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Update - Week 34, 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

An extended follow up 1.1 year follow up in the AIM-HIGH study confirm initial results
The add-on of extended release niacin to simvastatin, with or without ezetimibe was tested in the AIM-HIGH study. The participants were CVD patients with low baseline HDL-c and elevated triglycerides. After a mean follow up of almost 3 years the trial was stopped due to lack of benefit. In this updated analysis the effects of an extended follow up, a mean of 1.1 additional years, was evaluated in 2613 participants (82%) was studied. ERN was used by 1312 patient’s vs 1203 placebo users. After 4.1 years 343 CV endpoints were observed in the ERN using patients vs 305 CV events in the placebo group; HR: 1.11 (0.96-1.30). The results noted in the follow up part of the study, were in line with was observed in the main AMI-HIGH study. No benefits of using ERN as an add-on to standard lipid lowering therapy.  A non-significant increase of ischemic stroke events was observed in the ERN users, at the end of the blinded study period, but this did not reach statistical significance after an additional 1.1 year follow-up.
Probstfield JL, Boden WE, Anderson T et al. Cardiovascular outcomes during extended follow-up of the AIM-HIGH trial cohort. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30131256

Pleiotropic effects of statins beyond lipid lowering
In this article, co-authored by James K. Liao the pleiotropic effects of statins are reviewed and discussed. As one of the first authors to coin the term, in a 2001 ATVB review of this topic. In this recent review the two authors highlight why statins are viewed as more than merely LDL-cholesterol lowering drugs.  The inhibition of isoprenoids, intermediates of the cholesterol synthesis pathway, has an effect on Rac Rho proteins and these partly control NADPH oxidases. Downstream effects on endothelial nitric oxide synthase expression, atherosclerotic plaque stability, pro-inflammatory cytokines and reactive oxygen species production, platelet reactivity, and cardiac fibrosis and hypertrophy development have been observed. These mostly beneficial changes have been termed the pleiotropic effects of statins. The authors discuss in detail the different intrinsic pathways triggered by HMG-CoA inhibitors. New information in the review are the effects observed on the immune system, platelets, atrial fibrillation and ventricular tachyarrhythmias. Comparisons with ezetimibe and PCSK9ab therapies to statins are briefly discussed as well. This review provides a well-balanced and insightful update on the controversial topic of the pleiotropic effects of statins.
Liao JK, Oesterle A. The Pleiotropic Effects of Statins - From Coronary Artery Disease and Stroke to Atrial Fibrillation and Ventricular Tachyarrhythmia. Current vascular pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30124154

SVG for CABG procedures show similar outcomes after 1 year of 80 or 10 mg atorvastatin
Using saphenous grafts (SVG) remains a vessel source for CABG procedures in patients where multiple vascular jumps are needed. The internal mammary arteries are not always able to provide sufficient vessel length. The drawback is that graft occlusions are more frequently observed when SVG’s are used. Some observational data did show improved patency when high dose, high intensity statin was prescribed. In this double blind randomized controlled trial atorvastatin 80 mg is compared to atorvastatin 10 mg in 173 patients in whom SVG’s were used for their CABG procedures. The primary endpoints were SVG stenosis and major cardiovascular events. After 1 year no significant difference were observed for the 145 patients that completed the study and used atorvastatin 10 or 80 mg. SVG occlusions 12.9% and 11.4% respectively. No significant difference in graft stenosis (P=0.54) but a trend for the combined endpoint of vein graft disease (occlusion or stenosis) 19.2& and 29.2% respectively (P=0.18). Major cardiovascular events were similar in both treatment arm as well (P=0.27). In this 1-year pilot trial no differences could be discerned in patients that had an SVG-CABG procedure and were treated with 10 or 80 mg of atorvastatin.
Kulik A, Abreu AM, Boronat V, Ruel M. Intensive versus moderate statin therapy and early graft occlusion after coronary bypass surgery: The Aggressive Cholesterol Therapy to Inhibit Vein Graft Events randomized clinical trial. The Journal of thoracic and cardiovascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30122341

