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Update - Week 05,  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

MESA study evaluates cardiac remodeling with statins
The role statins in heart failure is confusing and remains to be properly elucidated. Conflicting evidence from Clinical trials as well as observational studies makes an objective evaluation of benefits or harms a challenge. To evaluate effects of statins in heart muscle remodeling the MESA (Multi Ethnic Study of Atherosclerosis study) data was re-analyzed to evaluate the changes in cardiac magnetic resonance imaging (CMR) parameters of cardiac (re-)modeling. Participants free of cardiac disease and who initiated statin therapy during the 10 years follow up of this study ware included in the analysis. Overall 2431 MESA participants had a base-line and follow-up CMR (median time interval 9.4 years). Patients that started moderate dosage statins (N= 873) were propensity score matched (accounting for age, sex, race, and other cardiovascular risk factors) with non-statin users. Patients treated with a statin showed reduced 10-year progression of Left Ventricular Mass Index (LVMI), −2.35 percentage points (−4.24 - −0.47; P = .01), and mass to volume ratio; −0.03 absolute difference (−0.07 -  −0.00; P = .02). Increasing dosages of statin uses were associated with less LVMI progression. The authors debate if these improvements could be solely responsible for the observed benefits observed in statin studies of primary prevention of heart failure. Future long‐term studies may elucidate the causal relationship between statins and heart failure outcomes.
Strand LN, Young RL, Bertoni AG et al. New statin use and left ventricular structure: Estimating long-term associations in the Multi-Ethnic Study of Atherosclerosis (MESA). Pharmacoepidemiol Drug Saf 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29380457
 
Managing lipids aggressively in PAD how low should we go?
Management of patients with peripheral artery disease has been the arena of the (vascular) surgeon that addressed the ultimate ischemic complications, performing by-pass operations, inserting vascular prostheses and ultimately amputations. The dramatically increased incidence of PAD 13% in developed and almost doubling in developing economies over the last decade prompted the ESC and the ESCVS to publish guidelines for PAD patients. They Aim to reduce cardiovascular risk and improve functional capacity by optimizing CVD risk factors. Standard treatment with anti-platelets, ACEi/ARB’s are part of the pharmacological portfolio as well ant-thrombotic agents in secondary prevention. In this narrative editorial review, more emphasis on preventive strategies early in the PAD development as well as preventing atherothrombotic complications in the coronary or cerebral vasculature are promoted as standard management strategies. Targets for LDL-c are in-line with guidelines for  patients with coronary or cerebral vascular complications; aiming for a target <70mg/dl by using high dose – high intensity statins, combined with ezetimibe if patients are unable to reach LDL target with statin mono therapy. The recent FOURIER outcome study included 3642 patients with PAD of whom 1505 had no prior stroke or coronary event. Patients were shown to have an increased prevalence of other CVD risk factors such as smoking, hypertension and diabetes, but these were less well controlled and MACE rates during the study were significantly higher in PAD patients compared to no PAD patients; 16.85 vs 12.1% respectively after 2.5 years. Patients that received evolocumab, on top of their statin. PAD patients had comparable reductions of LDL-C but had a 27% relative reduction of MACE and 37% relative reduction in major adverse limb events (MALE). In patients with absent CAD or stroke these numbers were even higher; 43% and 57% respectively. This translated in an absolute risk reduction of 6.3% and a NNT of 16, over the 2.5-year trial duration. These results may have important consequence for PAD management guidelines, however confirmation in properly designed randomized controlled studies are needed for this to be effectuated.
Stock JK. The challenge of peripheral arterial disease: How do we improve outcome? Atherosclerosis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29395100
 
