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Update - Week 02, 2019
 
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

Never too old to reduce CVD risk!
The lipid management of elderly patients is not an easy challenge. On the one hand, simply because of age their risk is high, and statins would be effective in reducing this risk, but we have to consider the potential harms related to drug-drug interactions, secondary disease/pathology, competing for risk of deaths and preference of patients as well. Particularly in primary prevention and in the 70+ populations clinical trial data is scarce. In this updated 20 pages review the authors present their case of addressing the increased risk of elderly patients by statins or by combining statins with ezetimibe or even PCSK9ab. The authors show that dyslipidemia continuous to be a relevant important and manageable risk factor in the elderly. They share the published evidence on statins for primary and secondary prevention, comment on issues like adverse effects and adherence and present their recommendations regarding the use of statins in elderly patients. The potential role of other lipid-lowering drugs such as ezetimibe, niacin, PCSK9ab, fibrates, and Omega-3 fatty acids are reviewed as well. They conclude that the elderly should not be automatically exempted from lipid-lowering drugs, despite the limited data that is available, especially in primary prevention. Lowering pro-atherogenic lipoproteins does reduce CV risk and statins are to be considered in elderly. Weighing the pro’s and con’s, including the co-morbidities and co-medications is pivotal with a strong emphasis on well informed shared decision making.
Yandrapalli S, Gupta S, Andries G et al. Drug Therapy of Dyslipidemia in the Elderly. Drugs Aging 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30613912
 
Mortality 71% lower in patients that used statins after carotid artery stenting or endarterectomy
The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) study was set up to compare the outcomes of patients that had one of two carotid surgical procedures; a carotid endarterectomy or a carotid artery stent procedure. The study was quite unique in that it used a “real world “setting a single vascular surgeon to evaluate the two procedures. The period covered started in September 2005 and lasted until June 2017. Over 2000 patients were evaluated and 313 revascularization procedures were performed. No significant differences were observed after 30 days (stroke, MI, as well as combined endpoints of stroke MI and death). The long term follow-up of 7 years showed no significant differences in survival, stroke-free survival and restenosis-free survival, either. Significant predictors of worse survival (all p values <0.05) were diabetes (HR: 2.41), CKD (HR:4.89) and COPD (HR: 3.3). Statin use was associated with a significantly reduced mortality risk of 71%; HR 0.29 (0.12-0.67; P=0.004). Although this prospective observational study was not designed to evaluate the effects of statins in patients with severe carotid artery stenosis one cannot help but be impressed by the observed benefits of statins.  These results confirm the importance of using statins in patients with severe carotid atherosclerosis  that need to have a surgical intervention.
Rizwan M, Aridi HD, Dang T et al. Long-Term Outcomes of Carotid Endarterectomy and Carotid Artery Stenting When Performed by a Single Vascular Surgeon. Vascular and endovascular surgery 2019:1538574418823379. http://www.ncbi.nlm.nih.gov/pubmed/?term=30614413
 
Real world US data on statin persistence and adherence
Perhaps the greatest challenge to improve CVD morbidity – mortality is not starting but continuous use of prescribed medication for reducing cholesterol and blood pressure. The authors of this study present a sobering yet realistic view of what is real-world evidence of statin adherence in the US. Data collected in MarketScan (Truven Health Analytics) and Medicare databases was used to evaluate patients that started with statins between 2007 and 2014. These were post-MI patients (N= 201 573); diabetics (DM) without CVD (N=610 049) and patients without CVD or DM (N= 2 244 868). Persistence (not stopping statins) and high adherence, in the year following statin initiation in the three groups, were 78.1% and 79.1% in post-MI patients; 66.5% and 67.3% in diabetics and 64.3% and 63.9% in patients without CVD or DM. Between 2007 and 2014 adherence improved slightly in post-MI patients 57.9% to 63.8% and in diabetics 34.9% to 37.6% (each Ptrend <0.001). For the third group, no significant changes were noted between 2007 and 2004, 35,7% vs 36.8% (Ptrend=0.14). Patients with lower adherence rates were younger (<55years), black and Hispanic patients versus Caucasian patients and the ones that started with high-intensity statins. Low adherence to prior anti-hypertensive medication also predicted worse adherence to statins. Increased adherence was observed in men and those that were managed by a cardiologist. The authors suggested that regular follow-up visits Other interventions, nurse-led cardiovascular risk factor counseling, drug-regimen simplification, reminders, and phone calls of the groups identified in this study could help to improve persistence and adherence. Monitoring statins use after starting treatment and identifying barriers to taking cholesterol-lowering drugs should be part of managing high CVD risk patients.
Colantonio LD, Rosenson RS, Deng L et al. Adherence to Statin Therapy Among US Adults Between 2007 and 2014. J Am Heart Assoc 2019; 8:e010376. http://www.ncbi.nlm.nih.gov/pubmed/?term=30616455
 
