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Update - Week 13, 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

Diminished variability in aspirin response with (atorva)statin?
Despite the evidence that statins exert their CVD protective properties by reducing plasma LDL-c, non-LDL-c lowering effects have been postulated to explain the rapid onset of statin associated protective effects. In this article the authors show that atorvastatin can improve the bio-availability of aspirin and reduce aspirin non-responsiveness. Between June 2008 and July 2010, 182 patients with established CVD or with CV risk factors chronically and treated with 100 mg enteric coated (EC) aspirin were enrolled. A comparable control group (matched for age gender and incidence of hypertension) but without cardiovascular risk factors and/or previous vascular events were added as well. The aim was to determine difference in thromboxane (TX)B2 levels in blood, reflecting diminished platelet generation in patients unresponsive to aspirin treatment. Patients were treated with 100 mg EC aspirin for 7 days followed by a urine collection on the morning of day 8. An threshold of 3.9ng/ml was chosen as the upper limit of TXb2 to determine (un)responsiveness to aspirin. In the high-risk patients 14% were shown to have an inadequate response, reflected by greater COS-1-dependent TXA2 biosynthesis. After adding excess aspirin in vitro, serum TXB2 levels were <3.9 ng.ml in 98% of the patients. Linear multiple regression analysis of serum TXB2 levels in the 182 participants showed that a history of MI was a predictor of increased TXb2 serum concentration and that atorvastatin improved aspirin responsiveness. Serum levels of TXB2 were 1.88 (0.150-97.70) vs 0.82 (0.02-155.50) ng/ml (P<0.05) in patients without and with statins respectively. The authors postulated that the MRP4 transporter, that actively extrudes aspirin from the platelets, is inhibited by atorvastatin; increasing the intracellular aspirin concentration. Similar effects were observed with a specific MRP4 inhibitor: MK-571. The authors concluded that adding (atorva)statin to aspirin could reduce the number of patients inadequately protected by aspirin; however these results need to be confirmed in larger properly designed randomized trials.
Tacconelli S, Dovizio M, Di Francesco L et al. Reduced variability to aspirin antiplatelet effect by the coadministration of statins in high-risk patients for cardiovascular disease. Clinical pharmacology and therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574792
 
Is there a multiplicative effect on MACE when combining anti-hypertensives with statins?
Combining two CVD risk lowering strategies could have a multiplicative risk reducing effect. In this meta-analysis the authors examined the reduced risk of statins added to blood pressure lowering medications in a primary prevention setting. Including seven factorial randomized studies, out of a total of 1017 screened trials. the period used in the search strategy covered the time when statins were first introduced (1987) and December 2017. A total number of 27 027 patients participated in these studies; 857 major cardiovascular events and 735 deaths were recorded. In patients randomized to statins, MACE were not significantly different in patients with active/more intense blood pressure-lowering regimen RR 0.81 (0.66 - 1.00) or placebo RR 0.94 (0.79 - 1.11). Similar patients randomized to active/more intense blood pressure lowering the benefits of statins were not substantially different in subgroups randomized to active/more intense blood pressure lowering regimen; RR 0.69 (0.57 - 0.85) or placebo/less intense regimen RR 0.80 (0.67 - 0.96). Limited experimental evidence supports synergism between blood pressure lowering drugs and statins, potentiating the effects on blood pressure and lipids. In the ASCOT trial this was confirmed but the HOPE-3 trial was unable to replicate these results. The authors concluded that there is a multiplicative risk reducing effect when statins and anti-hypertensive medication are combined, and this supports treatment decisions based on CVD risk estimation rather than blood pressure and cholesterol numbers as well as favoring fixed combination pills e.g. poly pills in a primary prevention setting.
were observed. Heterogeneity was lowSundstrom J, Gulliksson G, Wiren M. Synergistic effects of blood pressure-lowering drugs and statins: systematic review and meta-analysis. BMJ evidence-based medicine 2018; 23:64-69. http://www.ncbi.nlm.nih.gov/pubmed/?term=29595132
 
What is the LDL-c target, to prevent cardiac allograft vasculopathy?