Traumatic brain injury a new indication for statins?
Traumatic brain injury (TBI) is not an uncommon occurrence in elderly and is associated with significant mortality of 24.1, 51.4 and 103.8 per 100 000 adults in 65-74, 75-84 and >85-year olds respectively. Additional unfavorable outcomes including stroke, depression, and Alzheimer’s disease and related dementias (ADRD) have been observed as well. The Operation Brain Trauma Therapy consortium was established to highlight acute and long-term potential pharmacotherapies for TBI. Statins were suggested as a potential therapeutic intervention in TBI patients, because these drugs have shown potential benefits in reducing chronic neuro-inflammation and increasing cerebral blood flow following TBI. Medicare beneficiaries that survived a TBI hospitalization (N=100 515) between 2006 and 2010 were included in this study. Exposure to statins were evaluated after monthly treatment durations and related to the outcomes of interest: mortality, stroke, depression, and ADRD. The use of statins showed improved outcomes of all studied parameters. Statin use was also associated with a decrease in any stroke, RR 0.86 (0.81-0.91); depression, RR, 0.85 (0.79-0.90), and Alzheimer’s disease and related dementias, RR 0.77 (0.73-0.81). The two most commonly used statins, atorvastatin and simvastatin, showed superior outcomes compared to other statins. The authors concluded that their findings can be considered a sound basis for the benefits of statins in TBI patients, but additional research will be needed to confirm and further explore their findings.
Khokhar B, Simoni-Wastila L, Slejko JF et al. Mortality and Associated Morbidities Following Traumatic Brain Injury in Older Medicare Statin Users. The Journal of head trauma rehabilitation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29385012
 
Optimal medical therapy in post ACS patients remains a challenge!
CVD risk factor management including CVD risk management guidelines have changed dramatically. In clinical practice a large number of patients remain undertreated not receiving the preventive treatments that guidelines advocate. In this analysis 9202 patients from a single Dutch tertiary hospital were re-evaluated. Patients admitted for an ACS between 2006 and 2014 were included and followed for 1 1 year to evaluate mortality and optimal medical therapy (OMT). OMT was defined OMT was defined as prescription of aspirin, P2Y12inhibitors, statin, beta-blockers, and ACEi/ARB. At discharge 43.7% of patients were prescribed OMT, after 30-days this increased to 46.6% and at 1 year only 25.5% of the post ACS patients were still on OMT. OMT prescription at discharge was lower among NSTEMI patients (34.5% vs. 49.2%, p<0.001). The 30-day and 1 year mortality were not significantly different. Corrections for baseline and admission characteristics, OMT at discharge was associated with a reduction in mortality in patients who survived hospitalization for the index event, adjusted HR: 0.66, (0.46-0.93). In patients not on OMT, there was an overall decreasing trend in 1-year mortality among survivors of ACS hospitalizations. In OMT patients this was not observed. In this tertiary hospital < 50% of post ACS patients received OMT at discharge. OMT was associated with a significant lower mortality. Strategies to increase these numbers are warranted, especially in long term management, where OMT was observed in only 25.5%, after 1 year post ACS events.
Hoedemaker NPG, Damman P, Ottervanger JP et al. Trends in Optimal Medical Therapy Prescription and Mortality After Admission for Acute Coronary Syndrome: a 9-Year Experience in a Real-World Setting. European heart journal. Cardiovascular pharmacotherapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29394340
 
LAL disease patients respond favorably to ezetimibe therapy
Cholesterol ester storage diseases cover a spectrum of complete absent Lysosomal Acid Lipase (LAL) enzyme function, and patients were residual activity of the enzyme is present. The most serious type results in death before the age of one year while the later one presents with clinical features of isolated hepatomegaly, hepatosplenomegaly, increased plasma transaminases, type IIa or IIb hypercholesterolemia, and hypo-alphalipoproteinemia. The long-term complications of LAL-D include hepatic fibrosis with unpredictable progression to micro nodular cirrhosis, as well as premature atherosclerosis. Statins have not been able to arrest progression or decrease the long term hepatic complications seen in LAL-D patients. In this observational study of 3 LAL-D patients, ezetimibe was used for a period of almost 10 years. In all patients ALT plasma levels improved and arrested progression of liver fibrosis. Cholesterol and triglyceride levels reduced significantly as well. Ezetimibe blocks Niemann Pick C1-like 1(NPC1L1) protein. This reduces intestinal cholesterol absorption and also improves enterohepatic circulation of cholesterol. The observational nature of this small study warrants properly designed study protocol to evaluate if ezetimibe is a viable treatment alternative for patients with LAL-D. At this moment there is an enzyme replacement treatment with sebelipase alpha available. This novel treatment option has been approved by the FDA and EMEA. Evidence that the feared long-term disease complications are reduced or even avoided by using this expensive treatment alternative are still lacking.   
Di Rocco M, Pisciotta L, Madeo A et al. Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency. Orphanet journal of rare diseases 2018; 13:24. http://www.ncbi.nlm.nih.gov/pubmed/?term=29374495
 
