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Update - Week 26, 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

Statins for non-cardiac vascular surgery; “conditio sine qua non”?
For non-cardiac, vascular surgery the use of statin has been shown to improve survival and reduce CVD events. This meta-analysis evaluated the impact of statins in 34 observational studies, 8 prospective cohort studies and 4 randomized controlled clinical trials. Studies were published between 1995 – 2017, with a follow-up period of 30 days – 15 years and included patients that had a vascular, non-cardiac surgery. Statin use improved mortality in patients that had lower limb, carotid, aortic and mixed types of vascular surgery. In patients that had lower limb revascularizations primary and secondary patency rates as well as amputations rates improved significantly. Reduced CVE complications were observed in patients that had mixed type surgeries. Patients that had carotid artery procedures and used statins experienced less CV events including strokes. Based on this meta-analysis patients that have vascular surgery should be treated with statins not only did this improve their chances of enduring vascular patency and protection of CVE’s; overall survival rates were superior as well. The authors concluded that statins are strongly recommended for this group of patients.
Yu W, Wang B, Zhan B et al. Statin therapy improved long-term prognosis in patients with major non-cardiac vascular surgeries: a systematic review and meta-analysis. Vascul Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29953967
Polypill:  1+1+1+1 = 4?
Successfully realizing ESC 2016 guidelines targets using a polypill approach is evaluated in this meta-analysis. Individual patient data of 3 RCT’s comparing a polypill vs usual care in secondary prevention patients were included in this assessment. Patients (N=3140) from Australia, England, India, Ireland, the Netherlands and New Zealand participated in the individual studies; 75% were males, mean age 62 years and 76% with a prior CVD event. After 12 months patients on the polypill regimen were more likely to reach recommended targets for Blood pressure (BP), 62% vs 58%. RR 1.08 (1.02-1.15); LDL-c, 39% vs 34%. RR 1.13 (1.02-1.25). No difference in adherence to antiplatelet medication, 96% vs 96%, RR 1.00 (0.98-1.01). Achieving targets for all three interventions was seen in 24% vs 19% of participants. RR 1.27 (1.10-1.47). An effect of treatment intensity at baseline was observed. Patients that used 3, 2 or 0-1 therapeutic interventions were able to reach all three guideline goals as follows:  RR 1.10 (0.94-1.30) - 22% vs 20%. RR 1.62 (1.09-2.42) - 27% vs 17%) and RR 3.07 (1.77-5.33) - 35% vs 11%, respectively. Using a polypill based therapeutic regimen resulted in improved achievement of ESC Guideline targets in secondary prevention patients, compared to usual care.
Selak V, Webster R, Stepien S et al. Reaching cardiovascular prevention guideline targets with a polypill-based approach: a meta-analysis of randomised clinical trials. Heart 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29954855
Surprising calcium score changes in patients using PCSK9ab vs statins
Changes in calcium score severity were evaluated in this Japanese unpaired cross-sectional study I patients that used no statin/no PCSK9ab (N=41), statin(N=60) and PCSK9ab + statin (N=19). This was followed by a paired longitudinal study where CTA was repeated in patients using statins (N=15), mean treatment duration 2.79 years and patients using statins + PCSK9ab (N=16), add on treatment of PCSK9ab, 0.75 year. In the cross-sectional study 40 patients (33%) had a CAC score >100 AUs. An incremental increase of the median CAC score in was observed in the following order: statin group, statin and PCSK9 group, and no-statin-no-PCSK9 group. Annual CAC score progression in the paired longitudinal study was 29.7% in patients using statin monotherapy and 14.3% following the addition of the PCSK9 inhibitor to statin therapy. The results of this study point toward a mitigating effect of PCSK9ab vs statin monotherapy. The clinical consequences, if confirmed in better designed studies, is unclear. Despite the limitations of this study, including the confusing design and small number of participants, the observed results warrant further exploration to determine the effects of PCSK9ab on CAC progression as well as clinical relevance of the observed attenuation of the CAC scores.
Ikegami Y, Inoue I, Inoue K et al. The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. NPJ aging and mechanisms of disease 2018; 4:7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29951223
Statins for kidney donors?
The benefits of statins in renal transplant patients is well accepted and most importantly the non-lipid lowering effects seem to be relevant in improving graft survival. In this study living kidney donors (n=24) were randomized to 40 mg atorvastatin or placebo 4 weeks prior to the renal transplant. Inflammation (hsCRP) and renal function were analyzed in the kidney recipients 1, 6 and 24 hrs. post-surgery. After 4 weeks the hsCRP concentrations in the donors reached 5.62 ±3.82 mg/d in the control group and 3.27 ±0.62 mg/dl in the statin users. The organ recipients hsCRP concentrations were 5.8±3.9 and 3.8±1.0 mg/dL, in patients that received a kidney from a donor in the control group vs a donor that used atorvastatin 40 mg (P=0.04). Serum creatinine levels 24 hrs. post transplantation were 2.5±1.5 mg/dL and 3.7±2.4 mg/dL in patients that received a kidney from statin users vs the control group (P=0.04). The authors suggest that providing atorvastatin 40 mg to designated kidney donors 4 weeks prior to transplantation, has favorable effects on inflammation and possible on the intrinsic ischemia-reperfusion injury in the kidney recipients. The promising results of this small study reinforces the need to further explore not only pre-op treatment strategies in kidney donors but optimize statin therapy (dosage and duration) in renal transplant recipients as well.  
