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Update - Week 47, 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

EAT a novel target of statin therapy?
The benefits of statins beyond their primary LDL-C lowering effects is illustrated in this retrospective study of patients with isolated severe calcific aortic stenosis scheduled for aortic valve replacement. Of the 193 enrolled patients, 87 (45.1%) were using statins (3-72 months), and 106 patients were not using statins. The latter were individual without a prior diagnosis of CAD. Patients with inflammatory co-morbidities or cancer were excluded as well, to avoid possible confounding due to an increased visceral fat inflammation that is frequently observed in these patients. The study aimed to evaluate the effects of statin on epicardial adipose tissue (EAT) thickness and inflammation. Using echocardiographic parameters as well as EAT biopsies, tissue content of cytokines based on immunoassay of EAT secretomes were quantified. Patients using statins had a significantly reduced EAT burden (P<0.0001) and reduced inflammasome related biomarkers (P<0.0001). The measured EAT thickness showed a significant positive correlation with the pro-inflammatory status. Compared with an in-vitro analysis of subcutaneous adipose tissues (SCAT) biopsy material and statin incubation response, the anti-inflammatory effects of atorvastatin on EAT was significantly stronger compared to the in-vitro SCAT response to atorvastatin (P<0.0001). The authors concluded that these findings support the direct effects of atorvastatin on EAT thickness as well as modulating the inflammatory status.  The in-vitro data points towards a direct effect of atorvastatin on EAT activation as well as supporting EAT as a potential novel target for statin therapy.
Parisi V, Petraglia L, D'Esposito V et al. Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue. Int J Cardiol 2019; 274:326-330. http://www.ncbi.nlm.nih.gov/pubmed/?term=30454723
 
TNT study:  Atorvastatin 80 mg improves FGF21 level related MACE
Liver secreted fibroblast growth factor 21 (FGF21) plays a role in lipid and glucose metabolism regulation. Anti-inflammatory anti-diabetic and hypolipidemic effects of FGF21 have been observed in animal studies. Increased plasma concentrations of FGF21 are frequently found in patients with obesity, dyslipidemia, insulin resistance, metabolic syndrome, type 2 diabetes, nonalcoholic fatty liver disease, and coronary artery disease. As such it could be considered a biomarker of cardiometabolic dysfunction, resulting from impaired FGF21 signaling or compensatory responses to the underlying metabolic stress. FGF21 has been recognized as a risk marker for CVD in diabetic patients. Using data collected in the TNT study, the authors set out to determine if FGF21 plasma concentration could predict MACE in the statin-treated general population included in the TNT. Of the 10 001 TNT participants, FGF21 measurements were available in 1996 individuals at randomization and 1835 had FGF21 measured 1-year post randomization. In patients with increased FGF21 levels after 1 year, the risk for MACE increased; adjusted HR/SD increase = 1.18 (P = 0.019). Patients allocated to atorvastatin 80 mg had on average lower FGF21 plasma concentrations as compared to patients that used atorvastatin 10 mg; 186.9 versus 207.5 pg/mL respectively (P =0.006). Higher transformed FGF21 levels, 1-year post-randomization also reflected an increase MACE risk. adjusted HR/SD increase=1.24 (P=0.009). The authors concluded that analyzing plasma FGF21 levels had significant incremental values in improving MACE risk reclassification. Measuring FGF21 in a statin-treated patient could improve risk prediction, and potentially qualify patients for add-on therapy to reduce their increased risk. The use of Atorvastatin 80 mg showed lower FGF21 levels compared to patients using atorvastatin 10 mg, underlining the superior benefits of 80 mg vs 10 mg of atorvastatin.
