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Update - Week 14, 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

Week 14

Not Ethnicity but SNP’s determine plasma levels of Rosuvastatin
Pharmacogenetics of statins is gaining ground in this analysis of Rosuvastatin exposure in Asians compared to Caucasians. The FDA advised to reduce Rosuvastatin dosage in Asian patients, based on pharmacokinetic data of a two-fold increase in median exposure to Rosuvastatin. In this an investigator-initiated, prospective, two arm, crossover, randomized, controlled trial Caucasians (N=8) and Asians(N=8) were compared and no significant differences were observed in wild type carriers of the Solute Carrier Organic anion transporter1B1 *1a and ATP 8 Binding Cassette Subfamily G Member 2 c.421 transporters. The AUC0-48 were 92.5(±36.2) and 83.5(±32.2) ng/mL*hr. and Cmax were 10.0(±4.1) and 7.6(±3.0) 11 ng/mL for Asians and Whites, respectively. Both SLCO1B1 *1a and ABCG2 c.421 alleles impact the pharmacogenetics of Rosuvastatin and Caucasians carrying these SNP’s have increased plasma concentrations of Rosuvastatin as well. The authors conclude that both SLCO1B1 and ABCG2 polymorphisms are better predictors of rosuvastatin exposure than ethnicity and could be considered when determining dosage of Rosuvastatin but additional studies are needed to confirm these results.
Wu HF, Hristeva N, Chang J et al. Rosuvastatin Pharmacokinetics in Asian and White Subjects wild-type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions. Journal of pharmaceutical sciences 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28385543
Statin use not related to polyneuropathy
In earlier, but smaller studies a relationship between polyneuropathy and statin use was noted. The data set used in this study was significantly larger and aimed to re-asses the relationship between chronic statin exposure and the increased risk of developing chronic polyneuropathy. A retrospective case – control analysis based on data from two large Danish registries, the Odense University Hospital Registry and the Odense Pharmaco-epidemiologic Prescription database. For each case (N=370), 20 controls (N=7400) were recruited from the Danish general population. No association between polyneuropathy risk and statin was observed, for ever use: OR 1,14 (95% CI: 0.84-1.54); current use OR: 1.11 (95% CI: 0.79-1.53), long-term use: OR 1.13 (95%CI: 0.66-1.92), or high intensity use: OR 1.05 (95%CI: 0.59-1.84). This analysis had sufficient statistical power and was unable to detect a relationship between statin use and chronic polyneuropathy.
Svendsen TK, Hansen PN, Garcia Rodriguez LA et al. Statins and polyneuropathy revisited: Case-control study in Denmark, 1999-2013. Br J Clin Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28370351
Real world evidence statins reduce CVD and non-CVD mortality in post ACS patients
Long term follow up data on the benefits of high dose high intensity statins (HS) post ACS is for the first time presented in this analysis of a large Swedish National Health Registry and medical record data of different sources. This type of analysis provides a more realistic reflection of real world clinical practice than what can be determined by prospective studies. Over the period 2001 – 2012, 49 857 ACS patients were identified, 10 992 (20.2%) receiving HS and 21 174 (42.7%) no using statins. The endpoints, second CVD event and death, stratified by gender, age and diabetic status, were analyzed. HS was defined as using 40 mg of atorvastatin, simvastatin or pravastatin; 40 mg of lovastatin;20 mg of rosuvastatin and 80 mg of fluvastatin daily with an average prescription rate of > 1.3/year of follow-up. Noteworthy results were the reduced non-CVD mortality, as well as a reduced impact of gender and diabetes on CVD, and non-CVD mortality in the statin group. The risk of a second CVD event developed similarly in both treatment groups, but was much higher in the no statin group. In the statin users, the risk of CVD-related death remained relatively constant but over time increased significantly in the no-statin group. CVD mortality rates of males were higher in the no-statin group, but not in the high-statin group. Similar trends were observed for all-cause mortality and non-CVD-related death. The authors noted that the increased mortality for diabetics and males not on statins emphasizes the importance of statin treatment in secondary prevention