STARS confirms that rosuvastatin can reduce coagulation factors in VT patients
The first study to explore the benefits of rosuvastatin in patients with a history of venous thrombosis (VT) is the STAtins Reduce Thrombophilia Study (STARS). Designed as placebo controlled randomized trial in patients with a history of VT and using vitamin K antagonist. Between December 2012 and December 2016, 500 Patients were assigned to 20 mg of rosuvastatin (N=250) or placebo (N=250) and followed for 28 days. Beneficial effects of rosuvastatin were noted after only 3-days of study medication. Primary end-points of the study were changes in coagulations factors; FVIII:C, factor XI:C, vonWillebrand factor:Ag  and Ln D-dimer. Of all tested coagulation factors, FVIII:C showed the most robust results. This was the coagulations factor used for the power calculations of the study. There was a shift to a reduced pro-coagulant stated in the other coagulation factors as well, but these changes were not consistently statistically significant. A mean decrease in FVIII:C levels of 7–8 IU/dL in rosuvastatin users was observed and in participants with unprovoked VT a 10–12 IU/dL decrease of FVIII: C was noted. Every 10 IU/dL decrease in FVIII:C levels is associated with a 15% (7–22%) decrease in the risk of VT! In the Jupiter trial a 25-50% reduced risk of recurrent VT was one of the surprise findings, the results from the STARS trial confirm that these finding were not a chance occurrence. Important to note is that no bleeding complications were observed in the Jupiter study patients. The authors conclude that a drug that can prevent VT recurrence in patients at risk of bleeding complications could be an attractive therapeutic alternative to the more potent, but associated with an increased risk for bleeding complications, standard anti-coagulant drugs. The results of the STARS trial warrant additional research to confirm these positive benefits as well as further explore the pathophysiology of VT in the context of statin use.
Biedermann JS, Kruip M, van der Meer FJ et al. Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. Eur Heart J 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29394348
 
 

Relevant publications
  1. Zhao C, Zhu P, Shen Q, Jin L. Prospective association of a genetic risk score with major adverse cardiovascular events in patients with coronary artery disease. Medicine (Baltimore) 2017; 96:e9473. http://www.ncbi.nlm.nih.gov/pubmed/?term=29390587
  2. Zhang J, Wang H, Yang S, Wang X. Comparison of lipid profiles and inflammation in pre- and post-menopausal women with cerebral infarction and the role of atorvastatin in such populations. Lipids Health Dis 2018; 17:20. http://www.ncbi.nlm.nih.gov/pubmed/?term=29391065
  3. Whayne TF. Outcomes, Access, and Cost Issues Involving PCSK9 Inhibitors to Lower LDL-Cholesterol. Drugs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29396831
  4. Turgeon RD, Pearson GJ, Graham MM. Pharmacologic Treatment of Patients With Myocardial Ischemia With No Obstructive Coronary Artery Disease. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29394999
  5. Osborn D, Burton A, Hunter R et al. Clinical and cost-effectiveness of an intervention for reducing cholesterol and cardiovascular risk for people with severe mental illness in English primary care: a cluster randomised controlled trial. The lancet. Psychiatry 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29396118
  6. Muniz F, Taminski K, Cavagni J et al. The effect of statins on periodontal treatment-a systematic review with meta-analyses and meta-regression. Clinical oral investigations 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29396642
  7. Ko KD, Kim KK, Baek JO et al. A Possible Case of Statin-Induced Ichthyosis in an Elderly Woman. Korean journal of family medicine 2018; 39:51-53. http://www.ncbi.nlm.nih.gov/pubmed/?term=29383212
  8. Dimmitt SB, Stampfer HG, Warren JB. The pharmacodynamic and clinical trial evidence for statin dose. Br J Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29393975