Ong KL, Hui N, Januszewski AS et al. High plasma FGF21 levels predicts major cardiovascular events in patients treated with atorvastatin (from the treating to new targets [TNT] study). Metabolism 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30452928
 
Statins show benefits in selected HF patients
The benefits of prescribing statins in heart failure (HF) patients is not a simple “one treat all” concept. Defining specific HF characteristic could help in selecting patients that benefit. In this study, the aim was to evaluate the effects of statins in patients with ischemic cardiomyopathy without active ischemia and mild to moderate heart failure. The authors evaluated cardiac sympathetic nerve activity by using iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy, an analog of norepinephrine and used to detect cardiac sympathetic nerve activity (CSNA) abnormalities. This study was a sub-study of an earlier analysis that used 123I-MIBG Scintigraphy to evaluate the prognosis of HF patients with an LVEF <45% plus echocardiographic evaluation, immediately before hospital discharge and after 6 months. This allowed visualizing the % denervation, heart/mediastinum count ratio, and washout rate. In this sub-study 76 patients were selected based on a propensity score matching, statin using patients (n=38) were compared to those who did not (n=38). The follow-up time was a median of 4.74 years. The primary and secondary endpoints were incidences of fatal cardiac events and major adverse cardiac events (MACEs), respectively. Left ventricular end-systolic volume, and LVEF were also determined. Both the 123I-MIBG scintigraphic and echocardiographic parameters improved in all patients but showed significantly more favorable changes in patients that used statins (P<0.001). A similar pattern was observed for cardiac death and MACE (P<0.05). These preliminary findings indicate that statin therapy may improve CSNA, prevent LV remodeling and reduce fatal + non-fatal cardiac events in patients with ischemic cardiomyopathy. However, these results do need to be confirmed in a larger RCT before mainstream recommendations can be formulated.
Kasama S, Toyama T, Suzuki S et al. Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity and cardiac events in patients with ischemic cardiomyopathy and mild to moderate heart failure. Nuclear medicine communications 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30461696
 
Could pre-transplant dialysis patients benefit from statins?
The use of statins in patients with advanced renal disease failed to show any significant benefit in the 4D and AURORA studies but. Based on these finding major guidelines do not recommend the use of statins in these patients. If dialysis patient receives a kidney transplant a sharp increase in cardiovascular events is observed, and statins are indicated in post-transplant patients to reduce cardiovascular events and contribute to reduced organ rejections as well. The authors reviewed published data on the effects of statins in post-transplant patients and show that, in the studies highlighted in their review, benefits were observed. They suggest that statins could significantly reduce ASCVD events in patients that receive a donor kidney particular the ones with a history of CVD complications. From this perspective dialysis patients with an elevated CVD risk, such as those with genetic dyslipidemias, type II diabetes mellitus, or a high ASCVD risk scores could benefit from statin treatment while awaiting transplant and this might improve peri-operative mortality as well as short- and long-term survival. Based on the highlighted observational findings, a large randomized prospective clinical trial is warranted.
Aziz F, Garg N, Parajuli S et al. Lipid-lowering in dialysis patients with cardiovascular disease who are awaiting kidney transplantation. Clinical transplantation 2018:e13452. http://www.ncbi.nlm.nih.gov/pubmed/?term=30466167

Can statins be prescribed to breastfeeding mothers?
Whether to prescribe statins to breastfeeding mothers is not dilemma physician will be confronted with on a regular basis. However, in specialized lipid clinics referrals of female patients that have suffered a (recent) ASCVD event and delivered a newborn child can occur. Although common practice is to stop statins during breastfeeding or stop breastfeeding, the harms of either scenario have to be considered as well. To examine how much of a daily oral dose of rosuvastatin can be found in breast milk, a young 38-year old breastfeeding mother agreed to participate in this study. She was prescribed rosuvastatin 20 mg because of a recent ACS and over a 24-hr. period 8 plasma and 8 maternal breast milk samples were collected and analyzed using liquid chromatography-mass spectrometry. Rosuvastatin, despite its hydrophilic nature, does transfer preferentially to milk. A milk/plasma ratio of 16.49 was observed 14 hrs. post-oral administration and a peak concentration of 30.84 ng/ml occurred 17 hours after rosuvastatin was ingested. To determine clinical relevancy the authors determined the relevant infant dose (RID), based on the mother’s weight-adjusted dosage, this was 1.5%. In general, a RID <10% is regarded compatible with breastfeeding. The theoretical infant dose (TID) for rosuvastatin, based on an average milk consumption of 150mg/kg/day, was 4.63 µg/kg/day. In comparison, a 50 kg adult taking 20 mg/day would have an exposure of 400 µg/kg/day. The authors concluded that rosuvastatin is found in higher concentration in breast milk, compared to plasma, but the estimated exposure of the child is very low. Based on these findings physicians can consider prescribing (rosuva)statin in breastfeeding mothers, after carefully weighing the pros and cons for mother and child. They do advise careful monitoring of exposed infants for growth, weight gain, and developmental milestones.
