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Update - Week 30, 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

What to expect from Co-Q10 supplements to address SAMS
Statin associate muscle side effects (SAMS) remains one of the major hurdles that prevents patients using statins or using the appropriate high dose – high intensity statin. Incidence of SAMS is <1% in RCT’s but as high as 10-25% in observational registries and clinical practice. The nocebo effect plays an important role in explaining this discrepancy. One of the suggested SAMS causes is the depletion of mevalonate by inhibition of HMG-CoA and subsequent reduction of the isoprenylated proteins that in turn cause a decrease in the production of co-enzyme Q10 (CoQ10), potentially leading to mitochondrial dysfunction. The authors provide a concise overview of the deductive line of reasoning that fueled the hypothesis of CoQ10 involvement in SAMS. They show that despite several congruent studies that provided support for this hypothesis, the study that was able to include true SAMS patients and treat them with a more than adequate dosage of CoQ10 (600 mg/day), plasma concentrations of CoQ10 increased 4 fold. However, SAMS were not resolved and there was even a signal for an increase in SAMS in patients using CoQ10. Despite the disappointing results, they do not advise against using CoQ10 in patients that report SAMS, they point out that some patients do report improvements, although a placebo effect might be responsible for this. Based on their findings they see only a limited role for Co-Q10 in addressing SAMS.
Zaleski AL, Taylor BA, Thompson PD. Coenzyme Q10 as Treatment for Statin-Associated Muscle Symptoms-A Good Idea, but. Advances in nutrition (Bethesda, Md.) 2018; 9:519s-523s. http://www.ncbi.nlm.nih.gov/pubmed/?term=30032220
 
Asian diabetic ACS patients are better off with high dose statins
Why do so many doctors persist in using low dose/low intensity statins in their high or very high-risk patients? One of the arguments, frequently suggested in discussions during conferences or after talks, is that they are convinced low dose and/or low intensity statins is sufficient for their patients. The authors of this paper show that it is not. In a prospective open-label single blinded randomized trial of 72 Korean diabetic Non-STEMI ACS patients. Participants were randomized to pitavastatin 1 mg or 4 mg and followed for 12 months. All patients underwent a PTCA procedure and an everolimus coated stent was placed in the culprit vessels. Primary endpoints were normalized neo-intima volume using OCT. Secondary endpoints included brachial measured flow mediated dilatation (baFMD) and a number of relevant plasma biomarkers. The primary endpoint, normalized neo-intimal volume, was markedly lower when comparing patients that used the high dose vs the low dose of pitavastatin, 4.00 ± 2.80 vs. 8.24 ± 2.83 mm3/mm (p < 0.01). Similar effects were observed for neo-intimal area size, 0.41 ± 0.28 vs 0.74 ± 0.23 mm2 (p < 0.01). FMD values were significantly better in the pitavastatin 4 mg users as well, 0.15 ± 0.15 vs. − 0.03 ± 0.19 mm (p < 0.001). Plasma levels of adiponectin, inflammatory markers and lipoproteins showed better levels in patient using the 4mg pitavastatin vs the 1 mg dose. No clinically relevant safety signal was noted in patients using pitavastatin either 1 or 4 mg. This results of this study re-affirm that in very high-risk diabetic ACS patients the use of low dose pitavastatin did not improve (inflammatory) biomarkers lipids, baFMD and neoinitmal hyperplasia.
Lim JW, Jeong HS, Hong SJ et al. Effects of lowest-dose vs. highest-dose pitavastatin on coronary neointimal hyperplasia at 12-month follow-up in type 2 diabetic patients with non-ST elevation acute coronary syndrome: an optical coherence tomography analysis. Heart Vessels 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30047013
 
Finding FH patients by exploring CAD registries
The Italian START (STable Coronary Artery Diseases RegisTry), collecting national data of patients with stable coronary artery disease, was used to select patients with FH based on the Dutch Lipid Clinic Network (DLCN) score. The SART registry included 4030 patients of which 132 (3.3%) were classified as FH (2.3% definite/probable and 1.1% as possible). The age of FH patients in this registry was younger and mean LDL-c levels (on treatment were: 107.8±41.5 and 84.4±40.9 mg/dl vs. 85.8±32.3 mg/dl in the remaining patients. The guideline target of LDL-c <70mg/dl was reached in 10.9%, 30.0% and 22.0% respectively. Statin treatment was used by 85 (92.4%) patients with definite/probable FH; 38 (95.0%) with possible FH and in 3621 (92.9%) with unlikely FH (p=0.86). Adding ezetimibe to statins was more frequently observed in FH patients, 31.5% vs 17.5% vs 9.5% (p<0.0001). Atorvastatin was the most prescribed statin overall, however in patients with definite/probable FH rosuvastatin was used more frequently. This study illustrates the high prevalence of FH patients in a cohort of CAD patients. Overall 1 in 30 patients were classified as FH and 1 in 45 as definite/probable FH. Only a small number of FH patients received the recommended dosages of lipid lowering drugs and or reached the guideline formulated target of LDL-c <70 mg/dl. This study re-enforces the importance to intensify efforts to identify and adequately manage FH patients.   
De Luca L, Arca M, Temporelli PL et al. Prevalence and Pharmacologic Management of Familial Hypercholesterolemia in an Unselected Contemporary Cohort of Patients With Stable Coronary Artery Disease. Clin Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30039543
 