Rockberg J, Jorgensen L, Taylor B et al. Risk of mortality and recurrent cardiovascular events in patients with acute coronary syndromes on high intensity statin treatment. Preventive medicine reports 2017; 6:203-209. http://www.ncbi.nlm.nih.gov/pubmed/?term=28373930
Benefits of statin observed in Ghanese heart failure patients
This retrospective longitudinal study included 1488 patients (60.3 ±14.2 years); 54% females
Statins were prescribed to 552 (37.2%) patients. The included patients were discharged after a first admission for heart failure (HF) between January 1, 2009 and December 31, 2013 in a tertiary health care center. Only 10% of the patients had ischemic HF and were a mix of NYHA functional classes with a mean ejection fraction of 52.9 (±16.4). Approximately 76.2% of the participants were NYHA class II and III; class I 11.1% and class IV 12.7%. Non-statin users were more likely to be in class NYHA IV. Most patients were using lipophilic statins 81.3%, atorvastatin being the most frequently used in 49.3% of the patients; 18.7% used Rosuvastatin.  During follow-up, 472 (31.7%) patients died; 166 (30.1%) of statin users and 306 (32.6%) in the non-statin group. The mean survival time was 3.26, 4.13, and 2.97 years; number of patients surviving after 1, 3, and 5 years was 90.3%, 64.7%, and 38.4%, for overall cohort, statin users, and non-statin users, respectively. The crude 5-year all-cause mortality was 11.2% in patient treated with statins and 20.6% for those without statins (P=0.065). CVD mortality: 157 (10.5%) in statin users and 297 (19.9%) of non-statin users(P=0.039). Worsening HF accounted for 5-year crude mortality of 146 (9.8%) among statin users and 286 (19.2%) in non-statin users (P=0.019).  The 5-year adjusted HR for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55–0.83), 0.67 (0.54–0.82), and 0.63 (0.51– 0.79), compared with no statin use. The authors concluded that in this exploratory observational study they showed a significant association between statin use and reductions in all-cause mortality, cardiovascular mortality, and HF mortality among Ghanese Africans with newly diagnosed HF.
Cholesterol crystallizationBonsu KO, Owusu IK, Buabeng KO et al. Statin Treatment and Clinical Outcomes of Heart Failure Among Africans: An Inverse Probability Treatment Weighted Analysis. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28365564
Review discussing new challenges to reduce AS plaques in the statin era
Manifestations of CAD have changed since statins were introduced 30 years ago. A marked reduced CVD mortality and a shift from a dominance of ST segment elevation myocardial infarction (STEMI) towards non-STEMI. Studies using optical coherence tomography show that non-STEMI generally is caused by a thrombus being formed on the surface of plaques with a thick fibrous cap without a visible rupture. The author propose that new therapies will be needed to address other mechanisms than lipid driven inflammation. This review discusses some of these possible future treatment targets to reduce coronary atherosclerosis and recurrent events in patients already on statins and other current guideline dictated therapies. Suggested targets are diabetes & impaired vascular repair; plaque stenosis & shear stress; endothelial function & repair; autoimmune responses against plaque antigens; cholesterol crystallization and Infections & plaque vulnerability. The authors recommend that novel biomarkers and other diagnostics, as well as therapies targeting these mechanisms, need to be developed.
