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Update - Week 12, 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

Starting statins pre-dialysis improves outcomes during dialysis
Patients with end-stage kidney disease, requiring dialysis, did not show benefit when statins were initiated; both the 4 D study (atorvastatin) and the AURORA trial (rosuvastatin) were unable to demonstrate benefits (or harms). In this retrospective, observational analysis of 47 730 American Veterans, that transitioned to end-stage renal disease, the use of statins prior to the transition did have a positive impact on clinical outcomes, during a 1-year period that dialysis was performed. Patient data were collected between 2007 and 2014 from the Transition of Care in Chronic Kidney Disease US Renal Data System (USRDS) Special Study Center. Post-transition all-cause death, CVD death, and hospitalizations were the evaluated endpoints. A Cox variable proportional hazard models and negative binomial regressions model, as well as propensity score and sub group matching, was used to compare the statin-users with the patients not using statins. The cohort’s mean age was 71±11 years, 4% females, 23% blacks, and 66% were diabetics. Over the 12-month follow-up period, 13 411 patients died, 35.3 (34.7-35.8)/100 person-years. All studied parameters showed improved outcomes over the 12 months that patients received dialysis. Patients using statins were less likely to die from all causes 0.79 (0.76–0.82), CV causes 0.83 (0.78–0.88), and had a reduced risk for hospitalizations 0.89 (0.87–0.92). The authors concluded, that statin use prior to dialysis transition, was associated with favorable end-stage renal disease outcomes in the first year of dialysis. The observed benefits provide support for a guideline recommendation of statin therapy for all adult patients with non-dialysis dependent-CKD and specifically identifies the benefit of statin therapy in pre-ESRD patients.
Soohoo M, Moradi H, Obi Y et al. Statin Therapy Before Transition to End-Stage Renal Disease With Posttransition Outcomes. J Am Heart Assoc 2019; 8:e011869. http://www.ncbi.nlm.nih.gov/pubmed/?term=30885048
 
AF patient need the statins-on board to improve outcomes of CE strokes
The benefits of statins in patients that suffered an AF related cardio-embolic (CE) stroke was evaluated in this study. A retrospective analysis was performed using the data collected of 2000 Polish ischemic stroke patients; of which 234 suffered an embolic stroke. Statins were used by 181 patients vs 153 patients that had not taken statins, 1-year before they suffered a CE-stroke. Patients in the latter group had a greater National Institutes of Health Stroke Scale (NIHSS) score, both at admission as well as at hospital discharge 10 vs. 11.9 (p < 0.05) and 7.6 vs. 9.5 (p < 0.05) respectively. In-hospital mortality was greater in this group as well; 9.9% vs. 18.3% (p < 0.05). The authors suggested that based on these findings using statins during the pre-stroke period seems to positively affect important clinical outcomes in the acute stroke phase. They affirmed that AF patients, should be screened for statin use and strategies to ensure statin initiation, implemented.
Kotlega D, Golab-Janowska M, Meller A et al. Beneficial effects of pre-stroke statins use in cardioembolic stroke patients with atrial fibrillation: a hospital-based retrospective analysis. Archives of medical science : AMS 2019; 15:385-392. http://www.ncbi.nlm.nih.gov/pubmed/?term=30899291
 
Intriguing results for NODM when comparing statins with PCSK9ab
The effects of statins and PCSK9ab treatments on new-onset diabetes (NODM), is the focus of this meta-analysis, based on 33 RCT trials. Statin was used in 21 studies and 12 trials evaluated PCSK9ab. Overall 163 688 patients were assigned to a more potent LDL-c lowering strategy (N=83 123); drugs used were either PCSK9ab or statins. Reduced LDL-c lowering corresponded to the control group, using a placebo or usual care (N= 80 565). The Meta-regression and meta-analyses (random-effects model) were unable to show an association between 1-mmol/l LDL-c reduction and NODM in the patients using the more intensive lipid-lowering approach, RR: 0.95 (0.87–1.04; P=0.30; R2=14%), both for statins and PCSK9ab. When comparing more intensive lipid-lowering approach vs the control/less intensive LDL-c management, there was an increased risk for NODM, 1.07 (1.03–1.11; P<0.001; I2=0%).However only statins and not PCSK9ab were responsible for this observed difference, RR: 1.10 (1.05–1.15; P<0.001; I2=0%) vs RR: 1.00 (0.93–1.07; P=0.96; I2=0%; P=0.02 for interaction), respectively. The authors concluded that only for statins a more intensive treatment showed an increased risk for NODM and this could not be observed in patients using a PCSK9ab therapy (on a background of statins). 
Khan SU, Rahman H, Okunrintemi V et al. Association of Lowering Low-Density Lipoprotein Cholesterol With Contemporary Lipid-Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2019; 8:e011581. http://www.ncbi.nlm.nih.gov/pubmed/?term=30898075
 
