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Update - Week 37, 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

Risk of recurrence remains high in Asia-Pacific CAD patients caused by inadequate lipid lowering treatment
The DYSIS II study is a global observational program that examines how well lipids are managed in patients with CAD. In this Asia-Pacific sub -study patients from Hong Kong, India, Indonesia, the Philippines, Singapore, South Korea, Taiwan, Thailand and Vietnam were enrolled between July 2013 and October 2014. These were patients admitted to a hospital for ACS (N=1798) or treated in an outpatient department for stable CHD (N=2794). How well patients were treated, was assessed by medication history and attained LDL-c plasma concentrations. In the participants with stable CHD, 91.7% used lipid lowering therapy, but their mean LDL-c was 86.9 mg/dl; 31% reached an LDL-c < 70mg/dl. In the ACS patients the corresponding values were 63.4%, 103 mg/dl and 23% respectively. Mean atorvastatin equivalent dosages were 20 ± 15 and 22 ± 18 mg/dl in the stable CAD and ACS patients. Only 13.0% and 6.8 % used add on treatment e.g. ezetimibe. In the ACS patient’s improvement was noted at follow-up but majority were unable to reach an LDL-c < 70 mg/dl (58.3%). The authors concluded that the risk of recurrence in Asia Pacific patients remains very high, despite the universal use of lipid lowering medication. patients were unable to reach guideline recommended LDL-c targets due to the prescription of inadequate statin type and/or dosage.
Poh KK, Ambegaonkar B, Baxter CA et al. Low-density lipoprotein cholesterol target attainment in patients with stable or acute coronary heart disease in the Asia-Pacific region: results from the Dyslipidemia International Study II. Eur J Prev Cardiol 2018:2047487318798927. http://www.ncbi.nlm.nih.gov/pubmed/?term=30198749
Is pharmacogenetic testing in patients with statin intolerance cost effective?
Statin related muscle complaints seem to be omnipresent in clinical practice despite very infrequent reports in RCT’s. The need for an objective test to distinguish true myopathy from the nocebo type of myopathy would be helpful to properly distinguish the real statin intolerant patients from patients in whom muscle problems are of a different nature. In this analysis a Markov model was used to determine the cost effectiveness of offering pharmacogenetic testing to individuals that present with statin induced myopathy (SIM) in combination with a diagnostic tool to evaluate individual CPK values. The aim to improve a more customized approach to ensure compliance by differing the strategy in secondary prevention patients that are determined to be true statin intolerant, based on the results of their genetic test, vs the ones that are negative. This test needs to be highly accurate and also help to successfully guide patients to adhere to their statin therapy in the absence of SIM. This strategy to be incorporated in lipid lowering guidelines as practical tool to ensure improved compliance. The authors conclude that the addition of an accurate pharmacogenomic test for SIM would be of (economic) value to complement CPK monitoring for managing patients that experience statin adverse effect and intolerance, if this would help to convince patients with to adhere to lifelong statin therapy. The potential switch from statins to a more expensive PCK9ab therapy in statin intolerant patients was not included in this economic evaluation. 
Mitchell D, Guertin JR, LeLorier J. Value of a Hypothetical Pharmacogenomic Test for the Diagnosis of Statin-Induced Myopathy in Patients at High Cardiovascular Risk. Molecular diagnosis & therapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30218425
Statins use OK in HFpEF but not in HFrEF patients?
After the GISI Heart Failure and the CORONA studies did not prove that rosuvastatin reduced CV complications in heart failure (HF) patients ,the use of statins in HF patients was advised against. Post hoc analysis of sub-groups in both trials as well as observational studies did point out that some HF patients could potentially be better off with statins. In this retrospective cohort study, of the Kaiser Permanente Southern California health care system, data was collected in 13 440 HF patients; 9 903 (73.7%) were using statins. Endpoints studied were total mortality, hospitalizations and cardiovascular outcomes. Ejection fraction was determined to be a powerful predictor of outcomes. In patients with HFpEF statin use showed significant improved all-cause mortality, clinical outcomes and hospitalizations. HR 0.73 (0.66-0.81, p<0.001), 0.48 (0.13-0.84, p<0.007) and 0.82 (0.76-0.89, p<0.001). For HFrEF patients there were no significant improved outcomes HR 0.86 (0.74-1.0, p<0.054), 0.41 (-0.09-0.93, p<0.11) and 0.92 (0.82-1.04, p<0.17.) For patients in the mid-range ejection fraction very similar results were observed as in the HFrEF patients; HR 0.76 (0.60-0.95, p=0.02), 0.3 (0.84-1.43, p=0.61) and  1.07 (0.9-1.27, p=0.44) respectively. The authors conclude that in HFpEF patient’s statin seem to provide benefits but not in patients with reduced EF or even with mid-range EF values. These observations need to be confirmed in larger RCT’s before definite recommendations regarding statin use in in HF patients can be formalized.
