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Update - Week 11, 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 tested in sickle cell mouse model showed remarkable renal protection
This week’s key publications contains a basic science report. In this article a transgenic human sickle cell mouse model was used to evaluate the effects of atorvastatin on renal function. Despite the fact this is a mouse and not human study it is noteworthy that with a dosage of 10mg/kg atorvastatin produced remarkable improvements that highlight the non-lipid lowering effects as well as renal protective effect in very high plasma concentrations. Albuminuria, GFR, urine concentration ability as well as markers of kidney injury, endothelial function and oxidative stress all improved significantly. This points to the shielding effects of atorvastatin in preserving renal function even when extremely high dosages are used. The ultimate proof if sickle cell patients will receive similar benefit as observed in mice remains to be proven by proper designed studies in patients that suffer sickle cell disease but the findings add to the growing burden of evidence that statins and perhaps atorvastatin persé are not harming the renal system when used in patients with normal or impaired renal function although the results from the 4D and Aurora study, in patients on renal dialysis or end stage renal disease, showed similar outcomes in the statin treated patients the ones that were in control/placebo arm.
Zahr RS, Chappa P, Yin H et al. Renal protection by atorvastatin in a murine model of sickle cell nephropathy. British journal of haematology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29527679
Atorvastatin, prior to CAG, reduces risk of CIAKI substantially
In line with the previous study again atorvastatin appears to have renal-protective features that are not directly related to its LDL- cholesterol lowering properties. In this meta-analysis of randomized controlled studies, high dose-high intensity statin vs low dose statin/placebo were evaluated. Nine RCT’s were included that examined the outcomes of pre-treating patients, prior to a scheduled coronary angiography or PTCA, with atorvastatin 40/80 mg.  Contrast-induced acute kidney injury (CIAKI) was observed significantly less in patients on atorvastatin 40/80 mg compared to the controls. Overall the odds ratio for CIAKI in patients on atorvastatin as compared to placebo: OR 0.46 (0.27–0.79; p=0.004). For high-dose atorvastatin pretreatment a OR 0.45 (0.21–0.95; p=0.04) was observed. Based on these finding the authors concluded that atorvastatin pretreatment prior to CAG significantly reduced the risk for CIAKI.
Liu LY, Liu Y, Wu MY et al. Efficacy of atorvastatin on the prevention of contrast-induced acute kidney injury: a meta-analysis. Drug design, development and therapy 2018; 12:437-444. http://www.ncbi.nlm.nih.gov/pubmed/?term=29535505
Benefits of 2 tablets of atorvastatin 80 in ACS patients scheduled for PCI
In this second publication of this week’s key articles, atorvastatin is evaluated in 4191 Brazilian patients scheduled for a PCI procedure and 30-day MACE. Patient were randomized for 2 loading dosages of atorvastatin 80 mg vs placebo right before and 24 hr. after the planned procedure. Atorvastatin 40 mg was started in all patients 24 hr. after the intervention. PCI was performed in 2710 patients (64.7%), 333 (8%) received a CABG and 1144 (27.3%) no procedure but medical management was initiated. MACE within 30 days occurred 130 patients (6.2%) using atorvastatin and 149 (7.1%) patients in the placebo group experienced complications. An absolute difference of 0.85% (-0.70-+2.40) with a calculated OR of 0.88 (0.69-1.11, p=.27). In the patients that had a PCI atorvastatin did reduce MACE; 81 patients (6%) in the treatment arm and 112 (8.2%) in the placebo group. HR 0.71 (0.54-0.97, P=0.02). The authors concluded that in ACS patients with a planned PCI procedure two loading doses of atorvastatin 80 mg did not reduce 30-day MACE. However, the subgroup of patients that did actually had a PCI did showed improved outcomes. With the lack of harm and the potential benefits in ACS patients using a high dose atorvastatin loading dose seems a reasonable practice.  
Berwanger O, Santucci EV, de Barros ESPGM et al. Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial. Jama 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29525821
Mendelian randomization shows differential effects of LDL-c on stroke sub types
In this study the authors examined the causal role of cholesterol on ischemic stroke subtypes. Using data collected in the Global Lipids Genetics Consortium and the Stroke Genetics Network, 1685 ischemic stroke were compared to 32473 controls. This included large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. For each 1-SD genetically elevated LDL cholesterol the risk of ischemic stroke increased; OR 1.12 (1.04–1.20). Large artery atherosclerosis stroke; OR: 1.28 (1.10–1.49) but not with small artery occlusion or cardioembolic stroke. There was an association with HDL-c for this stroke sub-type. For each 1-SD genetically elevated HDL-c the risk of small artery occlusion stroke decreased; OR: 0.79 (0.67–0.90). studying genetic polymorphisms related to lower triglyceride rich lipoproteins, no effects of triglycerides on ischemic stroke or sub-types could be discerned. Based on these observations the authors concluded that lowering cholesterol, using statins, would most likely benefit large artery related stroke outcomes but would not protect against small artery related or embolic stroke sub-types.