Hemorrhagic stroke and statins, who is at risk?
The risk of hemorrhagic stroke (ICH) is evaluated in a new meta-analysis of 39 lipid-lowering trials and 287 651 patients. For the first time a range of lipid-lowering drugs was included in this analysis; statins, fibrates, ezetimibe, PCSK9ab, and CETPi. Potential predictors such as baseline LDL-c level, percentage LDL-c reduction, and baseline CVD risk were evaluated. No clear significant relationship could be discerned when primary and secondary prevention studies were combined, OR 1.12 (0.98-1.28). After secondary and primary prevention studies were analyzed separately, only in secondary prevention patients, a slightly increased risk was observed, OR 1.18 (1.00-1.38) and OR, 1.01 (0.78-1.30) respectively. The test for interaction was not significant (P for interaction = .31). Both baseline LDL-c and percentage of LDL-c changes were not causally related to the observed differences. The risk of ischemic stroke improved with 9,17 (5.78-12.66) fewer strokes when a 1000 secondary prevention patients used statins for 1 year for secondary prevention. Risk of ICH increased with 0.48 (0.6-1.02) events/1000 patients were treated for 1 year, a Number Needed to Harm for ICH 2451 (1158-20875), in contrast with an NNT of 206 (150-328). Overall A net reduction of 8.77 all strokes per 1000 person-years. These results confirm a clear benefit of lipid-lowering therapy in the prevention of ischemic stroke. This is reassuring and affirms the importance of initiating statins in patients with increased CVD risk.
Judge C, Ruttledge S, Costello M et al. Lipid Lowering Therapy, Low-Density Lipoprotein Level and Risk of Intracerebral Hemorrhage - A Meta-Analysis. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30878368

Lipid Management in the ACC/AHA 2019 Primary Prevention Guidelines
The recently updated ACC/AHA Primary Prevention Guidelines were presented at the ACC 2019 congress in New Orleans and simultaneously published in Circulation and JACC. The key focus for CVD prevention is a healthy lifestyle, comprising a nutritious diet (vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish, and minimizes the intake of trans fats, processed meats, refined carbohydrates, and sweetened beverages) and 150 minutes/week moderate intensity and 75 minutes/week of high intensity physical activity. CVD risk evaluation in adults (40 -75 years) includes an ASCVD risk estimation and clinician-patient discussion before initiating pharmacotherapy. Patients (40 -75 years) would be eligible for moderate dosage/intensity statin treatment (LDL-c reduction >30%), if diagnosed with diabetes or a with a an intermediate (>7.5% - < 20%) 10-year CVD risk. High dose-high intensity statins (LDL-c reduction >50%) are reserved for FH patients and high (>20%) CVD risk individuals. The presence of other relevant risk factors and/or a positive Ca Score, allows for an individualized evaluation of CVD risk and could result in an upgrading of the calculated risk and advice to start high dose–high intensity statins, in patients with intermediate (>7.5% - <20%) 10-year CVD risk. Moderate dose–moderate intensity statins are advised for those with borderline (5%-7.5%) CVD risk. A Ca Score = 0, as well as the absence of serious risk factors such as smoking diabetes or family history of premature CHD, would disqualify patients for statins and a re-evaluation after 10-years is advised. Non-statin lipid-lowering medications such as ezetimibe and PCSK9ab are reserved for FH patients, that continue to have LDL-c > 100 mg/dl, despite maximally tolerated dosage of statin therapy. Aspirin is recommended in patients with a high CVD risk, but without increased bleeding risk only. Blood pressure medication is recommended if patients with a BP of >130/80 mmHg or >140/90 mmHg and a CVD risk >10% or < 10% respectively.
Arnett DK, Blumenthal RS, Albert MA et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary. Circulation 2019:Cir0000000000000677. http://www.ncbi.nlm.nih.gov/pubmed/?term=30879339
Arnett DK, Blumenthal RS, Albert MA et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation 2019:Cir0000000000000678. http://www.ncbi.nlm.nih.gov/pubmed/?term=30879355
Relevant publications
  1. Wong ND, Shapiro MD. Interpreting the Findings From the Recent PCSK9 Monoclonal Antibody Cardiovascular Outcomes Trials. Frontiers in cardiovascular medicine 2019; 6:14. http://www.ncbi.nlm.nih.gov/pubmed/?term=30895178
  2. Lopez-Jaramillo P, Barbosa E, Molina DI et al. Latin American Consensus on the management of hypertension in the patient with diabetes and the metabolic syndrome. J Hypertens 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30882601
  3. Lo-Kioeng-Shioe MS, Vavere AL, Arbab-Zadeh A et al. Coronary Calcium Characteristics as Predictors of Major Adverse Cardiac Events in Symptomatic Patients: Insights From the CORE 320 Multinational Study. J Am Heart Assoc 2019; 8:e007201. http://www.ncbi.nlm.nih.gov/pubmed/?term=30879377
  4. LaBoy SM, Pulley MT. Statin Associated Muscle Symptoms: Does the benefit outweigh the risk factor? Muscle Nerve 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30882912
  5. Kim SW, Kang HJ, Jhon M et al. Statins and Inflammation: New Therapeutic Opportunities in Psychiatry. Frontiers in psychiatry 2019; 10:103. http://www.ncbi.nlm.nih.gov/pubmed/?term=30890971
  6. Jukema JW, Szarek M, Zijlstra LE et al. Patients with Recent Acute Coronary Syndrome and Polyvascular Disease Derive Large Absolute Benefit from Alirocumab: ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30898609
  7. Jeong HS, Hong SJ. Benefit of Early Statin Therapy in Acute Myocardial Infarction in Korea. Korean Circ J 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30891965
  8. Hosio M, Urpilainen E, Marttila M et al. Association of antidiabetic medication and statins with breast cancer incidence in women with type 2 diabetes. Breast Cancer Res Treat 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30895533
  9. Chan DC, Watts GF, Coll B et al. Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol-Lowering Therapy. J Am Heart Assoc 2019; 8:e011781. http://www.ncbi.nlm.nih.gov/pubmed/?term=30897995
  10. Bhatt DL, Steg PG, Miller M et al. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30898607
  11. Yan J, Qiao L, Tian J et al. Effect of statins on Parkinson's disease: A systematic review and meta-analysis. Medicine (Baltimore) 2019; 98:e14852. http://www.ncbi.nlm.nih.gov/pubmed/?term=30896628
  12. Seftel AD. Re: Statin Safety and Associated Adverse Events: A Scientific Statement from the American Heart Association. The Journal of urology 2019:10109701ju00005547914083509. http://www.ncbi.nlm.nih.gov/pubmed/?term=30888895
  13. Nam YH, Bilker WB, Leonard CE et al. Effect of statins on the association between high temperature and all-cause mortality in a socioeconomically disadvantaged population: a cohort study. Scientific reports 2019; 9:4685. http://www.ncbi.nlm.nih.gov/pubmed/?term=30886182
  14. Jang HJ. Can Statin Prevent the Risk of Colorectal Cancer in Patients with Inflammatory Bowel Disease? Gut Liver 2019; 13:138-139. http://www.ncbi.nlm.nih.gov/pubmed/?term=30893984
  15. Henker C, Kriesen T, Scherer M et al. Association Between Tumor Compartment Volumes, the Incidence of Pretreatment Seizures, and Statin-Mediated Protective Effects in Glioblastoma. Neurosurgery 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30888031
  16. Cook EH, Masaki JT, Guter SJ, Najjar F. Lovastatin Treatment of a Patient with a De Novo SYNGAP1 Protein Truncating Variant. Journal of child and adolescent psychopharmacology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30901256
  17. Amioka N, Miyoshi T, Otsuka H et al. Serum malondialdehyde-modified low-density lipoprotein levels on admission predict prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention. J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30898480
Basic Science publications
 