Prolactin levels impact the metabolic effects of statins
The effects of statins are not always as predictable. In this prospective follow up study (A) 19 women with untreated hyperprolactemia (A), 20 normoprolactinemic women, treated with bromocriptine because of previous hyperprolactemia (B), and 20 untreated normoprolactinemic women (C) were all given atorvastatin 40. At baseline and after 12 weeks of treatment, lipids, glycemic parameters hormone levels, uric acid, hs CRP, homocysteine and fibrinogen were measured. Difference at baseline biomarkers were observed for insulin resistance markers which were higher in group A. after atorvastatin treatment all participants experienced similar LDL-c reductions, but only in group B and C, circulating levels of nonlipid cardiometabolic risk factors were reduce significantly. In group A insulin sensitivity significantly deteriorated after 12 weeks of atorvastatin 40 mg.  Based on their findings the authors concluded that the metabolic effects of statins could depend on the prolactin status of patients.
Krysiak R, Szkrobka W, Okopien B. Different Effects of Atorvastatin on Cardiometabolic Risk Factors in Young Women With and Without Hyperprolactinemia. Journal of clinical pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30129670

Would you like your exercise with or without statins?
Lifestyle or statins is a debate that surfaces regularly in social media discussions. In this study the addition of exercise to statins vs statin and vs exercise only was evaluated in elderly high CVD risk patients (60+). The endpoints were functional status and CVD risk. The participants (N=981) were divided in 3 groups: (a) multicomponent exercise training (EX; n = 298; 74% females); (b) statins (ST; n = 178; 65% females); (c) combined therapy—exercise plus ST therapy (ST+EX; n = 505; 79% females). Patients were followed for 2 years and functional fitness, anthropometry, hemodynamic and lipid profiles were assessed at baseline and after study completion. The muliti compartment exercise program was an extensive supervised regime that had a build in step wise increase. Statins use was prescribed by their primary care physician and consisted of low dose and/or low intensity statins (Atorvastatin (10 mg), Pravastatin (20 mg), Pitavastatin (2 mg), Rosuvastatin (20 mg), and Simvastatin (20 mg). functional status improved only in patients that participated in the exercise program. In patients that only used statins these functional parameters deteriorated. Total cholesterol decreased in all 3 groups and TG + HDL remained unchanged. Intriguingly LDL-c decreased in the both groups were exercise was incorporated but not in the statin only group. Statins dosage as well as adherence could be important to explain this surprising effect on LDL-c in statin users. On a similar note BMI, and BP (diastolic and systolic) improved as well and worsened in the patients that used statins only. Based on the results of this study intensive and continuous exercise in elderly patient is an effective strategy to improve functional status and improve lipid levels. Age and statin induce adverse events could respond favorably as well. Emphasizing improved lifestyle strategies should include exercise program in managing elderly patients at increased risk for CVD. The authors concluded that in asymptomatic elderly dyslipidemic patients introducing exercise could help to ward of the negative effects of statins therapy. For those presenting with myalgia or myositis, they advise to substitute satins with a long-term exercise program instead of change of statin or statin dosage reduction. However, this could be debated if, based on guidelines, statins are indicated in high CVD risk patients
Baptista LC, Verissimo MT, Martins RA. Statin combined with exercise training is more effective to improve functional status in dyslipidemic older adults. Scandinavian journal of medicine & science in sports 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30137683