Lee MS, Duan L, Clare R et al. Comparison of Effects of Statin Use on Mortality in Patients With Heart Failure and Preserved Versus Reduced Left Ventricular Ejection Fraction. Am J Cardiol 2018; 122:405-412. http://www.ncbi.nlm.nih.gov/pubmed/?term=30201108
HMG-CoA ab mediated necrotizing myopathy frequent in statin naïve patients
The role of statins in causing serious anti-body mediated necrotizing myopathy might be overestimated. Based on the finding in this specialized neurology clinic, muscle biopsy biobank, patients that were diagnosed with anti-3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMGCR) antibody-mediated necrotizing myopathy. Between July 2013 and February 2016, 23 patients were diagnosed with Anti-HMGCR antibody related necrotizing myopathy. Only 2/23 patients were using statins and 21 were statin naïve. The statin naïve patients age ranged from 6-67 years and presented with Proximal weakness and neck flexion weakness. The average maximal CK level was 7968.6 ± 4408.7U/L. Lower limb muscle edema was present in 88.2%, moderate or severe fatty replacement in70.6% and muscle atrophy in 88.2% of the patients. Patients with early-onset presented with more sever clinical features and worse therapeutic response. Statin exposed patients were older average age in statin naive patients average age 23.5 (16.4-30.6) years vs 36.4 (21.9-51.0) years in statin users. Young onset age and remarkable elevated CK was the significant clinical feature of statin-naïve patients. But statin-exposure patients presented old onset age with normal or high CK.
Jiao Y, Cai S, Lin J et al. Statin-naive anti-HMGCR antibody-mediated necrotizing myopathy in China. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30205933
Statin Intolerance - Review
Statin intolerance is the biggest hurdle that needs to be conquered if we want to ensure continuous – lifelong statin treatment in patient that have a (very) high risk of developing ASCVD complications. This recent update is helpful for clinicians evaluating symptoms and signs of statin intolerant patients. Reviewing muscle, hepatic, cognitive impairment and new onset diabetes reported side effects as well as showing a complete overview of statin drug-drug interactions for the all available statins. The review also includes a step by step strategy for evaluating statin intolerance as well as a very illustrative insight on the effects of discontinuing statins in terms mortality and cardiovascular complications. The authors sing off with a number of simple but helpful suggestions how to reduce the odds to develop statin side effects as well as what might help to reduce them.
Brown AS, Watson KE. Statin Intolerance. Rev Cardiovasc Med 2018; 19:S9-s19. http://www.ncbi.nlm.nih.gov/pubmed/?term=30207553
Relevant publications
  1. Robinson JG, Watson KE. Identifying Patients for Nonstatin Therapy. Rev Cardiovasc Med 2018; 19:S1-s8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30207552
  2. Grad R, Ebell MH. Top POEMs of 2017 Consistent with the Principles of the Choosing Wisely Campaign. American family physician 2018; 98:93-98. http://www.ncbi.nlm.nih.gov/pubmed/?term=30215987
  3. Cheng KH, Lin JR, Anderson CS et al. Lipid Paradox in Statin-Naive Acute Ischemic Stroke But Not Hemorrhagic Stroke. Frontiers in neurology 2018; 9:541. http://www.ncbi.nlm.nih.gov/pubmed/?term=30210423
  4. Choi JY, Choi CU, Hwang SY et al. Effect of Pitavastatin Compared with Atorvastatin and Rosuvastatin on New-Onset Diabetes Mellitus in Patients With Acute Myocardial Infarction. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30217375
  5. Beltowski J. Epicardial adipose tissue: The new target for statin therapy. Int J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30196996
  6. Arian A, Mortazavi Moghadam SG, Kazemi T et al. Trial of Atorvastatin on Serum Interleukin-6, Total Antioxidant Capacity, C-Reactive Protein, and Alpha-1 Antitrypsin in Patients with Chronic Obstructive Pulmonary Disease. Journal of research in pharmacy practice 2018; 7:141-146. http://www.ncbi.nlm.nih.gov/pubmed/?term=30211239
  7. Zou G, Song L, Chang L, Wang H. Comparison and analysis of statins drug use in the treatment of diastolic dysfunction in patients. Pak J Pharm Sci 2018; 31:1725-1730. http://www.ncbi.nlm.nih.gov/pubmed/?term=30203770
  8. Tang R, Shi J, Li X et al. Corrigendum to "Effects of Atorvastatin on Surgical Treatments of Chronic Subdural Hematoma" [World Neurosurgery 117 (2018) e425-e429]. World neurosurgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30213465
