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Update - Week 46,  2017 
 
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

DYSIS – China
Urbanization and the associated westernized lifestyle comes with a price tag: a sharp increase in non-communicable diseases and China is having a first-hand experience. The Dyslipidemia International Study (DYSIS) China appraised how well lipids were managed in North East China (NE) compared to the other regions. The study, conducted in 2012, include 122 centers and 25 137 patients that were treated with lipid lowering drugs for ≥3 months. From the NE 4 559 patients (18%) participated in this study. Patients from the NE were more likely to be younger, female, obese, have more co-morbidities and higher plasma cholesterol levels (P< 0.01). Comparing goal attainments, in the NW 45.3% were reaching target lipid levels compared to 65.1% in the other regions. For high and very high-risk patients a similar pattern was observed: 38.5% vs 56.8% and 22.6% vs 43.7% respectively. Use of high intensity statins was lower in the NE region but add-on lipid lowering drugs like ezetimibe similar for both NE and other regions (∼2%). No improved goal attainment was observed for the patients taking higher statin dosages. Predictors of goal attainment, based on logistic regression analysis, in the NE regions were: DM, CHD, cerebrovascular disease (CBD), being female, BMI >24kg/m2, drinking alcohol, smoking and NE resident. The authors noted that despite persistent use of lipid lowering medications treatment strategies need to improve. More emphasis on high dose, high intensity statins as well as add-on lipid lowering therapy combined with better control of co-morbidities e.g. obesity are desirable.
Zheng W, Zhang YJ, Bu XT et al. LDL-cholesterol goal attainment under persistent lipid-lowering therapy in northeast China: Subgroup analysis of the dyslipidemia international study of China (DYSIS-China). Medicine (Baltimore) 2017; 96:e8555. http://www.ncbi.nlm.nih.gov/pubmed/?term=29145263
 
How can we prevent premature ASCVD?
Predicting risk in premature MI patients (<50 years) is insufficiently address by the standard CVD risk scoring tools. Using the 2013 ACC/AHA and the 2016 USPSTF recommendations for initiating statin in a primary prevention setting patients that experienced an MI at a young age were retrospectively analyzed. The authors used data collected in the YOUNG-MI registry, a retrospective cohort from two large US academic centers. Risk prior to the event was estimated by using the Pooled Cohort Risk Equations (PCE). Out of the 1 685 patients, 210 (12.5%) were using a statin prior the MI, and excluded. The median age of the remaining 1475 patients was 45 years. STEMI was diagnosed in 846 (57%)individuals and 294 (20%) were females. Although at least  1 CV risk factor was present in 1 225 (83%) patients, the median 10-year ASCVD risk score was low: 4.8% (interquartile range 2.8-8.0). Based on the ACC/AAH guidelines and USPSTF recommendations only 729 (49%) and 184 (63%) respectively, would have been eligible for statin therapy. In women, the numbers were even lower 184 (63%) would not qualify for statins vs 549 (46%) of the men (P<0.001). The authors emphasize that current risk assessment tools are inadequate if we want to prevent early manifestations of CAD and that improved strategies are urgently needed to identify premature ASCVD patients in a primary prevention setting. Singh A, Collins BL, Gupta A et al. Cardiovascular Risk and Statin Eligibility of Young Adults After an Myocardial Infarction: Partners YOUNG-MI Registry. J Am Coll Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29141201
 