preventing vasculopathy after cardiac transplantation (CAV), remains a major therapeutic challenge. A feared complication and observed in 30 % of all cardiac transplant patients after 5 years, and increases to 50% at 10 years. Immunologic and non-immunologic mechanisms play an important role in CAV development. For the first antibody mediated rejection and presence of anti-HLA anti-bodies are relevant. For the latter donor age, active cytomegalovirus infection, history of hypertension in the recipient as well as hyperlipidemia are tagged as potential exacerbating factors. Targeting cholesterol with statins seems a logical approach to reduce this potent risk factor for CAV. Current guidelines by the International Society of Heart and Lung Transplantation do not give specific LDL-c treatment goals. The authors of this retrospective cardiac transplant cohort analysis, aimed to assess the effects of LDL-c concentrations on the risk of developing CAV. Achieving LDL-c levels < 100 mg/dl was shown to be associated with a reduced risk of CAV compared to patients that were unable to reach this target. Respectively 25/157 (15.9%) vs 12/37 (32.4%) developed CAV (P=0.021). Patients that reached an LDL-c <100 mg/dl developed CAV later as well. Reaching an LDL-c < 70 mg/dl was not associated with improved outcomes compared to an LDL-c < 100 mg/dl.  
Harris JR, Teuteberg JJ, Shullo MA. Optimal Low Density Lipoprotein Concentration in Cardiac Allograft Vasculopathy. Clinical transplantation 2018:e13248. http://www.ncbi.nlm.nih.gov/pubmed/?term=29603413
 
Statins in insulin resistant patients shows surprising effects?

Pitavastatin affects IR dyslipidemia by improving multiple aspects of lipid abnormalities that characterize (pre) diabetic patients, A remaining enigma is how statins can affect mixed dyslipidemia in patients with metabolic syndrome. To evaluate the effect of pitavastatin 4 mg/d, 12 males with MS features were treated for 180 days. Complex lipid and lipoprotein analyses were performed after 6,42 and 180 days. All studied lipid parameters improved. Reductions of LDL-c, Apo B and triglycerides reached a nadir at 42 days, -38%, -32% and -35% respectively. At day 6 a rapid decrease of remnant cholesterol, Apo CII, CIII and E were observed with reductions of -35%, -50%, -25% and -26% respectively. Small dense LDL predominated at baseline, and markedly reduced on treatment (-25% vs total LDL-c mass). CETP activity and mass were diminished as well, -18% and -16%. This was reflected by a TG depletion (-49%) and CE enrichment in all HDL particle sub populations. Normalization of CE/TG ratio was noted at 180 days. Structure of HDL, and potential function of HDL particles, improved as well. Apo AI was re-allocated from LpA1 to LpAI:AII particles, in the HDL.2a and HDL.3a sub populations. The observations in this relatively small trial using complex analysis of lipids and lipoprotein showed promising results that revealed not only lower LDL-c but improved values of atherogenic lipoprotein markers, as well as changes in HDL-particles reflecting normalization of their composition in patients with marked insulin resistance and associated atherogenic dyslipidemia. The observed attenuated CETP activity was postulated as a potential biomarker to monitor impaired HDL metabolism. These preliminary results will need to be confirmed by additional studies in metabolic syndrome and other types of patients.
Chapman MJ, Orsoni A, Robillard P et al. Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication of CETP. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574070
 
