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Update - Week 43,  2017 
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

Effects of colchicine on plaque characteristics
The recent positive results from the CANTOS trial, using a mono-clonal anti-body against IL6, and presented at the ESC in Barcelona in 2017, have re-ignited the interest in targeting inflammation CAD patients. The authors of this article studied the plaque modifying effects of low dose Colchicine + optimal medical therapy (OMT). This was designed as a non-randomized, prospective follow up study.  CTA was used to study the anti-inflammatory effects of colchicine in 80 ACS (< 1 month since event) patients. Primary outcome change in low attenuation plaque volume (LAPV). Secondary endpoints were other CTA measurements and hsCRP levels. Patients were randomized to 0.5 mg colchicine + OMT or OMT only. LAPV improved significantly in the colchicine users. LAPV mean 15.9 mm3 (40.9%) vs. 6.6 mm3 (17.0%); p = 0.008. Similar hsCRP was lower in the colchicine users as well: mean 1.10 mg/l (37.3%) vs. 0.38 mg/l (14.6%); p < 0.001). No significant changes were observed in total atheroma volume:  mean 42.3 mm3 vs. 26.4 mm3 (p = 0.28), and LDL-C: mean 0.44 mmol/l vs. 0.49 mmol/l; (p = 0.21). There was a significant linear association (p < 0.001) and strong positive correlation (r ¼ 0.578) between change in LAPV and hsCRP. The authors concluded that based on the results of their study there seems to be an additive beneficial effect of low dose colchicine in ACS patients on OMT that is most likely to be driven by the anti-inflammatory effects. Randomized placebo controlled trial(s) are needed to confirm these observations.
Vaidya K, Arnott C, Martinez GJ et al. Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study. JACC. Cardiovascular imaging 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29055633
PCSK9ab are not a luxury but vital in selected patients
The role of PCSK9ab remains reserved for a limited number of patients where the more affordable statins (and/or Ezetimibe) are incapable of protecting in patients at risk for CVD. IN this case report a patient suffering from myotonic dystrophy, DM2 and progressive CAD, did not tolerate any of the 4 statins (including atorvastatin and Rosuvastatin). Elevated CK, myalgia and muscle weakness prohibited the use of HMG-CoA reductase inhibitors. A combination of ezetimibe + bile acid sequestrants did not lower his LDL-C (baseline level = 210 mg/dl) sufficiently. Starting with Alirocumab 75s mg every two weeks reduced his LDL-C to 90 mg/dl and was well tolerated. This case illustrates the importance of PCSK9ab in a selected number of very high CVD risk patients that are unable to tolerate statins and where lowering their (very) high LDL-C levels is pivotal to reduce the risk of subsequent (fatal) CVD events. 
Shakir MKM, Shin T, Hoang TD, Mai VQ. Successful treatment of a patient with statin-induced myopathy and myotonic dystrophy type II with proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab (Praluent). J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29056268
Should we measure vitamin D in statin related myopathy?
Statin adherence reamins one of the major hurdles physicians are unable to effectively address when caring for patients at (high) risk for ASCVD. Misinformation from questionable sources makes patients distrust the protective effects and fearful of the suggested harms. Properly addressing the perceived symptoms and providing reassurance and/or solutions for muscle related complaints is important. In this small retrospective analysis of 105 patients that attended a US cardiometabolic clinic (2006-2008). Patients were grouped in those with low vitamin D levels (<32ng/dl) and normal vitamin D (>32 ng/dl). The 24 statin intolerant patients reported 41 statin specific myopathies. Low vitamin D was (borderline) significantly associated with muscle related complaints in statin users (P=0.048). Supplementing vitamin D resulted in reduced myopathy related complaints in patients with a baseline vitamin D <20 ng/ml as compared to patients with higher vitamin D; >20 ng/dl (90% vs 33%; P=0.036). Based on the observed data, and within the limitations of the study design, vitamin D deficient patients and statin related myopathy seem to benefit from correcting this metabolic problem.