Meta-analysis of erectile dysfunction and statins
Statin adherence is one of the big challenges to ensure proper protection of patients at (high) risk of CVD. Paramount is to ensure patients that these lifesaving drugs are not only efficacious (when used!) but very safe as well. Erectile dysfunction (ED) is not uncommon in males that are reaching an age where CVD complications are becoming manifest. With advancing age, receding testosterone levels as well as atherosclerotic vascular wall changes and endothelial dysfunction, reported incidences of ED will increase as well. Statins have been implicated in causing ED and this is a topic that can surface when discussing the pro’s and cons of starting statins. A meta-analysis of three large RCT’s and three observational studies was used to estimate the risk of developing ED when starting/using statins, five of these were considered high quality studies. In total 69 448 men, 24 661 statin users were included. Using two statistical tools, both the random effects model and the fixed effect model showed no increased risk for new onset ED, RR: 0.96 (0.84 – 1.10, P = 0.58), and OR: 0.95, (0.88 - 1.02, P = 0.20) respectively. In the randomized trials as well as the observational studies observed effects were similar. The authors concluded that in men with CVD or CVD risk factors statin use did not appear to increase the reported ED problems. However, to ultimately confirm these findings, adequately powered and high quality randomized trials are needed.
Elgendy AY, Elgendy IY, Mahmoud AN et al. Statin Use in Men and New Onset of Erectile Dysfunction: a Systematic Review and Meta-Analysis. Am J Med 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29146233
 
Should survivors of hospital acquired AKI start with statins?
A not uncommon complication during a hospital admission is acute kidney injury (AKI) with an estimated incidence of 3/100 patient years. AKI survivors that progress to chronic kidney disease (CKD) have ab increased risk of dying and CVD complications. Strategies to improve long term outcomes of AKI have not been published. This observational retrospective analysis aims to fill this gap. Using data collected in the (Canadian) Alberta Kidney Disease Network Population database. Adult patients admitted to a hospital that developed AKI during their stay between July 1st 2008 and March 31st 2011 were entered in the registry. The primary outcome was mortality; secondary outcomes: all cause re-hospitalization and CVD events. Overall 19 707 patients were analyzed, mean age 69.9 years and eGFR at discharge 43.0 ml/min/m2. Statin prescriptions, within 2 years of discharge, occurred in 38.3% of the participants and was associated with a lower mortality; HR 0.74 (0.69-0.79). Hospitalizations were reduced as well 0.90 (0.85-0.94) however no CVD reduction was noted. Due to the observational design of this study prospective studies to evaluate post discharge care strategies for AKI survivors are needed to provide more definitive evidence, particular to evaluate the purported benefits  of post discharge statins in this population.
Brar S, Ye F, James M et al. Statin Use and Survival After Acute Kidney Injury. Kidney international reports 2016; 1:279-287. http://www.ncbi.nlm.nih.gov/pubmed/?term=29142930
 
PAD patients are better off with PCSK9ab on top of maximum statin treatment
The FOURIER study investigators published a sub analysis that highlighted the severe CVD risk of patients with peripheral artery disease (PAD) and the benefits of Evolocumab on reducing this risk. Of the 27 564 participants of Fourier 3 642 were diagnosed with PAD (13.2%), of those 1 505 did not have a prior MI or stroke. Adding Evolocumab to statin treated patients for 2.2 years translated in a significant reduction of the primary endpoint (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization), HR 0.79 (0.66-0.94; P=0.0003). Secondary endpoint (composite of cardiovascular death, myocardial infarction, or stroke) improved as well; HR 0.73 (0.59-0.91; P=0.004). Major adverse limb events (acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia) (MALE) were 42% less frequently observed in the Evolocumab treated patients; HR 0.58 (0.38-0.88; P=0.0093). PAD patients, because of their raised risk, had markedly greater absolute risk reductions of their primary endpoint (-3.5% with PAD, -1.6% without PAD) and secondary endpoints (-3.5% with PAD, -1.4% without PAD). The LDL-c levels on trials consistently correlated with the observed risk in PAD patients, including patients with levels as low as < 10 mg/dl. Despite the use of high dose – high intensity statins and having a baseline LDL-C of 90mg/dl PAD patients were observed to have markedly increased CVD risk. The addition of the PCSK9ab evolocumab resulted in impressive relative risk and absolute risk reductions of MACE and MALE. This was not offset by any safety issues. When translated to a 5-year NNT for MACE + MALE of 13, for PAD patients without prior MACE or stroke the estimated 5-year NNT= 8. The authors concluded that LDL-C reduction to very low levels should be considered in patients with PAD, regardless of a history of MI or stroke, to reduce the risk of MACE and MALE.  
Bonaca MP, Nault P, Giugliano RP et al. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29133605
 