Long term adherence in IMPROVE-IT
Adherence to lipid-lowering has not been reported in most landmark statin studies. The investigators of the IMPROVE-IT share their finding on long term adherence in participants of this trial comparing simvastatin + placebo vs simvastatin + Ezetimibe in 17 706 ACS patients that initiated the study medication. Patients were enrolled between October 2005 and July 2010. Follow up data were available through June 2014. The median follow-up duration was 71.9 months (interquartile range 51.8 – 85.5 months). Kaplan Meyer (KM) discontinuation rates were evaluated at 30 days, 1 year and through year 7. Overall 46.7% of study participants stopped their medication, KM rate at study end 50.9% (50.1%-51.7%). Patient characteristics that were associated with increased discontinuation rates were using placebo + simvastatin vs ezetimibe + simvastatin KM rate (52.0% versus 49.8%, P=0.049) and geographical locations, US patients had the worst adherence, 7-year KM rate 57,4%. Smoking, prior revascularization, hypertension, unstable angina, female , ex and nonwhite race were, after multivariable modeling, associated with higher discontinuation rates as well. Discontinuation rates were high in the early phase of the trial and diminished later in the trial. A terminal KM rate per 100 person-years was calculated as 8.4 (8.2–8.6) from years 1 to 7. The authors concluded that although the highest discontinuation rates were observed in the early phase of the study, most non-adherence occurred after 1 year. Ezetimibe did not have a negative impact on the on discontinuation risk, in contrast with geographical location and patient level factors that did.
Navar AM, Roe MT, White JA et al. Medication Discontinuation in the IMPROVE-IT Trial. Circ Cardiovasc Qual Outcomes 2019; 12:e005041. http://www.ncbi.nlm.nih.gov/pubmed/?term=30630361
 