Fuentes-Orozco C, Garcia-Salazar SJ, Gomez-Navarro B et al. Anti-Inflammatory Effect of Atorvastatin on the Kidney Graft of Living Donor Transplants. Annals of transplantation 2018; 23:442-449. http://www.ncbi.nlm.nih.gov/pubmed/?term=29955032
Expert opinion paper on Nutraceuticals for lipid lowering

Despite the pivotal role of statins in CVD prevention, for some patient’s other lipid lowering strategies are needed to be used as an add on to statins or, in intolerant patients, as alternative to statins. The authors of this elaborate expert opinion paper explored nutraceutical approaches that have been published in peer reviewed journals. They systematically discuss each suggested nutraceutical alone, in combination with other nutraceuticals, or in association with lipid-lowering drugs. The postulated mechanism of action, effective dosages, non-lipid lowering effects, efficacy and safety are reviewed. For each nutraceutical approach the level of evidence (level A, B or C) as well as the strength of recommendation (class I, II, IIa, IIb and III) are provided. Although effectiveness and safety of nutraceuticals have not been studied as well as pharmacological interventions, the evidence shared in this expert review provides clinicians with relevant information in order to choose alternatives lipid lowering intervention for patients at risk for SCVD and where statins are insufficient or not tolerated/accepted.
Banach M, Patti AM, Giglio RV et al. The Role of Nutraceuticals in Statin Intolerant Patients. J Am Coll Cardiol 2018; 72:96-118. http://www.ncbi.nlm.nih.gov/pubmed/?term=29957236
Relevant publications
  1. Zagelbaum NK, Yandrapalli S, Nabors C, Frishman WH. Bempedoic Acid (ETC-1002): ATP Citrate Lyase Inhibitor: Review Of A First In Class Medication With Potential Benefit In Statin-Refractory Cases. Cardiology in review 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29939848
  2. Usategui-Martin R, Vega G, Abad-Manteca L et al. Role of Bone Morphogenetic Protein 2 (BMP-2) Polymorphisms in Bone Mineral Density after the Start of Treatment with Atorvastatin. Basic & clinical pharmacology & toxicology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29956474
  3. Tseng CH. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver international : official journal of the International Association for the Study of the Liver 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29956875
  4. Naidoo P, Mothilal R, Blom DJ. Therapeutic Management of Dyslipidemia Patients at Very High Cardiovascular Risk (CARDIO TRACK): Protocol for the Observational Registry Study. JMIR research protocols 2018; 7:e163. http://www.ncbi.nlm.nih.gov/pubmed/?term=29959115
  5. Litke J, Spoutz L, Ahlstrom D et al. Impact of the clinical pharmacy specialist in telehealth primary care. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 2018; 75:982-986. http://www.ncbi.nlm.nih.gov/pubmed/?term=29941537
  6. Ho LT, Lin FJ, Tseng WK et al. On-treatment lipid profiles to predict the cardiovascular outcomes in ASCVD patients comorbid with chronic kidney disease - The multi-center T-SPARCLE registry study. Journal of the Formosan Medical Association = Taiwan yi zhi 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29945742
  7. Dave CV, Winterstein AG, Park H et al. Comparative risk of lipophilic and hydrophilic statins on incident depression: A retrospective cohort study. Journal of affective disorders 2018; 238:542-546. http://www.ncbi.nlm.nih.gov/pubmed/?term=29936394
  8. Chen S, Xiang Q, Zhao X et al. Impact of the 719Arg variant of KIF6 and major cardiovascular events on patients who received statins: a systematic review and meta-analysis. Current pharmaceutical design 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29938614
  9. Brandt EJ, Benes LB, Lee L et al. The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Sterol Absorption Markers in a Cohort of Real-World Patients. Journal of cardiovascular pharmacology and therapeutics 2018:1074248418780733. http://www.ncbi.nlm.nih.gov/pubmed/?term=29940784
  10. Bai X, Zhang B, Wang P et al. Effects of SLCO1B1 and GATM gene variants on rosuvastatin-induced myopathy are unrelated to high plasma exposure of rosuvastatin and its metabolites. Acta pharmacologica Sinica 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29950617
  11. Whyte J, Ketchum J, Bogner JA et al. The Effects of Statin Treatment on Outcomes following Traumatic Brain Injury. Journal of neurotrauma 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29954258
  12. Verdoia M, Galasso G, Filardi PP, De Luca G. Statins and elderly: from clinical trials to daily practice. Current vascular pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29956633