Lwin EMP, Leggett C, Ritchie U et al. Transfer of rosuvastatin into breast milk: liquid chromatography-mass spectrometry methodology and clinical recommendations. Drug design, development and therapy 2018; 12:3645-3651. https://www.ncbi.nlm.nih.gov/pubmed/?term=Transfer+of+rosuvastatin+into+breast+milk%3A+liquid+chromatography-mass+spectrometry+methodology+and+clinical+recommendations
Relevant publications
  1. Zhang J, Guo Y, Jin Q et al. Meta-analysis of rosuvastatin efficacy in prevention of contrast-induced acute kidney injury. Drug design, development and therapy 2018; 12:3685-3690. http://www.ncbi.nlm.nih.gov/pubmed/?term=30464400
  2. Wu NQ, Guo YL, Zhu CG et al. Comparison of statin plus ezetimibe with double-dose statin on lipid profiles and inflammation markers. Lipids Health Dis 2018; 17:265. http://www.ncbi.nlm.nih.gov/pubmed/?term=30470229
  3. Stokkeland K, Hoijer J, Bottai M et al. Statin Use is Associated with Improved Outcomes of Patients With Primary Sclerosing Cholangitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30448601
  4. Spence AD, Busby J, Hughes CM et al. Statin use and survival in patients with gastric cancer in two independent population-based cohorts. Pharmacoepidemiol Drug Saf 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30456916
  5. Lwin EMP, Leggett C, Ritchie U et al. Transfer of rosuvastatin into breast milk: liquid chromatography-mass spectrometry methodology and clinical recommendations. Drug design, development and therapy 2018; 12:3645-3651. http://www.ncbi.nlm.nih.gov/pubmed/?term=30464396
  6. Guan S, Zhang Y, Wang B, Li W. Medical Therapy Induced Regression of Plaque in a Female Patient with ASCVD. Int Heart J 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30464115
  7. Sampalis JS, Psaradellis E, Stutz M et al. Post Hoc Analysis of the CONFIDENCE II, PROTECT I, SHAKE THE HABIT I and SHAKE THE HABIT II Observational Studies in Mild to Moderate Hypertensive Patients Treated with Perindopril and Atorvastatin Concomitantly. Drugs in R&D 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30448890
  8. Liu Z, Alsaggaf R, McGlynn KA et al. Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink. Gut 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30448774
  9. Liping Z, Xiufang L, Tao Y et al. Efficacy comparison of rosuvastatin and atorvastatin in the treatment of atherosclerosis and drug safety analysis. Pak J Pharm Sci 2018; 31:2203-2208. http://www.ncbi.nlm.nih.gov/pubmed/?term=30463813
  10. Li J, Liu R, Sun Z et al. The association between statin use and endometrial cancer survival outcome: A meta-analysis. Medicine (Baltimore) 2018; 97:e13264. http://www.ncbi.nlm.nih.gov/pubmed/?term=30461633
  11. Kunwar S, Parekh JD, Chilukuri RS, Andukuri VA. Necrotizing Autoimmune myopathy: A case report on statin induced rhabdomyolysis requiring immunosuppressive therapy. Drug discoveries & therapeutics 2018; 12:315-317. http://www.ncbi.nlm.nih.gov/pubmed/?term=30464165
  12. Humphries SE, Cooper JA, Capps N et al. Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register. Atherosclerosis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30458964
  13. Beckwitt CH, Brufsky A, Oltvai ZN, Wells A. Statin drugs to reduce breast cancer recurrence and mortality. Breast cancer research : BCR 2018; 20:144. http://www.ncbi.nlm.nih.gov/pubmed/?term=30458856
  14. Abdel-Rahman O. Statin treatment and outcomes of metastatic pancreatic cancer: a pooled analysis of two phase III studies. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30465184
  15. Kosmas CE, Silverio D, Ovalle J et al. Patient adherence, compliance, and perspectives on evolocumab for the management of resistant hypercholesterolemia. Patient preference and adherence 2018; 12:2263-2266. http://www.ncbi.nlm.nih.gov/pubmed/?term=30464416