Statins could decreathe se progression of diabetic retinopathy
The globally increasing prevalence of diabetes is of major concern for those affected as well as the healthcare professional caring for diabetics. One of the most feared complications of DM is blindness. Therapeutic strategies to reduce vision-threatening diabetic retinopathy, such as laser, intravitreal anti–vascular endothelial growth factor (anti-VEGF) injections, and vitrectomy, surgical interventions that can only stop or decrease the progression of advanced diabetic retinopathy and are associated with complications, such as peripheral vision loss and infections.
Control of glucose levels, blood pressure, lipid levels, and body weight contribute to the delay of diabetic retinopathy progression. The authors of this paper examined if statin use could prevent, delay diabetic retinopathy in Chinese diabetic patients. They assessed patient data of 1 648 305 diabetic patients from the Taiwanese National Health Insurance Research Database (NHIRD) between January 1, 1998, and December 31, 2013. Using a propensity score matching 18 947 statin users were compared to 19 947 patients not using statins. The mean follow-up was 7.6 years and 7.3 years respectively. All studied endpoints were less frequently observed in the patients on statins vs controls. Retinopathy, HR:0.86 (0.81-0.91); non-proliferative diabetic retinopathy, HR: 0.92 (0.86-0.99); proliferative diabetic retinopathy, HR: 0.64 ( 0.58-0.70); vitreous hemorrhage, HR:  0.62 (0.54-0.71); tractional retinal detachment, HR: 0.61 (0.47-0.79) and macular edema, HR: 0.60; (0.46-0.79); retinal laser treatment, HR: 0.71 (0.65-0.77);  intravitreal injection, HR: 0.74 (0.61-0.89); vitrectomy, HR: 0.58 (0.48-0.69); retinal lasers, rate ratio: 0.61 (0.59-0.64); intravitreal injections, rate ratio: 0.68 (0.61-0.76), and vitrectomies, rate ratio: 0.54 (0.46-0.63). Major adverse, HR: 0.81 (0.77-0.85); new-onset diabetic neuropathy, HR:
0.85 (0.82-0.89), and new-onset diabetic foot ulcers, HR: 0.73 (0.68-0.78). Improved as well in patients using statins. The authors concluded that their findings support that statins are associated with a decreased prevalence of diabetic retinopathy and may decrease the progression of diabetic retinopathy in Chinese dyslipidemic DM2 patients.
Kang EY, Chen TH, Garg SJ et al. Association of Statin Therapy With Prevention of Vision-Threatening Diabetic Retinopathy. JAMA ophthalmology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30629109
Relevant publications
  1. Vuorio A, Watts GF, Kovanen PT. Lipoprotein(a) as a risk factor for calcific aortic valvulopathy in heterozygous familial hypercholesterolemia. Atherosclerosis 2018; 281:25-30. http://www.ncbi.nlm.nih.gov/pubmed/?term=30616181
  2. Thrift AP, Natarajan Y, Liu Y, El-Serag HB. Statin use after diagnosis of hepatocellular carcinoma and patient survival: findings from a retrospective cohort study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30625400
  3. Sui Z, Wang M, Zuo L. Statin therapy and erythropoiesis-stimulating agent hyporesponsiveness in patients with nondialysis chronic kidney disease: A retrospective study in Beijing, China. Medicine (Baltimore) 2019; 98:e13981. http://www.ncbi.nlm.nih.gov/pubmed/?term=30633179
  4. Ronnqvist J, Hallberg P, Yue QY, Wadelius M. Fusidic Acid: A Neglected Risk Factor for Statin-Associated Myopathy. Clinical Medicine Insights. Cardiology 2018; 12:1179546818815162. http://www.ncbi.nlm.nih.gov/pubmed/?term=30618488
  5. Kohler-Forsberg O, Gasse C, Petersen L et al. Statin treatment and the risk of depression. Journal of affective disorders 2018; 246:706-715. http://www.ncbi.nlm.nih.gov/pubmed/?term=30611914
  6. Khan R, Williams A, Dass DM et al. Investigating the risk of Incident diabetes mellitus among primary care patients treated with simvastatin in North-Central Trinidad. Journal of family medicine and primary care 2018; 7:1555-1560. http://www.ncbi.nlm.nih.gov/pubmed/?term=30613558
  7. Kanaya AM, Vittinghoff E, Lin F et al. Incidence and Progression of Coronary Artery Calcium in South Asians Compared With 4 Race/Ethnic Groups. J Am Heart Assoc 2019; 8:e011053. http://www.ncbi.nlm.nih.gov/pubmed/?term=30630376
  8. Zheng XF, Liu KX, Wang XM et al. MicroRNA192 acts as a tumor suppressor in colon cancer and simvastatin activates miR192 to inhibit cancer cell growth. Mol Med Rep 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30628692
  9. Zhao WB, Fu H, Chang F et al. Effects of various doses of atorvastatin on vascular endothelial cell apoptosis and autophagy in vitro. Mol Med Rep 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30628690
  10. Smith SM. ARB superiority over ACE inhibitors in Coronary Heart Disease: An Alternative Viewpoint. Pharmacotherapy 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30633371
  11. Sarpatwari A, Gagne JJ, Lu Z et al. A Survey of Patients' Perceptions of Pill Appearance and Responses to Changes in Appearance for Four Chronic Disease Medications. Journal of general internal medicine 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30632102
  12. Naz S, Saleem MW, Haider AW. Angioedema; An Unreported Adverse Effect Of Pitavastatin. Journal of Ayub Medical College, Abbottabad : JAMC 2018; 30:603-604. http://www.ncbi.nlm.nih.gov/pubmed/?term=30632346
  13. Mosepele M, Regan S, Massaro J et al. Impact of the American College of Cardiology/American Heart Association Cholesterol Guidelines on Statin Eligibility Among Human Immunodeficiency Virus-Infected Individuals. Open Forum Infect Dis 2018; 5:ofy326. http://www.ncbi.nlm.nih.gov/pubmed/?term=30619912
  14. Paseban M, Butler AE, Sahebkar A. Mechanisms of statin-induced new-onset diabetes. Journal of cellular physiology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30618154
  15. Menon S, Mathew R. Association between metabolic syndrome and hepatobiliary cancers: A case-control study. Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30628006
  16. Matsuo K, Hom MS, Yabuno A et al. Association of statins, aspirin, and venous thromboembolism in women with endometrial cancer. Gynecologic oncology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30616901
  17. Lanzillo R, Moccia M, Russo CV et al. Therapeutic lag in reducing disability progression in relapsing-remitting multiple sclerosis: 8-year follow-up of two randomized add-on trials with atorvastatin. Multiple sclerosis and related disorders 2019; 28:193-196. http://www.ncbi.nlm.nih.gov/pubmed/?term=30623857
  18. Jamil A, Mirza MA, Anwer K et al. Co-delivery of Gemcitabine and Simvastatin through PLGA polymeric nanoparticles for thetreatment of pancreatic cancer: In-vitro characterization, cellular uptake and pharmacokinetic studies. Drug development and industrial pharmacy 2019:1-34. http://www.ncbi.nlm.nih.gov/pubmed/?term=30632800
  19. Elkins JC, Fruh S. Early diagnosis and treatment of familial hypercholesterolemia. The Nurse practitioner 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30614895
  20. Chen YT, Kuo SC, Chao PW, Chang YY. Use of lipid-lowering agents is not associated with improved outcomes for tuberculosis patients on standard-course therapy: A population-based cohort study. PLoS One 2019; 14:e0210479. http://www.ncbi.nlm.nih.gov/pubmed/?term=30633771
  21. Chaudhary R, Kinderyte M, Chaudhary R et al. HDL3-C is a marker of coronary artery disease severity and inflammation in patients on statin therapy. Cardiovascular revascularization medicine : including molecular interventions 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30626544
  22. Borgquist S, Broberg P, Tojjar J, Olsson H. Statin use and breast cancer survival - a Swedish nationwide study. BMC Cancer 2019; 19:54. http://www.ncbi.nlm.nih.gov/pubmed/?term=30634941
  23. Biscetti F, Bonadia N, Santini F et al. Sortilin levels are associated with peripheral arterial disease in type 2 diabetic subjects. Cardiovascular diabetology 2019; 18:5. http://www.ncbi.nlm.nih.gov/pubmed/?term=30634965
Miscellaneous publications
 