Do statins benefit CKD patients with systemic inflammation?
The increased CVD risk observed in chronic kidney disease (CKD) patients, was shown to be independently correlated to inflammation. LDL-C associated CVD risk in patients with elevated markers of inflammation, such as hsCRP and IL-6 has been a subject of debate. The data collected in the SHARP study was used to investigate if statin + ezetimibe was able to reduce risk in patients with increased hsCRP. Of the 8 603 participants, randomized to simvastatin 20 mg + ezetimibe 10 mg in SHARP, 4 305 had a hsCRP ≥3 mg/dl, at baseline. Irrespective of LDL-C plasma levels, a 3-fold increase in hsCRP (1 SD) was associated with 28% higher rate of major vascular events (MVE), irrespective of LDL-C concentrations. There was no difference between ASCVD events and non-ASCVD events; HR 1.28 (1.12-1.31) and 1.34 (1.23-1.45) respectively. The patients randomized to simvastatin/ezetimibe had a 15% lower MVE risk, RR 0.85 (0.77-0.94; P=0.0012). A 0.6 mmol/l (1 SD) LDL-C increase was associated with 14% higher MVE risk; HR 1.14 (1.06-1.22). For ASCVD related events: HR 1.19 (1.11-1.28); but there was a weak and inverse association for non-ASCVD events; HR 0.90 (0.83-0.97) per 0.6 mmol/l LDL-C increase. Elevated hsCRP levels were associated with cardiovascular mortality and non-cardiovascular mortality in CKD patients. Increase LDL-C plasma concentrations showed a higher CVD risk but no impact on non-CVD deaths. The combination of simvastatin with ezetimibe did however reduce CVD risk irrespective of hsCRP levels. Based on this retrospective analysis of the SHARP study, benefits of a statin/ezetimibe combination in CKD patients were dependent on absolute ASCVD risk and independent of plasma hsCRP concentrations.  
Storey BC, Staplin N, Haynes R et al. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney international 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29146277
Relevant publications
  1. Watson KE, Fonarow GC. Closing the Remaining Evidence Gap: Randomized Controlled Trial Data to Support Statin Therapy for Low-Density Lipoprotein >/=190 mg/dL. Circulation 2017; 136:1892-1894. http://www.ncbi.nlm.nih.gov/pubmed/?term=29133529
  2. Wang Y, Zhu S, Du R et al. Statin initiation and renal outcomes following isolated coronary artery bypass grafting: a meta-analysis. J Cardiovasc Surg (Torino) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29145723
  3. Sun D, Li S, Zhao X et al. Association between lipoprotein (a) and proprotein convertase substilisin/kexin type 9 in patients with heterozygous familial hypercholesterolemia: a case control study. Metabolism 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29129821
  4. Suh DC, Griggs SK, Henderson ER et al. Comparative effectiveness of lipid-lowering treatments to reduce cardiovascular disease. Expert review of pharmacoeconomics & outcomes research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29148854
  5. Poly TN, Islam MM, Walther BA et al. Exploring the Association between Statin Use and the Risk of Parkinson's Disease: A Meta-Analysis of Observational Studies. Neuroepidemiology 2017; 49:142-151. http://www.ncbi.nlm.nih.gov/pubmed/?term=29145202
  6. Navar AM, Wang TY, Li S et al. Lipid management in contemporary community practice: Results from the Provider Assessment of Lipid Management (PALM) Registry. Am Heart J 2017; 193:84-92. http://www.ncbi.nlm.nih.gov/pubmed/?term=29129260
  7. Maki K, Diwadkar-Navsariwala V, Kramer MW. Statin use and risk for type 2 diabetes: what clinicians should know. Postgraduate medicine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29139315
  8. Lee HY, Kim SY, Choi KJ et al. A Randomized, Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and the Tolerability of a Triple Combination of Amlodipine/Losartan/Rosuvastatin in Patients With Comorbid Essential Hypertension and Hyperlipidemia. Clinical therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29150250