Nilsson J. Atherosclerotic plaque vulnerability in the statin era. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28387815
Meta-analysis of statins to prevent VTE and PE show promise
In this meta-analysis of 8 observational prospective cohort studies (no RCT’s were identified, but one study was based on a post hoc analysis of an extended follow-up of a RCT) including 103 767 participants and resulting in 3 168 recurrent VTE outcomes.  Statins were associated with a reduced risk for thrombosis related end-points. The pooled analysis of 7 studies, showed a RR for recurrent VTE of 0.73 (0.68–0.79).  For PE (3 studies) and DVT (2 studies), RR of 0.75 (95% CI: 0.58–0.96) and 0.66 (95% CI: 0.60–0.71) respectively. This resulted in an ARR of 0.27% and translates to about 1110 people that need to be treated to prevent one recurrent VTE in a year. Although these numbers are not that impressive compared to oral anticoagulation therapy, statins have an excellent safety profile and do not cause bleeding. Statins could prevent VTE’s by inhibiting the coagulation cascade leading to reduced thrombin formation, pro-fibrinolytic and antiplatelet effects. This is the first analysis to evaluate relevant studies that have assessed associations between statin and VTE recurrence and supports an association between statin use and a reduced risk for VTE, more importantly it highlights an important gap in existing literature and the urgent need for well-designed intervention studies to confirm if statins could play a clinical relevant role in the secondary prevention of VTE’s.
Kunutsor SK, Seidu S, Khunti K. Statins and secondary prevention of venous thromboembolism: pooled analysis of published observational cohort studies. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28369602

Relevant publications
Week 14
  1. Villa G, Lothgren M, Kutikova L et al. Cost-Effectiveness of Evolocumab in Patients With High Cardiovascular Risk in Spain. Clinical therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28366593
  2. Ridker PM, Lonn E, Paynter NP et al. Primary Prevention With Statin Therapy in the Elderly: New Meta-Analyses from the Contemporary JUPITER and HOPE-3 Randomized Trials. Circulation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28385949
  3. Rea F, Bonassi S, Vitale C et al. Exposure to statins is associated to fracture risk reduction in elderly people with cardiovascular disease: evidence from the AIFA-I-GrADE observational project. Pharmacoepidemiol Drug Saf 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28370905
  4. Parida S, Swain TR, Routray SN, Maiti R. Effect of Atorvastatin on Glycaemic Parameters in Normoglycaemic and Prediabetic Subjects: A Prospective, Panel Study. J Clin Diagn Res 2017; 11:Fc04-fc09. http://www.ncbi.nlm.nih.gov/pubmed/?term=28384881
  5. Okunrintemi V, Spatz ES, Di Capua P et al. Patient-Provider Communication and Health Outcomes Among Individuals With Atherosclerotic Cardiovascular Disease in the United States: Medical Expenditure Panel Survey 2010 to 2013. Circ Cardiovasc Qual Outcomes 2017; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=28373270
  6. Li Y, Lu G, Sun D et al. Inhibition of endoplasmic reticulum stress signaling pathway: A new mechanism of statins to suppress the development of abdominal aortic aneurysm. PLoS One 2017; 12:e0174821. http://www.ncbi.nlm.nih.gov/pubmed/?term=28369137
  7. Hirayama A, Yamashita S, Inomata H et al. One-Year Efficacy and Safety of Evolocumab in Japanese Patients- A Pooled Analysis From the Open-Label Extension OSLER Studies. Circulation journal : official journal of the Japanese Circulation Society 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28367845
  8. Wiggins BS, Lamprecht DG, Jr., Page RL, 2nd, Saseen JJ. Recommendations for Managing Drug-Drug Interactions with Statins and HIV Medications. Am J Cardiovasc Drugs 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28364370
  9. Taghizadeh M, Noruzinia M. Lovastatin Reduces Stemness via Epigenetic Reprograming of BMP2 and GATA2 in Human Endometrium and Endometriosis. Cell journal 2017; 19:50-64. http://www.ncbi.nlm.nih.gov/pubmed/?term=28367417