Can metformin decrease statin associated muscle symptoms?
As suggested in earlier articles by the authors, metformin might have properties that could diminish the risk of statin associated muscle symptoms. Reducing mitochondrial oxidative stress and its effect on AMP-activated protein kinase (AMPK) are the suggested mechanism for this. In this brief report, based on a retrospective analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, a sub group of the participants was evaluated for muscle cramps and leg/calve pain when walking. Patients on statins only (N=445) were compared with patients using a combination of statins and metformin (N=869). Patients were overall well balanced between the two groups. Unadjusted analysis proved that 35% of the statin + metformin users reported muscle cramps and 40% leg/calf pain when walking. In the statin only users these symptom were observed in 42% and 47% of the patients Multivariate regression showed a RR -22% for muscle cramps and -29% for leg/calf pain when walking. Based on these preliminary findings the authors concluded that metformin may have the potential to improve statin tolerability. The observational nature of this study requires validation in properly designed trials as well as additional research into the mechanisms of the observed effects of metformin.
Carris NW, Tsalatsanis A, Tipparaju SM et al. Metformin's Impact on Statin-Associated Muscle Symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29577553
Relevant publications
  1. Carris NW, Tsalatsanis A, Tipparaju SM et al. Metformin's Impact on Statin-Associated Muscle Symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29577553
  2. Chaffey P, Thompson M, Pai AD et al. Usefulness of Statins for Prevention of Venous Thromboembolism. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29576234
  3. Sahebkar A, Simental-Mendia LE, Mikhailidis DP et al. Effect of statin therapy on plasma apolipoprotein CIII concentrations: A systematic review and meta-analysis of randomized controlled trials. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29580713
  4. Pinal-Fernandez I, Casal-Dominguez M, Mammen AL. Immune-Mediated Necrotizing Myopathy. Curr Rheumatol Rep 2018; 20:21. http://www.ncbi.nlm.nih.gov/pubmed/?term=29582188
  5. Lichtenstein G, Perlman A, Shpitzen S et al. Correlation between coronary artery calcification by non-cardiac CT and Framingham score in young patients. PLoS One 2018; 13:e0195061. http://www.ncbi.nlm.nih.gov/pubmed/?term=29590197
  6. Licata A, Giammanco A, Minissale MG et al. Liver and statins: a critical appraisal of the evidence. Curr Med Chem 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29589533
  7. Dopheide JF, Papac L, Schindewolf M et al. Poor attainment of lipid targets in patients with symptomatic peripheral artery disease. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574071
  8. Cesena FHY, Laurinavicius AG, Valente VA et al. Low-density lipoprotein-cholesterol lowering in individuals at intermediate cardiovascular risk: Percent reduction or target level? Clin Cardiol 2018; 41:333-338. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574925
  9. Brinton EA, Ballantyne CM, Guyton JR et al. Lipid Effects of Icosapent Ethyl in Women with Diabetes Mellitus and Persistent High Triglycerides on Statin Treatment: ANCHOR Trial Subanalysis. Journal of women's health (2002) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29583081
  10. Armstrong EJ, Waldo SW. Under-utilization of statin medications in patients with peripheral artery disease or cerebrovascular disease. Vascular medicine (London, England) 2018:1358863x18758915. http://www.ncbi.nlm.nih.gov/pubmed/?term=29600738
  11. Ahmadi Y, Ghorbanihaghjo A, Naghi-Zadeh M, Yagin NL. Oxidative stress as a possible mechanism of statin-induced myopathy. Inflammopharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574631
  12. Ades S, Douce D, Holmes CE et al. Effect of rosuvastatin on risk markers for venous thromboembolism in cancer. Journal of thrombosis and haemostasis : JTH 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29575637
  13. Zeki AA, Elbadawi-Sidhu M. Innovations in asthma therapy: is there a role for inhaled statins? Expert review of respiratory medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29575963
  14. Willey J, Mentias A, Vaughan-Sarrazin M et al. Epidemiology of lower extremity peripheral artery disease in veterans. Journal of vascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29588132
  15. Ryu JH, Park JW, Hwang JY et al. The attenuation of neurological injury from the use of simvastatin after spinal cord ischemia-reperfusion injury in rats. BMC anesthesiology 2018; 18:31. http://www.ncbi.nlm.nih.gov/pubmed/?term=29587636