Relevant publications
  1. Yagi S, Kondo D, Ise T et al. Association of Decreased Docosahexaenoic Acid Level After Statin Therapy and Low Eicosapentaenoic Acid Level with In-Stent Restenosis in Patients with Acute Coronary Syndrome. J Atheroscler Thromb 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30135329
  2. Kim C, Choi D. Timing of high intensity statin for acute coronary syndrome: how earlier initiation makes better? J Thorac Dis 2018; 10:S2149-s2152. http://www.ncbi.nlm.nih.gov/pubmed/?term=30123546
  3. Veronese N, Koyanagi A, Stubbs B et al. Statin use and knee osteoarthritis outcomes: A longitudinal cohort study. Arthritis care & research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30144308
  4. Vassy JL, Chun S, Advani S et al. Impact of SLCO1B1 pharmacogenetic testing on patient and healthcare outcomes: A systematic review. Clinical pharmacology and therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30137643
  5. Nicholls SJ, Lincoff AM, Bash D et al. Assessment of Omega-3 Carboxylic Acids in Statin Treated Patients with High Levels of Triglycerides and Low Levels of High Density Lipoprotein Cholesterol: Rationale and Design of the STRENGTH Trial. Clin Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30125052
  6. Kannan S, Asch DA, Kurtzman GW et al. Patient and physician predictors of hyperlipidemia screening and statin prescription. The American journal of managed care 2018; 24:e241-e248. http://www.ncbi.nlm.nih.gov/pubmed/?term=30130024
  7. Ferrieres J, Gorcyca K, Iorga SR et al. Lipid-lowering Therapy and Goal Achievement in High-risk Patients From French General Practice. Clinical therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30126705
  8. Ahmadvand A, Yazdanfar A, Yasrebifar F et al. Evaluation the effects of oral and topical simvastatin as adjunct therapy in the treatment of acne vulgaris. Current clinical pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30129417
  9. Tani S, Matsuo R, Hirayama A. Does administration of eicosapentaenoic acid increase soluble thrombomodulin level in statin-treated patients with stable coronary artery disease? Heart Vessels 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30143885
  10. Roughead EE, Kim DS, Ong B, Kemp-Casey A. Pricing policies for generic medicines in Australia, New Zealand, the Republic of Korea and Singapore: patent expiry and influence on atorvastatin price. WHO South-East Asia journal of public health 2018; 7:99-106. http://www.ncbi.nlm.nih.gov/pubmed/?term=30136668
  11. Oleynikov VE, Dushina EV, Barmenkova YA et al. [The Impact of Effective Therapy With Atorvastatin on the Dynamics of Parameters of Electrical Instability in Patients with ST-Elevation Myocardial Infarction]. Kardiologiia 2018:18-24. http://www.ncbi.nlm.nih.gov/pubmed/?term=30131038
  12. Li Z, Li Y, Li X et al. Statins on hepatocellular carcinoma risk in hepatitis B or C patients protocol for a systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e11950. http://www.ncbi.nlm.nih.gov/pubmed/?term=30142817
  13. Habibi H, Atashi A, Abroun S, Noruzinia M. Synergistic Effect of Simvastatin and Romidepsin on Gamma-globin Gene Induction. Cell journal 2019; 20:576-583. http://www.ncbi.nlm.nih.gov/pubmed/?term=30124006
  14. Ciric D, Martinovic T, Petricevic S et al. Metformin exacerbates and simvastatin attenuates myelin damage in high fat diet-fed C57BL/6 J mice. Neuropathology : official journal of the Japanese Society of Neuropathology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30123961
Miscellaneous publications
  1. Rauca VF, Licarete E, Luput L et al. Combination therapy of simvastatin and 5, 6-dimethylxanthenone-4-acetic acid synergistically suppresses the aggressiveness of B16.F10 melanoma cells. PLoS One 2018; 13:e0202827. http://www.ncbi.nlm.nih.gov/pubmed/?term=30138430
  2. Kim K, Theusch E, Kuang YL et al. ZNF542P is a pseudogene associated with LDL response to simvastatin treatment. Scientific reports 2018; 8:12443. http://www.ncbi.nlm.nih.gov/pubmed/?term=30127457
  3. Dein E, Manno R, Syed A et al. Ranolazine-induced Elevation of Creatinine Kinase in the Absence of Statin Usage. Cureus 2018; 10:e2832. http://www.ncbi.nlm.nih.gov/pubmed/?term=30131925
  4. Aldalaen S, El-Gogary RI, Nasr M. Fabrication of rosuvastatin-loaded polymeric nanocapsules: A promising modality for treating hepatic cancer delineated by apoptotic and cell cycle arrest assessment. Drug development and industrial pharmacy 2018:1-29. http://www.ncbi.nlm.nih.gov/pubmed/?term=30139281
  5. Xia B, Li Y, Zhang Y et al. UHPLC-MS/MS method for determination of atorvastatin calcium in human plasma: Application to a pharmacokinetic study based on healthy volunteers with specific genotype. Journal of pharmaceutical and biomedical analysis 2018; 160:428-435. http://www.ncbi.nlm.nih.gov/pubmed/?term=30130726
  6. Oda Y, Sasaki H, Miura T et al. Bone marrow stromal cells from low-turnover osteoporotic mouse model are less sensitive to the osteogenic effects of fluvastatin. PLoS One 2018; 13:e0202857. http://www.ncbi.nlm.nih.gov/pubmed/?term=30142209
  7. Correction: Statin wars: have we been misled about the evidence? A narrative review. British journal of sports medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30131331
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