  10. Sana T, Aslam B, Aslam N et al. Therapeutic effect of atorvastatin on kidney functions and urinary excretion of Glimepiride in healthy adult human male subjects. Pak J Pharm Sci 2016; 29:2321-2326. http://www.ncbi.nlm.nih.gov/pubmed/?term=28375090
  11. Rozani V, Giladi N, El-Ad B et al. Statin adherence and the risk of Parkinson's disease: A population-based cohort study. PLoS One 2017; 12:e0175054. http://www.ncbi.nlm.nih.gov/pubmed/?term=28388626
  12. Momtazi AA, Banach M, Pirro M et al. Regulation of PCSK9 by nutraceuticals. Pharmacol Res 2017; 120:157-169. http://www.ncbi.nlm.nih.gov/pubmed/?term=28363723
  13. Manns L, Scott-Douglas N, Tonelli M et al. A Population-Based Analysis of Quality Indicators in CKD. Clin J Am Soc Nephrol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28377473
  14. Lunder M, Janic M, Savic V et al. Very low-dose fluvastatin-valsartan combination decreases parameters of inflammation and oxidative stress in patients with type 1 diabetes mellitus. Diabetes Res Clin Pract 2017; 127:181-186. http://www.ncbi.nlm.nih.gov/pubmed/?term=28384560
  15. Liu G, Sterling NW, Kong L et al. Statins may facilitate Parkinson's disease: Insight gained from a large, national claims database. Movement disorders : official journal of the Movement Disorder Society 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28370314
  16. Kovacevic SV, Miljkovic B, Culafic M et al. Evaluation of drug-related problems in older polypharmacy primary care patients. J Eval Clin Pract 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28370742
  17. Johnson PK, Mendelson MM, Baker A et al. Statin-Associated Myopathy in a Pediatric Preventive Cardiology Practice. J Pediatr 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28365026
  18. Hoppe C, Jacob E, Styles L et al. Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial. British journal of haematology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28369718
  19. Galway S, Adatia F, Grubisic M et al. Sex Differences in Cardiac Medication Use Post-Catheterization in Patients Undergoing Coronary Angiography for Stable Angina with Nonobstructive Coronary Artery Disease. Journal of women's health (2002) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28384013
  20. Dong YH, Choudhry NK, Krumme A et al. Impact of hospitalization on medication adherence estimation in claims data. Journal of clinical pharmacy and therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28370404
  21. Catapano AL, Lee LV, Louie MJ et al. Efficacy of alirocumab according to background statin type and dose: pooled analysis of 8 ODYSSEY Phase 3 clinical trials. Scientific reports 2017; 7:45788. http://www.ncbi.nlm.nih.gov/pubmed/?term=28374849
  22. Berquist SW, Lee HJ, Hamilton Z et al. Statin utilization improves oncologic and survival outcomes in patients with dyslipidemia and surgically treated Renal Cell Carcinoma. Minerva urologica e nefrologica = The Italian journal of urology and nephrology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28376607
  23. Bangalore S, Fayyad R, Laskey R et al. Body-Weight Fluctuations and Outcomes in Coronary Disease. N Engl J Med 2017; 376:1332-1340. http://www.ncbi.nlm.nih.gov/pubmed/?term=28379800

Miscellaneous publications
Week 14
  1. Soto-Acosta R, Bautista-Carbajal P, Cervantes-Salazar M et al. DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target. PLoS pathogens 2017; 13:e1006257. http://www.ncbi.nlm.nih.gov/pubmed/?term=28384260
  2. Mott M, Koroshetz W, Wright CB. CREST-2: Identifying the Best Method of Stroke Prevention for Carotid Artery Stenosis: National Institute of Neurological Disorders and Stroke Organizational Update. Stroke 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28386040
  3. He X, Zheng N, He J et al. Gut microbiota modulation attenuated the hypolipidemic effect of simvastatin in high-fat/cholesterol-diet fed mice. J Proteome Res 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28378586
  4. Guo Q, Liu C, Hai B et al. Chitosan conduits filled with simvastatin/Pluronic F-127 hydrogel promote peripheral nerve regeneration in rats. Journal of biomedical materials research. Part B, Applied biomaterials 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28371231

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