  9. Song L, Zou G, Wang X. Effect of doxycycline and atorvastatin on improving exercise tolerance in patients with angina pectoris. Pak J Pharm Sci 2018; 31:1731-1735. http://www.ncbi.nlm.nih.gov/pubmed/?term=30203771
  10. Shahbaz A, Mahendhar R, Fransawy Alkomos M et al. Drug-induced Angioedema: A Rare Side Effect of Rosuvastatin. Cureus 2018; 10:e2965. http://www.ncbi.nlm.nih.gov/pubmed/?term=30210953
  11. Ravnskov U, de Lorgeril M, Diamond DM et al. LDL-C Does Not Cause Cardiovascular Disease: a comprehensive review of current literature. Expert Rev Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30198808
  12. Ooi KG, Lee MH, Burlutsky G et al. Association of dyslipidemia and oral statin use, and dry eye disease symptoms in the Blue Mountains Eye Study. Clinical & experimental ophthalmology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30203595
  13. Majka DS, Lee JY, Peprah YA et al. Changes in Care After Implementing a Multifaceted Intervention to Improve Preventive Cardiology Practice in Rheumatoid Arthritis. American journal of medical quality : the official journal of the American College of Medical Quality 2018:1062860618798719. http://www.ncbi.nlm.nih.gov/pubmed/?term=30196708
  14. Liu M, Liu G, Wang M. Comparison and analysis of the therapeutic effect of different statins in the treatment of atherosclerosis. Pak J Pharm Sci 2018; 31:1737-1742. http://www.ncbi.nlm.nih.gov/pubmed/?term=30203772
  15. Jeemon P, Gupta R, Onen C et al. Management of Hypertension and Dyslipidemia for Primary Prevention of Cardiovascular Disease. In: Cardiovascular, Respiratory, and Related Disorders. Edited by: rd, Prabhakaran D, Anand S et al. Washington (DC): The International Bank for Reconstruction and Development / The World Bank(c) 2017 International Bank for Reconstruction and Development / The World Bank.; 2017.
  16. Firnhaber JM. CV risk prediction tools: Imperfect, Yes, but are they serviceable? The Journal of family practice 2018; 67:E3-e8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30216402
  17. Arefieva TI, Filatova AY, Potekhina AV, Shchinova AM. Immunotropic Effects and Proposed Mechanism of Action for 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors (Statins). Biochemistry. Biokhimiia 2018; 83:874-889. http://www.ncbi.nlm.nih.gov/pubmed/?term=30208827
Miscellaneous publications
  1. Raafat SN, Amin RM, Elmazar MM et al. The sole and combined effect of simvastatin and platelet rich fibrin as a filling material in induced bone defect in tibia of albino rats. Bone 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30208342
  2. Pentz R, Kaun C, Thaler B et al. Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue. Journal of cellular and molecular medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30216659
  3. Pelizzo G, Bussani R, Mazzon E et al. Effects of Simvastatin on Fetal Cardiac Impairment in the Diaphragmatic Experimental Hernia Model. Fetal diagnosis and therapy 2018:1-10. http://www.ncbi.nlm.nih.gov/pubmed/?term=30199868
  4. Nabih ES, El-Kharashi OA. Targeting HMGB1/TLR4 axis and miR-21 by rosuvastatin: role in alleviating cholestatic liver injury in a rat model of bile duct ligation. Naunyn-Schmiedeberg's archives of pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30203151
  5. Li Y, Liu H, Wu Y, Zhu M. Effect of atorvastatin on the apoptosis of human umbilical vein endothelial cells and its drug mechanism. Pak J Pharm Sci 2018; 31:1761-1766. http://www.ncbi.nlm.nih.gov/pubmed/?term=30203776
  6. Khalil S, Bardawil T, Saade S et al. Use of Topical Glycolic Acid Plus a Lovastatin-Cholesterol Combination Cream for the Treatment of Autosomal Recessive Congenital Ichthyoses. JAMA dermatology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30208477
  7. Askarizadeh A, Butler AE, Badiee A, Sahebkar A. Liposomal nanocarriers for statins: A pharmacokinetic and pharmacodynamics appraisal. Journal of cellular physiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30203471
  8. Afrouzian M, Al-Lahham R, Patrikeeva S et al. Role of the Efflux Transporters BCRP and MRP1 in Human Placental Bio-disposition of Pravastatin. Biochem Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30217571
  9. Luthje P, Walker S, Kamolvit W et al. Statins influence epithelial expression of the antimicrobial peptide LL-37/hCAP-18 independently of the mevalonate pathway. Clinical and experimental immunology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30216432
  10. Bond CM, Tang Y. Engineering Saccharomyces cerevisiae for production of simvastatin. Metabolic engineering 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30213650
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