  16. Knecht T, Borlongan C, Dela Pena I. Combination therapy for ischemic stroke: Novel approaches to lengthen therapeutic window of tissue plasminogen activator. Brain circulation 2018; 4:99-108. http://www.ncbi.nlm.nih.gov/pubmed/?term=30450415
  17. Kang WY, Seong SJ, Ohk B et al. Pharmacokinetic and bioequivalence study comparing a fimasartan/rosuvastatin fixed-dose combination with the concomitant administration of fimasartan and rosuvastatin in healthy subjects. Drug design, development and therapy 2018; 12:3607-3615. http://www.ncbi.nlm.nih.gov/pubmed/?term=30464392
  18. Huang L, Wang L, Yang Y et al. Coexistence of anti-HMGCR and anti-MDA5 identified by an unlabeled immunoprecipitation assay in a chinese patient cohort with myositis. Medicine (Baltimore) 2018; 97:e13236. http://www.ncbi.nlm.nih.gov/pubmed/?term=30461626
  19. Francesconi LP, Victorino AT, Salah IA et al. Proinflammatory and anti-inflammatory biomarkers in schizophrenia and influence of simvastatin on the interleukin-6. International clinical psychopharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30461427
  20. Chia PY, Htun HL, Ling WP et al. Hyperlipidemia, statin use and dengue severity. Scientific reports 2018; 8:17147. http://www.ncbi.nlm.nih.gov/pubmed/?term=30464247
  21. Cakir SS, Ozcan L, Polat EC et al. Statins are effective in the treatment of benign prostatic hyperplasia with metabolic syndrome. The aging male : the official journal of the International Society for the Study of the Aging Male 2018:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=30463466
  22. Allende C, Gusmano MK, Weisz D. Disparities in Statin Use in New York City: Implications for Health Reform. Journal of racial and ethnic health disparities 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30456578
Miscellaneous publications
 
 
  1. Zhang Z, Zhang HY, Zhang Y, Li H. Inactivation of the Ras/MAPK/PPARgamma signaling axis alleviates diabetic mellitus-induced erectile dysfunction through suppression of corpus cavernosal endothelial cell apoptosis by inhibiting HMGCS2 expression. Endocrine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30460485
  2. Yorulmaz H, Ozkok E, Demir G et al. Pretreatment of simvastatin on liver trace element levels during endotoxemia. Archives of physiology and biochemistry 2018:1-5. http://www.ncbi.nlm.nih.gov/pubmed/?term=30450988
  3. Wang Y, Wang X, Yang W et al. Effect of Simvastatin on the Intestinal Rho/ROCK Signaling Pathway in Rats With Sepsis. J Surg Res 2018; 232:531-538. http://www.ncbi.nlm.nih.gov/pubmed/?term=30463769
  4. Khoshnejad M, Patel A, Wojtak K et al. Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics. Molecular therapy : the journal of the American Society of Gene Therapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30449662
  5. Jang H, Lee J, Park S et al. Pravastatin Attenuates Acute Radiation-Induced Enteropathy and Improves Epithelial Cell Function. Frontiers in pharmacology 2018; 9:1215. http://www.ncbi.nlm.nih.gov/pubmed/?term=30459609
  6. Huang Y, Zhang J, Shao H et al. miR-33a Mediates the Anti-Tumor Effect of Lovastatin in Osteosarcoma by Targeting CYR61. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2018; 51:938-948. http://www.ncbi.nlm.nih.gov/pubmed/?term=30466075
  7. Magdy R, Hemdan A, Fares NV, Farouk M. Determination of amlodipine and atorvastatin mixture by different spectrophotometric methods with or without regression equations. Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy 2018; 210:203-211. http://www.ncbi.nlm.nih.gov/pubmed/?term=30453196
  8. Hassan R, Tammam SN, El Safy S et al. Prevention of Hepatic Stellate Cell Activation using JQ1- and Atorvastatin-Loaded Chitosan Nanoparticles as a Promising Approach in Therapy of Liver Fibrosis. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30471341
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