  9. Espinola-Klein C. [ESC guidelines 2017 on peripheral arterial diseases : Summary of the most important recommendations and innovations]. Herz 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29143147
  10. Brown F, Singer A, Katz A, Konrad G. Statin-prescribing trends for primary and secondary prevention of cardiovascular disease. Canadian family physician Medecin de famille canadien 2017; 63:e495-e503. http://www.ncbi.nlm.nih.gov/pubmed/?term=29138175
  11. Vaidean GD, Manczuk M, Vansal SS, Griffith J. The cholesterol-lowering effect of statins is potentiated by whole grains intake. The Polish Norwegian Study (PONS). Eur J Intern Med 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29137927
  12. Spannella F, Giulietti F, Balietti P et al. Renin-Angiotensin System Blockers and Statins Are Associated With Lower In-Hospital Mortality in Very Elderly Hypertensives. Journal of the American Medical Directors Association 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29128438
  13. Singh RK, Agarwal V, Baronia AK et al. The Effects of Atorvastatin on Inflammatory Responses and Mortality in Septic Shock: A Single-center, Randomized Controlled Trial. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine 2017; 21:646-654. http://www.ncbi.nlm.nih.gov/pubmed/?term=29142375
  14. Markovitz AA, Holleman RG, Hofer TP et al. Effects of Guideline and Formulary Changes on Statin Prescribing in the Veterans Affairs. Health services research 2017; 52:1996-2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29130272
  15. Madi M, Kassem A. Topical simvastatin gel as a novel therapeutic modality for palatal donor site wound healing following free gingival graft procedure. Acta odontologica Scandinavica 2017:1-8. http://www.ncbi.nlm.nih.gov/pubmed/?term=29145771
  16. Choi HK, Hwang JT, Nam TG et al. Welsh onion extract inhibits PCSK9 expression contributing to the maintenance of the LDLR level under lipid depletion conditions of HepG2 cells. Food & function 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29130084
  17. Al-Rasheed NM, Al-Rasheed NM, Hasan IH et al. Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats. Oxidative medicine and cellular longevity 2017; 2017:1092015. http://www.ncbi.nlm.nih.gov/pubmed/?term=29138670
Miscellaneous publications
  1. Raghu VK, Beckwitt CH, Warita K et al. Biomarker identification for statin sensitivity of cancer cell lines. Biochem Biophys Res Commun 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29146185
  2. Leenders GJ, Smeets MB, van den Boomen M et al. Statins Promote Cardiac Infarct Healing by Modulating Endothelial Barrier Function Revealed by Contrast-Enhanced Magnetic Resonance Imaging. Arterioscler Thromb Vasc Biol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29146749
  3. Chen S, Dong S, Li Z et al. Atorvastatin Calcium Inhibits PDGF-betabeta-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRbeta-PI3K-Akt Signaling Cascade. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2017; 44:215-228. http://www.ncbi.nlm.nih.gov/pubmed/?term=29131001
  4. Wang Q, Yang YB, Yang XQ et al. Lovastatin analogues and other metabolites from soil-derived Aspergillus terreus YIM PH30711. Phytochemistry 2017; 145:146-152. http://www.ncbi.nlm.nih.gov/pubmed/?term=29132077
  5. Pauchard LA, Blot M, Bruyere R et al. Linezolid and atorvastatin impact on pneumonia caused by Staphyloccocus aureus in rabbits with or without mechanical ventilation. PLoS One 2017; 12:e0187187. http://www.ncbi.nlm.nih.gov/pubmed/?term=29149185
  6. Karaji ZG, Houshmand B, Abbasi S et al. Biofunctionalization of Titanium Granules with Simvastatin for Improving Osteogenic Activity and Antibacterial Properties (Ex Vivo Study). The International journal of oral & maxillofacial implants 2017; 32:1266-1272. http://www.ncbi.nlm.nih.gov/pubmed/?term=29140371
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