause mortality in a primary prevention setting was observed. The observed risk reduction for  non-fatal MI RR 0.62 (0.53-0.72), CVD mortality RR 0.80 (0.71-0.91), all-cause mortality, RR 0.89 (0.85-0.93), non-fatal stroke, RR 0.83 (0.75-0.92), unstable angina RR 0.75 ( 0.63-0.91), and MACE, RR 0.74 (0.67-0.81) were consistent and convincing. The authors also addressed the harms associated with statin use, providing relative risk as well as absolute risk estimations for myopathy, RR 1.08 (1.01-1.15), Risk difference [RD] 13 (2-24) per 10,000 person-years. Renal dysfunction, RR 1.12 (1.00-1.26) RD 16 (0-36) per 10,000 person-years, and hepatic dysfunction, RR 1.16 (1.02-1.31), RD 8 (1-16) per 10,000 person-years. Atorvastatin and rosuvastatin showed superior CVD risk reductions, the first with the best safety profile, except for NODM where both rosuvastatin and atorvastatin showed the highest excess risk. Despite the relatively low quality of evidence for the individual statins, there were notable differences between the individual statins, not sharing the same benefit harm profiles. Atorvastatin and rosuvastatin were superior compared to the other lower potency statins and atorvastatin proved to be the safest statin across most of the reported outcomes.
Yebyo HG, Aschmann HE, Kaufmann M, Puhan MA. Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: A systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants. Am Heart J 2019; 210:18-28. http://www.ncbi.nlm.nih.gov/pubmed/?term=30716508
DWI positive TIA patients, show markedly reduced risk on high intensity statins
Diffusion-weighted imaging (DWI) is used for (early) identification of ischemic stroke. This relatively novel NMR technique was employed to determine the benefits of statins in patients diagnosed with a TIA and a heightened risk for subsequent ischemic stroke (IS). This was a retrospective analysis of a prospective TIA cohort and patient data was collected in a single hospital in Zhengzhou China. A total of 987 patients were available for analysis and evaluated for the primary endpoint of 7 days and 90 days IS incidence. Patients with a positive DWI had a fourfold increase in risk of developing an IS event. At 7 days, 10.9 versus 1.8 (p < 0.001) and at 90 days, 18.3 versus 4.2 (p < 0.001). After adjusting for confounding variables, high intensity statin use during hospitalizations, was associated with a statistically significant reduction in IS events, in DWI positive patients. At 7-day HR 0.331 (0.165–0.663; p = 0.002) and at 90-day, HR 0.480 (0.288–0.799; p = 0.005). The authors suggested that DWI could be used to distinguish high risk TIA patients in whom the use of high intensity statins would diminish their very high risk for an IS. Confounding cannot be ruled out in observational studies and the results of this analysis should be seen as a proof of principle; further prospective randomized trials will need to validate these findings.
Song B, Cao Y, Pei L et al. Efficacy of High-intensity Statin Use for Transient Ischemic Attack Patients with Positive Diffusion-weighted Imaging. Scientific reports 2019; 9:1173. http://www.ncbi.nlm.nih.gov/pubmed/?term=30718523
Limb salvage and overall survival of post PAD intervention patients, improve with statin use
Statins are recommended in patients with any type of ASCVD including patients with peripheral artery disease (PAD). The effects of statins on pure PAD related outcomes are less well established and demonstrated in this retrospective observational analysis. Between January 2009 and December 2010 488 PAD interventions were performed in a single academic institution in Boston, US. Surgery was performed in 297, endovascular procedures in 191 patients. Statins were used by almost half of the patients (41%). The patient that used statins were more often males (p=0.03), smokers (p=0.03) and co-morbidities were observed more frequently as well; coronary artery disease (P < .01), hypertension (P < .01), and diabetes (P < .01). Antiplatelet use had no effect on limb salvage (P=0.13) but improved survival (P<0.01). Dual antiplatelet medication was not superior to mono therapy both for limb salvage and survival, P=0.4 and P=0.3 respectively. Both limb salvage (P=.04) and survival (P<0.03) were superior in patients using statins; results were adjusted for severity of disease, risk factors and anti-platelet use. The authors cautioned that the observational nature of this study does not allow to attribute the observed benefits definitely to statins. They noted that, despite existing statin guidelines, the number of PAD patients not using statins was almost 60%! Efforts to improve this were carried out by adding statins and anti-platelets in the standard discharge documents.   