Hindy G, Engstrom G, Larsson SC et al. Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study. Stroke 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29535274
Comparing the effects of atorvastatin 20 mg with Rosuvastatin 10 mg on FMD
To study if equipotent dosages of atorvastatin (20 mg) and rosuvastatin (10 mg) would show different effects on vascular relaxation. The authors recruited 104 statin naïve hyperlipidemic patients that were assigned to atorvastatin(N=50) or rosuvastatin(n=54) for 12 months. Flow mediated dilatation (FMD) and nitrated-mediated endothelium-independent dilatation (EID) parameters were measured at baseline and 12 months. Overall all FMD and EID values improved compared to baseline. Mean changes in FMD and EID were not statistically different p=0.959 for FMD and p=0.827 for EID. Both atorvastatin and rosuvastatin showed similar changes of FMD and EID; p= 0.122 and p=0.115 respectively. When comparing rosuvastatin with atorvastatin % of LDL-c reductions were 58.5% vs 52.5% respectively. When comparing different parameters of brachial artery FMD, there was a significant difference between atorvastatin vs rosuvastatin in brachial artery hyperemia diameter 4.29 ±0.60 mm vs 4.6 ±0.52 mm (p=0.006) and brachial artery hyperemia velocity 80.03 ±16.8 cm/sec vs 71.12 ±18.5 cm/s. The authors concluded that no statistical significant differences were observed between atorvastatin 20 mg and rosuvastatin 10 mg after 1 year treatment on FMD and EID parameters.
Demir V, Dogru MT, Ede H et al. The effects of treatment with atorvastatin versus rosuvastatin on endothelial dysfunction in patients with hyperlipidaemia. Cardiovascular journal of Africa 2018; 29:1-5. http://www.ncbi.nlm.nih.gov/pubmed/?term=29528361
Relevant publications
  1. Xiao YH, He XY, Han Q et al. Atorvastatin prevents glomerular extracellular matrix formation by interfering with the PKC signaling pathway. Mol Med Rep 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29532876
  2. Warraich HJ, Salami JA, Khera R et al. Trends in Use and Expenditures of Brand-name Atorvastatin After Introduction of Generic Atorvastatin. JAMA Intern Med 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29525818
  3. Toth PP, Dwyer JP, Cannon CP et al. Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease. Kidney international 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29526502
  4. Kessler JB, Troxel AB, Asch DA et al. Partners and Alerts in Medication Adherence: A Randomized Clinical Trial. Journal of general internal medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29546659
  5. Saber-Ayad M, Manzoor S, El-Serafy A et al. Statin-induced myopathy SLCO1B1 521T>C is associated with Prediabetes, high Body mass index and normal lipid profile in Emirati Population. Diabetes Res Clin Pract 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29534995
  6. Ruan XC, Low LL, Kwan YH. Association of aspartate aminotransferase in statin-induced rhabdomyolysis. Journal of primary health care 2017; 9:316-320. http://www.ncbi.nlm.nih.gov/pubmed/?term=29530144
  7. Oikawa T, Sakata Y, Nochioka K et al. Prognostic Impact of Statin Intensity in Heart Failure Patients With Ischemic Heart Disease: A Report From the CHART-2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2) Study. J Am Heart Assoc 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29540427
  8. Navar AM, Peterson ED, Li S et al. Prevalence and Management of Symptoms Associated With Statin Therapy in Community Practice: Insights From the PALM (Patient and Provider Assessment of Lipid Management) Registry. Circ Cardiovasc Qual Outcomes 2018; 11:e004249. http://www.ncbi.nlm.nih.gov/pubmed/?term=29545393
  9. Liu Y, Yang H, Jia G et al. The Synergistic Neuroprotective Effects of Combined Rosuvastatin and Resveratrol Pretreatment against Cerebral Ischemia/Reperfusion Injury. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29525080
  10. Khan S, Khan I, Novak M et al. The Concomitant Use of Atorvastatin and Amlodipine Leading to Rhabdomyolysis. Cureus 2018; 10:e2020. http://www.ncbi.nlm.nih.gov/pubmed/?term=29531873
  11. Sarfo FS, Sarfo-Kantanka O, Adamu S et al. Stroke Minimization through Additive Anti-atherosclerotic Agents in Routine Treatment (SMAART): study protocol for a randomized controlled trial. Trials 2018; 19:181. http://www.ncbi.nlm.nih.gov/pubmed/?term=29540234
  12. Kerr AJ, Turaga M, Grey C et al. Initiation and maintenance of statins and aspirin after acute coronary syndromes (ANZACS-QI 11). Journal of primary health care 2016; 8:238-249. http://www.ncbi.nlm.nih.gov/pubmed/?term=29530207