  16. O'Donnell TFX, Deery SE, Shean KE et al. Statin therapy is associated with higher long-term but not perioperative survival after abdominal aortic aneurysm repair. Journal of vascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29580855
  17. McBride CL, Akeroyd JM, Ramsey DJ et al. Statin prescription rates and their facility-level variation in patients with peripheral artery disease and ischemic cerebrovascular disease: Insights from the Department of Veterans Affairs. Vascular medicine (London, England) 2018:1358863x18758914. http://www.ncbi.nlm.nih.gov/pubmed/?term=29600737
  18. Kotyla P. Low dose of simvastatin reduces disease activity and improves endothelial function in patients with SLE. Clinical and experimental rheumatology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29600937
  19. Korhonen MJ, Ilomaki J, Sluggett JK et al. Selective prescribing of statins and the risk of mortality, hospitalizations, and falls in aged care services. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574073
  20. Khokhar B, Simoni-Wastila L, Slejko JF et al. Patterns of Statin Use in Older Medicare Beneficiaries With Traumatic Brain Injury. The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians 2017; 33:156-166. http://www.ncbi.nlm.nih.gov/pubmed/?term=29577114
  21. Katsiki N, Triposkiadis F, Giannoukas AD, Mikhailidis DP. Statin loading in cardiovascular surgery: never too early to treat. Current opinion in cardiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29601328
  22. Kaewboonlert N, Thitisopee W, Sirintronsopon W et al. Lack of association between SLCO1B1 polymorphisms and lipid-lowering response to simvastatin therapy in Thai hypercholesterolaemic patients. Journal of clinical pharmacy and therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29575099
  23. Hodges GW, Bang CN, Forman JL et al. Effect of simvastatin and ezetimibe on suPAR levels and outcomes. Atherosclerosis 2018; 272:129-136. http://www.ncbi.nlm.nih.gov/pubmed/?term=29602140
  24. Ezad S, Cheema H, Collins N. Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction. Oxford medical case reports 2018; 2018:omx104. http://www.ncbi.nlm.nih.gov/pubmed/?term=29593874
  25. Dai Y, Zhao X. Therapeutic effects of simvastatin combined with kallistatin treatment for pediatric burn patients with sepsis. Experimental and therapeutic medicine 2018; 15:3080-3087. http://www.ncbi.nlm.nih.gov/pubmed/?term=29599842
  26. Bucholz EM, Rodday AM, Kolor K et al. Prevalence and Predictors of Cholesterol Screening, Awareness, and Statin Treatment Among US Adults With Familial Hypercholesterolemia or Other Forms of Severe Dyslipidemia (1999-2014). Circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29581125
  27. Al-Rasadi K, Al-Zakwani I, Alsheikh-Ali AA et al. Prevalence, management, and outcomes of familial hypercholesterolemia in patients with acute coronary syndromes in the Arabian Gulf. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574074
Miscellaneous publications
  1. Sezavar M, Bohlouli B, Farhadi S et al. Simvastatin Effects on Dental Socket Quality: A Comparative Study. Contemporary clinical dentistry 2018; 9:55-59. http://www.ncbi.nlm.nih.gov/pubmed/?term=29599585
  2. Munkboel CH, Baake MLK, Styrishave B. Atorvastatin decreases steroid production in H295R cells and in major endocrine tissues of male rats. Archives of toxicology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29574565
  3. Ghalwash M, Elmasry A, El-Adeeb N. Effect of L-carnitine on the skeletal muscle contractility in simvastatin-induced myopathy in rats. Journal of basic and clinical physiology and pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29584613
  4. Qi W, Cao D, Li Y et al. Atorvastatin ameliorates early brain injury through inhibition of apoptosis and ER stress in a rat model of subarachnoid hemorrhage. Bioscience reports 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29592873
  5. Peng J, Tian H, Du Q et al. A regenerable sorbent composed of a zeolite imidazolate framework (ZIF-8), Fe3O4 and graphene oxide for enrichment of atorvastatin and simvastatin prior to their determination by HPLC. Mikrochimica acta 2018; 185:141. http://www.ncbi.nlm.nih.gov/pubmed/?term=29594811
  6. Cosar E, Mamillapalli R, Moridi I et al. Serum MicroRNA Biomarkers Regulated by Simvastatin in a Primate Model of EMS. Reproductive sciences (Thousand Oaks, Calif.) 2018:1933719118765971. http://www.ncbi.nlm.nih.gov/pubmed/?term=29587611
  7. Antoniellis Silveira AA, Dominical VM, Morelli Vital D et al. Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes. Int Immunopharmacol 2018; 58:160-165. http://www.ncbi.nlm.nih.gov/pubmed/?term=29604489
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