Parmar GM, Novak Z, Spangler E et al. Statin use improves limb salvage after intervention for peripheral arterial disease. Journal of vascular surgery 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30718113
Post ACS, an LDL<70 mg/dl and plaque regression reduces MACCE
Benefits of plaque regression and achieving lower LDL-c levels were observed in Japanese patients that underwent an IVUS procedure in 4 prospective clinical trials (N=173). Patients admitted with ACS had serial IVUS measurement of non-culprit lesions at base lines and 6-8 months follow up; all patients were using statins. At baseline plaque volume and percent atheroma volume (PAV) were 79.6 mm3 and 46% respectively. The observed change in PAV was -1.5% and plaque regression (PR), PAV change from baseline <0,was noted in 67.1% of the patients. Patients were followed for a mean period of 3.5 years and in that time frame 37 majro coronary or cerebral events (MACCE) occurred. A non-significant trend was observed in patients with PR vs the ones that did not MACCE 18.1% vs 28.7% (P=0.14). using a Cox hazard model statistical analysis, the only significant predictors of MACCE reduction were low LDL-c levels (<70 mg/dl) and achieving PR. This resulted in a MACCE HR of 0.43 (0.19-0.88; P=0.02). the authors underlined the importance of adequately reducing LDL-c as well as  achieving plaque regression when managing post ACS patients.
Endo H, Dohi T, Miyauchi K et al. Clinical significance of non-culprit plaque regression following acute coronary syndrome: A serial intravascular ultrasound study. J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30737184
Relevant publications
  1. Yokote K, Yamashita S, Arai H et al. Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-alpha Modulator (SPPARMalpha), in Dyslipidemic Patients with Renal Impairment. Int J Mol Sci 2019; 20. http://www.ncbi.nlm.nih.gov/pubmed/?term=30736366
  2. Witsch J, Al-Mufti F, Connolly ES et al. Statins and perihemorrhagic edema in patients with spontaneous intracerebral hemorrhage. Neurology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30728307
  3. Warendorf JK, Vrancken A, van Eijk RPA et al. Statins do not increase risk of polyneuropathy: A case-control study and literature review. Neurology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30737334
  4. Tournadre A. Statins, myalgia, and rhabdomyolysis. Joint Bone Spine 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30735805
  5. Ogata A, Oho K, Matsumoto N et al. Stabilization of vulnerable carotid plaques with proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab. Acta neurochirurgica 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30729307
  6. Mitchell KA, Moore JX, Rosenson RS et al. PCSK9 loss-of-function variants and risk of infection and sepsis in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. PLoS One 2019; 14:e0210808. http://www.ncbi.nlm.nih.gov/pubmed/?term=30726226
  7. Huynh T, Lecca P, Montigny M et al. Ten-Year Statin Adherence in Survivors of ST-Segment Elevation Myocardial Infarction. Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharamcologie clinique 2018; 25:e63-e77. http://www.ncbi.nlm.nih.gov/pubmed/?term=30725543
  8. Hsu H, Hsu P, Cheng MH et al. Lipoprotein Subfractions and Glucose Homeostasis in Prediabetes and Diabetes in Taiwan. J Atheroscler Thromb 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30726792
  9. Cho Y, Kim MS, Nam CM, Kang ES. Statin Use is Associated with Decreased Hepatocellular Carcinoma Recurrence in Liver Transplant Patients. Scientific reports 2019; 9:1467. http://www.ncbi.nlm.nih.gov/pubmed/?term=30728421
  10. Chiadika SM, Shobayo FO, Naqvi SH et al. Lower femoral neck bone mineral density (BMD) in elderly women not on statins. Women & health 2019:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30721115