 
  1. Zarganes-Tzitzikas T, Neochoritis CG, Domling A. Atorvastatin (Lipitor) by MCR. ACS medicinal chemistry letters 2019; 10:389-392. http://www.ncbi.nlm.nih.gov/pubmed/?term=30891146
  2. Xiao A, Brenneman B, Floyd D et al. Statins affect human glioblastoma and other cancers through TGF-beta inhibition. Oncotarget 2019; 10:1716-1728. http://www.ncbi.nlm.nih.gov/pubmed/?term=30899443
  3. Hu F, Hu Y, Peng F. Synergistic and protective effect of atorvastatin and amygdalin against histopathological and biochemical alterations in Sprague-Dawley rats with experimental endometriosis. AMB Express 2019; 9:37. http://www.ncbi.nlm.nih.gov/pubmed/?term=30888523
  4. de Miranda JR, Choi IGG, Moreira MS et al. Histologic Evaluation of Early Bone Regeneration Treated with Simvastatin Associated with Low-Level Laser Therapy. The International journal of oral & maxillofacial implants 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30892287
  5. Chung CM, Lin MS, Lin YS. Reply to: "An update on statins: Pleiotropic effect on intracerebral hemorrhage". Atherosclerosis 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30898359
  6. Beltran D, Frutos-Lison MD, Espin JC, Garcia-Villalba R. Re-examining the role of the gut microbiota in the conversion of the lipid-lowering statin monacolin K (lovastatin) into its active beta-hydroxy acid metabolite. Food & function 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30882807
  7. Parks XX, Ronzier E, J OU, Lopes CM. Fluvastatin inhibits Rab5-mediated IKs internalization caused by chronic Ca(2+)-dependent PKC activation. Journal of molecular and cellular cardiology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30898664
  8. Knapik-Kowalczuk J, Chmiel K, Jurkiewicz K et al. Physical Stability and Viscoelastic Properties of Co-Amorphous Ezetimibe/Simvastatin System. Pharmaceuticals (Basel, Switzerland) 2019; 12. http://www.ncbi.nlm.nih.gov/pubmed/?term=30893881
  9. Kalani MM, Nourmohammadi J, Negahdari B et al. Electrospun core-sheath poly(vinyl alcohol)/silk fibroin nanofibers with Rosuvastatin release functionality for enhancing osteogenesis of human adipose-derived stem cells. Materials science & engineering. C, Materials for biological applications 2019; 99:129-139. http://www.ncbi.nlm.nih.gov/pubmed/?term=30889664
  10. Iyer S, Donnelly PE, Spaniel G et al. Locally Applied Simvastatin as an Adjunct to Promote Spinal Fusion in Rats. Spine 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30896582
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