Miscellaneous publications
  1. Pratchayasakul W, Thongnak LO, Chattipakorn K et al. Atorvastatin and insulin equally mitigate brain pathology in diabetic rats. Toxicology and applied pharmacology 2018; 342:79-85. http://www.ncbi.nlm.nih.gov/pubmed/?term=29391240
  2. Mao J, Doshi U, Wright M et al. Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling. CPT Pharmacometrics Syst Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29388346
  3. Li Y, Zhang Z, Zhang Z. Porous Chitosan/Nano-Hydroxyapatite Composite Scaffolds Incorporating Simvastatin-Loaded PLGA Microspheres for Bone Repair. Cells, tissues, organs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29393155
  4. Li H, Wang C, Sun J et al. Pravastatin Decreases Infarct Size Induced by Coronary Artery Ischemia/Reperfusion with Elevated eNOS Expression in Rats. Int Heart J 2018; 59:154-160. http://www.ncbi.nlm.nih.gov/pubmed/?term=29375110
  5. Jiang C, Zhao Y, Yang Y et al. Evaluation of the Combined Effect of Recombinant High-Density Lipoprotein Carrier and the Encapsulated Lovastatin in RAW264.7 Macrophage Cells Based on the Median-Effect Principle. Molecular pharmaceutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29382194
  6. Gu C, Wu Y, Fan Z, Han W. Simvastatin improves intracerebral hemorrhage through NF-kappaB-mediated apoptosis via the MyD88/TRIF signaling pathway. Experimental and therapeutic medicine 2018; 15:377-382. http://www.ncbi.nlm.nih.gov/pubmed/?term=29375693
  7. Del Campo JA, Garcia-Valdecasas M, Gil-Gomez A et al. Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy. PLoS One 2018; 13:e0191805. http://www.ncbi.nlm.nih.gov/pubmed/?term=29385181
  8. Chu F, Wang M, Ma H, Zhu J. Simvastatin Modulates Interaction Between Vascular Smooth Muscle Cell / Macrophage and TNF-alpha-activated Endothelial Cell. Journal of cardiovascular pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29389739
  9. Chen Z, Yang D, Peng X et al. Beneficial effect of atorvastatin-modified dendritic cells pulsed with myelin oligodendrocyte glycoprotein autoantigen on experimental autoimmune encephalomyelitis. Neuroreport 2018; 29:317-327. http://www.ncbi.nlm.nih.gov/pubmed/?term=29394220
  10. Subhan M, Faryal R, Macreadie I. Exploitation of Aspergillus terreus for the Production of Natural Statins. Journal of fungi (Basel, Switzerland) 2016; 2. http://www.ncbi.nlm.nih.gov/pubmed/?term=29376930
  11. Javed MN, Kohli K, Amin S. Risk Assessment Integrated QbD Approach for Development of Optimized Bicontinuous Mucoadhesive Limicubes for Oral Delivery of Rosuvastatin. AAPS PharmSciTech 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29388027
  12. He W, Liu Y, Tian X. Rosuvastatin Improves Neurite Outgrowth of Cortical Neurons against Oxygen-Glucose Deprivation via Notch1-mediated Mitochondrial Biogenesis and Functional Improvement. Frontiers in cellular neuroscience 2018; 12:6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29387001

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This activity is supported by an educational grant from Pfizer.