  11. Cardoso R, Blumenthal RS, Kopecky S et al. How Low to Go With Lipid-Lowering Therapies in a Cost-effective and Prudent Manner. Mayo Clinic proceedings 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30737057
  12. Cannon CP, Sanchez RJ, Klimchak AC et al. Simulation of the Impact of Statin Intolerance on the Need for Ezetimibe and/or Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor for Meeting Low-Density Lipoprotein Cholesterol Goals in a Population With Atherosclerotic Cardiovascular Disease. Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30736965
  13. Blom DJ, Raal F, Amod A et al. Management of low-density lipoprotein cholesterol levels in South Africa: the International ChoLesterol management Practice Study (ICLPS). Cardiovascular journal of Africa 2019; 30:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30720848
  14. Arbel R, Hammerman A, Azuri J. Usefulness of Ezetimibe Versus Evolocumab as Add-On Therapy for Secondary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus. Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30711247
  15. Statins: increased risk of type 2 diabetes. Prescrire international 2017; 26:18-19. http://www.ncbi.nlm.nih.gov/pubmed/?term=30730639
  16. Rosenblum JM, Lovasik BP, Hunting JC et al. Predicted Risk of Mortality Score predicts 30-day readmission after coronary artery bypass grafting. General thoracic and cardiovascular surgery 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30734216
  17. Rattanachotphanit T, Limwattananon C, Waleekhachonloet O. Trends and variations in outpatient coprescribing of simvastatin or atorvastatin with potentially interacting drugs in Thailand. Therapeutic advances in drug safety 2019; 10:2042098618820502. http://www.ncbi.nlm.nih.gov/pubmed/?term=30728944
  18. Pertiwi K, Kok DE, Wanders AJ et al. Circulating n-3 fatty acids and linoleic acid as indicators of dietary fatty acid intake in post-myocardial infarction patients. Nutrition, metabolism, and cardiovascular diseases : NMCD 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30718141
  19. Park JG, Oh GT. Current pharmacotherapies for atherosclerotic cardiovascular diseases. Archives of pharmacal research 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30725249
  20. Kim JR, Jung JA, Kim S et al. Effect of Cilostazol on the Pharmacokinetics of Simvastatin in Healthy Subjects. BioMed research international 2019; 2019:1365180. http://www.ncbi.nlm.nih.gov/pubmed/?term=30729119
  21. Han SN, Yang WH, Yin JJ et al. Drug Treatment of Hyperlipidemia in Chinese Patients: Focus on the Use of Simvastatin and Ezetimibe Alone and in Combination. Am J Cardiovasc Drugs 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30714088
  22. Ginsberg HN, Tuomilehto J, Hovingh GK et al. Impact of Age on the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia. Cardiovasc Drugs Ther 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30734207
  23. Climent E, Benaiges D, Pedro-Botet J. Statin treatment and increased diabetes risk. Possible mechanisms. Clin Investig Arterioscler 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30737072
  24. Chen Q, Zhang J, Feng H, Chen Z. An update on statins: Pleiotropic effect performed in intracerebral hemorrhage. Atherosclerosis 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30712828
  25. Chan JCM, Ng MH, Wong RSM, Tomlinson B. A case of simvastatin-induced myopathy with SLCO1B1 genetic predisposition and co-ingestion of linagliptin and Stevia rebaudiana. Journal of clinical pharmacy and therapeutics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30714173
Miscellaneous publications
  1. Tsur A, Kalish F, Burgess J et al. Pravastatin improves fetal survival in mice with a partial deficiency of heme oxygenase-1. Placenta 2019; 75:1-8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30712660