Riche KD, Arnall J, Rieser K et al. Impact of vitamin D status on statin-induced myopathy. Journal of clinical & translational endocrinology 2016; 6:56-59. http://www.ncbi.nlm.nih.gov/pubmed/?term=29067242
Meta-analysis of statins and non-statins on MACE
Lowering LDL-C is considered an essential step to prevent CVD in patients at risk. Statins have established the importance of not only reducing LDL-C but to aim for lower targets as well. The linear, continuous relationship between LDL-C and CVD risk remains, even at very low LDL-C levels. The so called non-statin drugs enable further LDL-C reductions beyond what can be achieved with maximum tolerated statins. Their CVD protective effects, based on their LDL-C lowering potential, seem to be on par with what has been observed in statin trials. In this updated meta-analysis, the authors studied published trials in which statin and non-statin lipid lowering medications were used to determine their CVD protective effects. They included 19 trials; 15 statin studies as well as 2 using PCSK9ab and 1 using Ezetimibe as add-on treatment. In total 152 507 patients were randomly assigned to more-intensive (n = 76 678) or less-intensive treatment (n = 75 829). Major coronary events (MACE) were used as the primary endpoint. No variation in clinical benefit could be observed for statins or PCSK9ab, RR 0.87 (0.80–0.94) vs. RR 0.81 (0.80–0.89), respectively; P-interaction= 0.36). For mortality, there was a significant difference. In trials comparing statin vs. no statin benefits were noted, RR 0.85 (0.78–0.92) for death and RR 0.78 (0.73–0.84) for cardiovascular death. However, no survival benefit of more-intensive treatment with ezetimibe or PCSK9ab was detected. Overall 19% relative risk reductions of MACE were noted in the more intensive vs the less intensive treatment arms, RR 0.81 (0.77–0.86). For each 1 mmol/l LDL-C, CVD risk was reduced by 19% Higher baseline LDL-C levels as well as greater LDL-C reductions were associated with superior risk reductions. A more intensive treatment showed reductions in total mortality, cardiovascular death, myocardial infarction, stroke, and coronary revascularization as well. The authors concluded that more intensive LDL-C lowering reduces MACE in secondary prevention. Combining statins with PCSK9ab or ezetimibe translates into favorable effects on cardiovascular morbidity, but not mortality. 
Koskinas KC, Siontis GCM, Piccolo R et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29069377
What is the risk for hemorrhagic stroke in post IS/TIA patients using statins
The Health Improvement Network (THIN) primary care database in the United Kingdom was used to evaluate the relations ship between pre-admission statin use in post ischemic stroke (IS) or TIA patients and risk of intracerebral hemorrhage (ICH). The THIN registry collected prospective data of >600 primary care practices that included approximately 6% of the total UK population. Participants (40-84 years) were registered between January 1, 2000 and December 31st, 2008 and had at least 2-year follow up. The analysis was based on a nested case-control design. Statin use was noted as no use, current use and past use. For patients that used statin within 1-year, between 1 year and 8-days or statin use at the time of the ICH the OR’s were 0.92 (0.6-1.4), 1.81 (0.99-3.22) and 0.77 (0.49-1.22) respectively. No increased bleeding risk was observed in the 157 ICH patients vs the 884 controls, after an IS or TIA. The 30-day rates of fatal (OR, 0.82; 95% CI, 0.41–1.64) or nonfatal (OR, 0.90; 95% CI, 0.51–1.57) ICH were similar in patients using statins and who did not use statins. The authors concluded that in the analysis of the large THIN registry no increased bleeding risk was observed in post IS/TIA patients using statins. Findings that are in agreement with two previous meta-analyses. Suggesting that the increased ICH risk with statin use, noted in the exploratory analyses of 2 randomized controlled trials, may have been a chance finding. Statins should therefore not be withheld in patients that suffered a IS/TIA because of concerns regarding ICH risk.
Gaist D, Goldstein LB, Cea Soriano L, Garcia Rodriguez LA. Statins and the Risk of Intracerebral Hemorrhage in Patients With Previous Ischemic Stroke or Transient Ischemic Attack. Stroke 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29070714
HIV patients and statins a tough choice?
Patients infected with HIV, and optimally treated with anti-retroviral therapy (ART)are experiencing an increased life expectancy from HIV related complications but a two-fold increased risk for CVD related complications. Statins are considered the mainstream treatment reduce CVD risk. However, clinicians should be aware for the potential drug-drug interactions with ART and some of the available statins. In this short review, currently available evidence on pharmacokinetic and clinical data of the different statins, combined with ART in HIV patients is reported.  The two statins that are safe and effective to use in patients treated with protease inhibitors (PI) non-nucleoside reverse transcriptase inhibitor-based ART, are atorvastatin and pravastatin. Low dose rosuvastatin is considered safe and effective as well, but should not be used in patients using PI’s. For pitavastatin the available data is limited, but seems safe based on its pharmacokinetic properties and limited number of drug interactions. Lovastatin, fluvastatin and simvastatin should not be used in HIV patients using ART. Limited clinical data drug-drug interactions and reported adverse events are the reasons the authors made this recommendation. The protective role of statins CVD prevention are especially relevant in the chronic care of HIV patients. Clinicians need to be aware of certain limitations of some of the available statins, when combined with ART in HIV positive patients. This updated review will help them decide the optimal therapy in this high CVD risk population.