  13. Turk Veselic M, Zorz N, Erzen B et al. Improvement of arterial wall phenotype in subjects at moderate cardiovascular risk induced by very low-dose fluvastatin/valsartan combination: a pilot study. International angiology : a journal of the International Union of Angiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29952159
  14. Taylor BA, Panza G, Ballard KD et al. Creatine supplementation does not alter the creatine kinase response to eccentric exercise in healthy adults on atorvastatin. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29945780
  15. Rasmussen L, Pratt N, Hansen MR et al. Using the "proportion of patients covered" and the Kaplan-Meier survival analysis to describe treatment persistence. Pharmacoepidemiol Drug Saf 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29952045
  16. Nguyen T, Khan A, Liu Y et al. The Association Between Statin Use After Diagnosis and Mortality Risk in Patients With Esophageal Cancer: A Retrospective Cohort Study of United States Veterans. Am J Gastroenterol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29946180
  17. Meza-Mauricio J, Soto-Penaloza D, Penarrocha-Oltra D et al. Locally applied statins as adjuvants to non-surgical periodontal treatment for chronic periodontitis: a systematic review and meta-analysis. Clinical oral investigations 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29948277
  18. Mazza A, Schiavon L, Rigatelli G et al. The short-term supplementation of monacolin K improves the lipid and metabolic patterns of hypertensive and hypercholesterolemic subjects at low cardiovascular risk. Food & function 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29951651
  19. Kang JH, Kao LT, Lin HC et al. Do outpatient statins and ACEIs/ARBs have synergistic effects in reducing the risk of pneumonia? A population-based case-control study. PLoS One 2018; 13:e0199981. http://www.ncbi.nlm.nih.gov/pubmed/?term=29953536
  20. Hamdan AL, Mourad M, Fakhri G et al. Vocal tract symptoms: Severity and frequency in patients on statins. Ear, nose, & throat journal 2018; 97:128-136. http://www.ncbi.nlm.nih.gov/pubmed/?term=29940682
  21. Chen YA, Shih HW, Lin YC et al. Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair. Frontiers in pharmacology 2018; 9:600. http://www.ncbi.nlm.nih.gov/pubmed/?term=29950990
Miscellaneous publications
  1. Wang X, Jia Z, Almoshari Y et al. Local Application of Pyrophosphorylated Simvastatin Prevents Experimental Periodontitis. Pharm Res 2018; 35:164. http://www.ncbi.nlm.nih.gov/pubmed/?term=29943090
  2. Mizrahi M, Adar T, Lalazar G et al. Glycosphingolipids Prevent APAP and HMG-CoA Reductase Inhibitors-mediated Liver Damage: A Novel Method for "Safer Drug" Formulation that Prevents Drug-induced Liver Injury. Journal of clinical and translational hepatology 2018; 6:127-134. http://www.ncbi.nlm.nih.gov/pubmed/?term=29951356
  3. Jaskiewicz A, Pajak B, Litwiniuk A et al. Geranylgeraniol Prevents Statin-Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy. Oxidative medicine and cellular longevity 2018; 2018:6463807. http://www.ncbi.nlm.nih.gov/pubmed/?term=29951166
  4. Gambhire VM, Salunkhe SM, Gambhire MS. Atorvastatin loaded lipid nanoparticles: Antitumor activity studies on MCF-7 breast cancer cells. Drug development and industrial pharmacy 2018:1-37. http://www.ncbi.nlm.nih.gov/pubmed/?term=29936872
  5. Chen L, Liu L, Chen Y et al. Modulation of transporter activity of OATP1B1 and OATP1B3 by the major active components of Radix Ophiopogonis. Xenobiotica 2018:1-22. http://www.ncbi.nlm.nih.gov/pubmed/?term=29944058
  6. Cai WY, Zhuang Y, Yan F et al. Effect of survivin downregulation by simvastatin on the growth and invasion of salivary adenoid cystic carcinoma. Mol Med Rep 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29956779
  7. Antonopoulos N, Machairas G, Migias G et al. Hydrophilic Interaction Liquid Chromatography-Electrospray Ionization Mass Spectrometry for Therapeutic Drug Monitoring of Metformin and Rosuvastatin in Human Plasma. Molecules (Basel, Switzerland) 2018; 23. http://www.ncbi.nlm.nih.gov/pubmed/?term=29954074
  8. Villani C, Sacchetti G, Bagnati R et al. Correction: Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice. eLife 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29957179
  9. Sarangi B, Jana U, Sahoo J et al. Systematic approach for the formulation and optimization of atorvastatin loaded solid lipid NANOAPARTICLES using response surface methodology. Biomedical microdevices 2018; 20:53. http://www.ncbi.nlm.nih.gov/pubmed/?term=29946758
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