  2. Sroda-Pomianek K, Michalak K, Palko-Labuz A et al. Simvastatin Strongly Augments Proapoptotic, Anti-inflammatory and Cytotoxic Activity of Oxicam Derivatives in Doxorubicin-resistant Colon Cancer Cells. Anticancer research 2019; 39:727-734. http://www.ncbi.nlm.nih.gov/pubmed/?term=30711951
  3. Schulz J, Vollmer C, Truse R et al. Effect of Pravastatin Pretreatment and Hypercapnia on Intestinal Microvascular Oxygenation and Blood Flow During Sepsis. Shock 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30724816
  4. Raafat SN. Response to: Letter to the editor: The sole and combined effect of simvastatin and platelet rich fibrin as a filling material in induced bone defect in tibia of albino rats. Bone 2019; 120:534. http://www.ncbi.nlm.nih.gov/pubmed/?term=30711057
  5. Mohamed AS, Ibrahim WM, Zaki NI et al. Effectiveness of Coelatura aegyptiaca Extract Combination with Atorvastatin on Experimentally Induced Hyperlipidemia in Rats. Evidence-based complementary and alternative medicine : eCAM 2019; 2019:9726137. http://www.ncbi.nlm.nih.gov/pubmed/?term=30713580
  6. Liu XM, Zhao XM, Deng C et al. Simvastatin improves olanzapine-induced dyslipidemia in rats through inhibiting hepatic mTOR signaling pathway. Acta pharmacologica Sinica 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30728467
  7. Lee HR, Jo MK, Park KY et al. Anti-TNF effect of combined pravastatin and cilostazol treatment in an in vivo mouse model. Immunopharmacology and immunotoxicology 2019:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=30714456
  8. Lee H, Lee H, Na CB, Park JB. The effects of simvastatin on cellular viability, stemness and osteogenic differentiation using 3-dimensional cultures of stem cells and osteoblast-like cells. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30729760
  9. Kaleli-Durman D, Alp-Yildirim FI, Ozdemir O, Uydes-Dogan BS. Relaxant Effect of Atorvastatin on Isolated Rat Gastric Fundus Strips: Implications for Ca2+ signalling mechanisms. Canadian journal of physiology and pharmacology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30730760
  10. Feng X, Wang C, Gu Z et al. Rosuvastatin Regulates Odontoblast Differentiation by Suppressing NF-kappaB Activation in an Inflammatory Environment. Cellular reprogramming 2019; 21:18-25. http://www.ncbi.nlm.nih.gov/pubmed/?term=30735076
  11. El-Ganainy SO, El-Mallah A, Abdallah D et al. A novel investigation of statins myotoxic mechanism: Effect of atorvastatin on respiratory muscles in hypoxic environment. Toxicology letters 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30735765
  12. Bruder-Nascimento T, Callera GE, Montezano AC et al. Atorvastatin inhibits pro-inflammatory actions of aldosterone in vascular smooth muscle cells by reducing oxidative stress. Life sciences 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30721707
  13. Alkreathy HM, Alkhatib MH, Al Musaddi SA et al. Enhanced anti-tumor activity of doxorubicin and simvastatin combination loaded nanoemulsion treatment against a Swiss albino mouse model of Ehrlich ascites carcinoma. Clin Exp Pharmacol Physiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30724380
  14. Holmes ST, Wang WD, Hou G et al. A new NMR crystallographic approach to reveal the calcium local structure of atorvastatin calcium. Physical chemistry chemical physics : PCCP 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30720026
  15. Boruta T, Bizukojc M. Application of Aluminum Oxide Nanoparticles in Aspergillus terreus Cultivations: Evaluating the Effects on Lovastatin Production and Fungal Morphology. BioMed research international 2019; 2019:5832496. http://www.ncbi.nlm.nih.gov/pubmed/?term=30733961
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