Chastain DB, Stover KR, Riche DM. Evidence-based review of statin use in patients with HIV on antiretroviral therapy. Journal of clinical & translational endocrinology 2017; 8:6-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=29067253
Relevant publications
  1. Yeh YT, Yin WH, Tseng WK et al. Lipid lowering therapy in patients with atherosclerotic cardiovascular diseases: Which matters in the real world? Statin intensity or low-density lipoprotein cholesterol level? Data from a multicenter registry cohort study in Taiwan. PLoS One 2017; 12:e0186861. http://www.ncbi.nlm.nih.gov/pubmed/?term=29073192
  2. Wang HH, Garruti G, Liu M et al. Cholesterol and Lipoprotein Metabolism and Atherosclerosis: Recent Advances In reverse Cholesterol Transport. Annals of hepatology 2017; 16:21-36. http://www.ncbi.nlm.nih.gov/pubmed/?term=29080338
  3. Visconti L, Benvenga S, Lacquaniti A et al. Lipid disorders in patients with renal failure: Role in cardiovascular events and progression of chronic kidney disease. Journal of clinical & translational endocrinology 2016; 6:8-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=29067238
  4. Stauffer ME, Hutson P, Kaufman AS, Morrison A. The Adherence Rate Threshold is Drug Specific. Drugs in R&D 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29076037
  5. Pang J, Hu M, Lin J et al. An enquiry based on a standardised questionnaire into knowledge, awareness and preferences concerning the care of familial hypercholesterolaemia among primary care physicians in the Asia-Pacific region: the "Ten Countries Study". BMJ Open 2017; 7:e017817. http://www.ncbi.nlm.nih.gov/pubmed/?term=29074516
  6. Marz W, Laufs U. Leucocyte immunoglobulin-like receptor subfamily-B5 (LILRB5) genetic variation and statin-associated muscle symptoms: another piece in a puzzling puzzle. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29059353
  7. Huesch MD. Serious Adverse Events Among SPRINT Trial Participants Taking Statins at Baseline. Drugs in R&D 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29058304
  8. Howard TM, Bavishi AA, Stone NJ. A New HOPE? Lessons From HOPE-3. Am J Med 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29074093
  9. Hawkes N. Statin initiation is unrelated to cardiovascular risk score, finds study. Bmj 2017; 359:j4898. http://www.ncbi.nlm.nih.gov/pubmed/?term=29066582
  10. Guo J, Zhang WZ, Zhao Q et al. Study on the effect of different doses of rosuvastatin on ventricular remodeling in patients with acute coronary syndrome after emergency percutaneous coronary intervention. Eur Rev Med Pharmacol Sci 2017; 21:4457-4463. http://www.ncbi.nlm.nih.gov/pubmed/?term=29077146
  11. Finnikin S, Ryan R, Marshall T. Statin initiations and QRISK2 scoring in UK general practice: a THIN database study. Br J Gen Pract 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29061715
  12. Ekici F, Ozcobanoglu S, Kardelen F. Premature Coronary Artery Disease due to Homozygous Familial Hypercholesterolemia in a 12-Year-old Girl. Balkan medical journal 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29072176
  13. Drakopoulou M, Toutouzas K, Michelongona A, Tousoulis D. Statins and vulnerable plaque. Current pharmaceutical design 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29065824
  14. Ceponiene I, Nakanishi R, Osawa K et al. Coronary Artery Calcium Progression Is Associated With Coronary Plaque Volume Progression: Results From a Quantitative Semiautomated Coronary Artery Plaque Analysis. JACC. Cardiovascular imaging 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29055625
  15. Bellosta S, Corsini A. Statin drug interactions and related adverse reactions: an update. Expert opinion on drug safety 2017:1-13. http://www.ncbi.nlm.nih.gov/pubmed/?term=29058944
  16. Alves-Cabratosa L, Garcia-Gil M, Comas-Cufi M et al. Statins and new-onset atrial fibrillation in a cohort of patients with hypertension. Analysis of electronic health records, 2006-2015. PLoS One 2017; 12:e0186972. http://www.ncbi.nlm.nih.gov/pubmed/?term=29073212
  17. Zhdan V, Khaymenova G, Shilkina L et al. Determine the effectiveness of lipid-lowering therapy in patients with chronic obstructive pulmonary disease combined with coronary heart disease. Wiadomosci lekarskie (Warsaw, Poland : 1960) 2017; 70:303-305. http://www.ncbi.nlm.nih.gov/pubmed/?term=29059648
  18. Zhang T, Shao B, Liu GA. Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-gamma. Eur Rev Med Pharmacol Sci 2017; 21:4464-4471. http://www.ncbi.nlm.nih.gov/pubmed/?term=29077145
  19. Tuteja S, Limdi N. Pharmacogenetics in Cardiovascular Medicine. Current genetic medicine reports 2016; 4:119-129. http://www.ncbi.nlm.nih.gov/pubmed/?term=29057167
  20. Tremoulet AH. Adjunctive therapies in Kawasaki disease. International journal of rheumatic diseases 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29076637