 
  1. Zhang J, Shi X, Hao N et al. Simvastatin Reduces Neutrophils Infiltration Into Brain Parenchyma After Intracerebral Hemorrhage via Regulating Peripheral Neutrophils Apoptosis. Frontiers in neuroscience 2018; 12:977. http://www.ncbi.nlm.nih.gov/pubmed/?term=30631264
  2. Vethe NT, Munkhaugen J, Andersen AM et al. A Method for Direct Monitoring of Atorvastatin Adherence in Cardiovascular Disease Prevention: Quantification of the Total Exposure to Parent Drug and Major Metabolites Using 2-Channel Chromatography and Tandem Mass Spectrometry. Therapeutic drug monitoring 2019; 41:19-28. http://www.ncbi.nlm.nih.gov/pubmed/?term=30633723
  3. Raafat SN. Response to letter to the editor: 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=30612981
  4. Novosvetska L, Chocholous P, Svec F, Sklenarova H. Fully automated method based on on-line molecularly imprinted polymer solid-phase extraction for determination of lovastatin in dietary supplements containing red yeast rice. Analytical and bioanalytical chemistry 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30617392
  5. Li F, Zheng X, Bao Y et al. Fenofibrate modified-release pellets with lag phase and high oral bioavailability. Drug design, development and therapy 2019; 13:141-151. http://www.ncbi.nlm.nih.gov/pubmed/?term=30613135
  6. Fang T, Guo B, Xue L, Wang L. Atorvastatin Prevents Myocardial Fibrosis in Spontaneous Hypertension via Interleukin-6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3)/Endothelin-1 (ET-1) Pathway. Medical science monitor : international medical journal of experimental and clinical research 2019; 25:318-323. http://www.ncbi.nlm.nih.gov/pubmed/?term=30631031
  7. de Faria CA, Zanette DL, Silva WA, Jr., Ribeiro-Paes JT. PAI-1 inhibition by simvastatin as a positive adjuvant in cell therapy. Molecular biology reports 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30612281
  8. Carrer A, Trefely S, Zhao S et al. Acetyl-CoA metabolism supports multi-step pancreatic tumorigenesis. Cancer discovery 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30626590
  9. Liyanage ADT, Chen AJ, Puleo DA. Biodegradable Simvastatin-Containing Polymeric Prodrugs with Improved Drug Release. ACS biomaterials science & engineering 2018; 4:4193-4199. http://www.ncbi.nlm.nih.gov/pubmed/?term=30631799
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