  13. Guerard B, Omachonu V, Perez B, Sen B. The Effectiveness of a Comprehensive Wellness Assessment on Medication Adherence in a Medicare Advantage Plan Diabetic Population. Journal of healthcare management / American College of Healthcare Executives 2018; 63:132-141. http://www.ncbi.nlm.nih.gov/pubmed/?term=29533324
  14. Glueck CJ, Brown A, Goldberg AC et al. Alirocumab in high-risk patients: Observations from the open-label expanded use program. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29525445
  15. Bohula EA, Giugliano RP, Leiter LA et al. Inflammatory and Cholesterol Risk in the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk). Circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29530884
  16. Wang ST, Sun XF. Role of Statins in Treatment and Prevention of Community-acquired Pneumonia:A Meta-analysis. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 2018; 40:30-40. http://www.ncbi.nlm.nih.gov/pubmed/?term=29532779
  17. Olkkonen VM, Sinisalo J, Jauhiainen M. New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk? Atherosclerosis 2018; 272:27-32. http://www.ncbi.nlm.nih.gov/pubmed/?term=29544086
  18. Nascimento RD, Guerra Jnr AA, Alvares J et al. Statin use in Brazil: findings and implications. Current medical research and opinion 2018:1-21. http://www.ncbi.nlm.nih.gov/pubmed/?term=29528246
  19. Malik M, Tasnim N, Mahmud G. Effect of Metformin Alone Compared with Metformin Plus Simvastatin on Polycystic Ovarian Syndrome in Pakistani Women. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 2018; 28:184-187. http://www.ncbi.nlm.nih.gov/pubmed/?term=29544572
  20. Kowalska K, Habrowska-Gorczynska DE, Neumayer C et al. Lower levels of Caveolin-1 and higher levels of endothelial nitric oxide synthase are observed in abdominal aortic aneurysm patients treated with simvastatin. Acta biochimica Polonica 2018; 65:111-118. http://www.ncbi.nlm.nih.gov/pubmed/?term=29549671
  21. Karalis DG, Mallya UG, Ghannam AF et al. Prescribing Patterns of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in Eligible Patients With Clinical Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29548678
  22. Caltabiano S, Mahar KM, Lister K et al. The drug interaction potential of daprodustat when coadministered with pioglitazone, rosuvastatin, or trimethoprim in healthy subjects. Pharmacol Res Perspect 2018; 6:e00327. http://www.ncbi.nlm.nih.gov/pubmed/?term=29545948
  23. Breza J, Jr., Durackova Z, Payer J et al. Lipoprotein particle sizes in patients undergoing kidney transplantation. Bratislavske lekarske listy 2018; 119:130-132. http://www.ncbi.nlm.nih.gov/pubmed/?term=29536739
Miscellaneous publications
  1. Yasar M, Erdi I, Kaya B. The preventive effects of atorvastatin and N-acetyl cysteine in experimentally induced ischemia-reperfusion injury in rats. Bratislavske lekarske listy 2018; 119:167-174. http://www.ncbi.nlm.nih.gov/pubmed/?term=29536746
  2. Xia K, Zhang P, Hu J et al. Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells. Oncology letters 2018; 15:4344-4350. http://www.ncbi.nlm.nih.gov/pubmed/?term=29541202
  3. Sheikh-Hasani V, Babaei M, Azadbakht A et al. Atorvastatin treatment softens human red blood cells: an optical tweezers study. Biomedical optics express 2018; 9:1256-1261. http://www.ncbi.nlm.nih.gov/pubmed/?term=29541518
  4. Cui X, Fu Z, Wang M et al. Pitavastatin treatment induces neuroprotection through the BDNF-TrkB signalling pathway in cultured cerebral neurons after oxygen-glucose deprivation. Neurol Res 2018:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29544396
  5. Wang JC, Li XX, Sun X et al. Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF-1alpha-induced pro-angiogenic factor. Cancer science 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29532562
  6. Song H, Moon C, Lee BJ, Oh E. Mesoporous pravastatin solid dispersion granules incorporable into orally disintegrating tablets. Journal of pharmaceutical sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29530714
  7. Kany S, Woschek M, Kneip N et al. Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation. International journal of oncology 2018; 52:1285-1294. http://www.ncbi.nlm.nih.gov/pubmed/?term=29532878
  8. Jeong C, Kim SE, Shim KS et al. Exploring the In Vivo Anti-Inflammatory Actions of Simvastatin-Loaded Porous Microspheres on Inflamed Tenocytes in a Collagenase-Induced Animal Model of Achilles Tendinitis. Int J Mol Sci 2018; 19. http://www.ncbi.nlm.nih.gov/pubmed/?term=29534523
  9. Angelo ML, Moreira FL, Morais Ruela AL et al. Analytical Methods for the Determination of Rosuvastatin in Pharmaceutical Formulations and Biological Fluids: A Critical Review. Critical reviews in analytical chemistry 2018:1-13. http://www.ncbi.nlm.nih.gov/pubmed/?term=29533074
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