  21. Shahbazi S, Kaur J, Kuanar A et al. Risk of Late-Onset Alzheimer's Disease by Plasma Cholesterol: Rational In Silico Drug Investigation of Pyrrole-Based HMG-CoA Reductase Inhibitors. Assay and drug development technologies 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29077483
  22. Schaffer AL, Buckley NA, Pearson SA. Who benefits from fixed-dose combinations? Two-year statin adherence trajectories in initiators of combined amlodipine/atorvastatin therapy. Pharmacoepidemiol Drug Saf 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29067759
  23. Park JB, Jung JH, Yoon YE et al. Long-term Effects of high-doSe pitavaStatin on Diabetogenicity in comparison with atorvastatin in patients with Metabolic syndrome (LESS-DM): study protocol for a randomized controlled trial. Trials 2017; 18:501. http://www.ncbi.nlm.nih.gov/pubmed/?term=29078817
  24. Myftiu S, Sulo E, Burazeri G et al. Clinical Profile and Management of Patients with Incident and Recurrent Acute Myocardial Infarction in Albania - a Call for More Focus on Prevention Strategies. Zdravstveno varstvo 2017; 56:236-243. http://www.ncbi.nlm.nih.gov/pubmed/?term=29062398
  25. Gumbiner B, Joh T, Liang H et al. The effects of single- and multiple-dose administration of bococizumab (RN316/PF-04950615), a humanized IgG2Deltaa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies. Cardiovasc Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29078037
  26. Fazio S, Robertson DG, Joh T et al. Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin. Cardiovasc Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29057618
  27. Endo A, Okada T, Pak M et al. Comparison of the low-density lipoprotein cholesterol target value and the preventive effect of statins in elderly patients and younger patients. Journal of geriatric cardiology : JGC 2017; 14:383-391. http://www.ncbi.nlm.nih.gov/pubmed/?term=29056945
  28. Bock CH, Jay AM, Dyson G et al. The effect of genetic variants on the relationship between statins and breast cancer in postmenopausal women in the Women's Health Initiative observational study. Breast Cancer Res Treat 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29063981
  29. Amrock SM, Duell PB, Knickelbine T et al. Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH patient registry. Atherosclerosis 2017; 267:19-26. http://www.ncbi.nlm.nih.gov/pubmed/?term=29080546
Miscellaneous publications
  1. Zhang Y, Rong S, Feng Y et al. Simvastatin attenuates renal ischemia/reperfusion injury from oxidative stress via targeting Nrf2/HO-1 pathway. Experimental and therapeutic medicine 2017; 14:4460-4466. http://www.ncbi.nlm.nih.gov/pubmed/?term=29067120
  2. Wu X, Song M, Qiu P et al. A metabolite of nobiletin, 4'-demethylnobiletin and atorvastatin synergistically inhibits human colon cancer cell growth by inducing G0/G1 cell cycle arrest and apoptosis. Food & function 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29063088
  3. Schneiders FL, Huijts CM, Reijm M et al. The effects of systemic treatment with aminobisphosphonates and statins on circulating Vgamma9Vdelta2-T cells in patients with advanced cancer. Immunobiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29055564
  4. Kobayashi Y, Kashima H, Rahmanto YS et al. Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer. Oncotarget 2017; 8:72147-72156. http://www.ncbi.nlm.nih.gov/pubmed/?term=29069775
  5. Han JS, Sung JH, Lee SK. Inhibition of Cholesterol Synthesis in HepG2 Cells by GINST-Decreasing HMG-CoA Reductase Expression Via AMP-Activated Protein Kinase. Journal of food science 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29065216
  6. Ekanayaka RA, Rupasinha AD, Sooriyarachchi MR, Goonaratna C. The effect of thriphala, a herbal Ayurveda formulation, on serum lipids, in patients on a maintenance dose of atorvastatin for hyperlipidaemia: a randomized controlled trial. The Ceylon medical journal 2017; 62:128-140. http://www.ncbi.nlm.nih.gov/pubmed/?term=29072054
  7. Bao XC, Mao AR, Fang YQ et al. Simvastatin Decreases Hyperoxic Oxygen-Induced Acute Lung Injury by Upregulating eNOS. American journal of physiology. Lung cellular and molecular physiology 2017:ajplung.00520.02016. http://www.ncbi.nlm.nih.gov/pubmed/?term=29074491
  8. Abd El Aal HA, Ahmed LA, Hassan WA et al. Combination of carvacrol with simvastatin improves the lipid-lowering efficacy and alleviates simvastatin side effects. Journal of biochemical and molecular toxicology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29071762
  9. Lopez-Alvarez M, Lopez-Puente V, Rodriguez-Valencia C et al. Osteogenic effects of simvastatin-loaded mesoporous titania thin films. Biomedical materials (Bristol, England) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29068320
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