Lifestyle important in patients using drugs to manage lipids and hypertension  
The interactions between healthy lifestyle and pharmacological management of risk factors were explored in the HOPE-3 trial. The effects of 4 basic healthy lifestyle parameters (nonsmoking status, physical activity, optimal body weight, and healthy diet) were matched with lipid management using rosuvastatin and/or blood pressure management with candesartan/hydrochlorothiazide. The 12 521 participants were followed for a period of 5.6 years and outcomes were defined as composite of CVD events. Overall the adherence to ≥2 healthy lifestyle factors (HLF) offered better protection from CVD complications as compared to those with fewer HLF, HR: 0.85 (0.73–1.00). Participants using Rosuvastatin and ≥2 healthy lifestyle factors had an HR: 0.74 (0.62–0.90), this was not significantly different when compared to participants with <2 factors, HR: 0.79 (0.61–1.01). Patients that used a combination of rosuvastatin and blood pressure lowering drugs showed very similar results; ≥2 factors, HR: 0.74; (0.57–0.97); <2 factors; HR: 0.61 (0.43–0.88). Only in patients using candesartan/hydrochlorothiazide and no rosuvastatin, benefits were noted in participants with <2 healthy lifestyle factors only; HR: 0.78 (0.61–1.00). These results re-emphasize the importance of healthy lifestyle in combination with the pharmacological treatment of dyslipidemia and hypertension. Only in patients that used candesartan/hydrochlorothiazide benefits were observed in patients that had fewer HLF’s.
Dagenais GR, Jung H, Lonn E et al. Effects of Lipid-Lowering and Antihypertensive Treatments in Addition to Healthy Lifestyles in Primary Prevention: An Analysis of the HOPE-3 Trial. J Am Heart Assoc 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30033433
 
Majority of very-high risk diabetic patients are not reaching LDL-c targets
Determining how well guidelines are implemented when caring for very-high risk patients in clinical practice was studied in this prospective cohort. Diabetic patients (N=654) from the Nutrition-Diabetes unit of Montpellier University Hospital in France were recruited to participate between 2014 and 2017. Patients were diagnosed with type 1 (N=131) or type 2 (N=556) diabetes and had a very-high cardiovascular risk, based on 2016 ESC guidelines. The mean age was 63.8 years, 41.9% were women and 42.3% had a history of CVD. Only patients using statins, were included.  Only 41% of these very high-risk diabetic patients reached the ESC guideline dictated LDL-c target of <1.8 mmol/ (70 mg/dl). Patients at target had a median LDL-c of 1.4 mmol/l (interquartile range 1.1-1.6) vs 2.4 mmol/l (2.1-2.9) in patient not at target. Patient with a CVD history were less likely to not-attain the LDL-c target, OR 0.64 (0.45-0.89) in patients with CAD; OR 0.59 (0.33-1.07), patients that suffered a stroke or TIA. Women had higher risk not to be optimally treated OR 2.27 (1.62-3.17). The gap between recommended and observed LDL-c level in very high-risk diabetic patients is exposed in this study. The findings support the notion that greater efforts are needed to ensure adequate lipid management in diabetic patients, with a special emphasis on women, in whom CVD risk may be still be underestimated.
Breuker C, Clement F, Mura T et al. Non-achievement of LDL-cholesterol targets in patients with diabetes at very-high cardiovascular risk receiving statin treatment: Incidence and risk factors. Int J Cardiol 2018; 268:195-199. http://www.ncbi.nlm.nih.gov/pubmed/?term=30041785
Relevant publications
  1. Galan I, Verdalles U, Garcia de Vinuesa M et al. Impact of the application of the JNC 8 and KDIGO-2013 guidelines on hypertension and lipid control in a Nephrology outpatient clinic. Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia 2018; 38:379-385. http://www.ncbi.nlm.nih.gov/pubmed/?term=30032855
  2. Zhang X, Wen J, Zhang Z. Statins use and risk of dementia: A dose-response meta analysis. Medicine (Baltimore) 2018; 97:e11304. http://www.ncbi.nlm.nih.gov/pubmed/?term=30045255
  3. Walther CP, Richardson PA, Virani SS et al. Association between intensity of statin therapy and mortality in persons with chronic kidney disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30053252
  4. Seyam E, Hefzy E. Long-term effects of combined simvastatin and metformin treatment on the clinical abnormalities and ovulation dysfunction in single young women with polycystic ovary syndrome. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2018:1-8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30044162
  5. Murtola TJ, Syvala H, Tolonen T et al. Atorvastatin Versus Placebo for Prostate Cancer Before Radical Prostatectomy-A Randomized, Double-blind, Placebo-controlled Clinical Trial. European urology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30031572
  6. Mohammad S, Nguyen H, Nguyen M et al. Pleotropic Effects of Statins: untapped potential for statin pharmacotherapy. Current vascular pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30033872
  7. Lyons SK, Boyle CT, DeSalvo DJ et al. Dyslipidemia and statin use in youth and adults ages 10-<40 years in the T1D Exchange Clinic Registry. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30039636
  8. Kodera S, Morita H, Kiyosue A et al. Cost-Effectiveness of PCSK9 Inhibitor Plus Statin in Patients With Triple-Vessel Coronary Artery Disease in Japan. Circulation journal : official journal of the Japanese Circulation Society 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30033948
  9. Janssen VE, Visseren FL, de Boer A et al. Combined use of polypill components in patients with type 2 diabetes mellitus. Eur J Prev Cardiol 2018:2047487318789494. http://www.ncbi.nlm.nih.gov/pubmed/?term=30033753
  10. Braekkan SK, Caram-Deelder C, Siegerink B et al. Statin use and risk of recurrent venous thrombosis: results from the MEGA follow-up study. Research and practice in thrombosis and haemostasis 2017; 1:112-119. http://www.ncbi.nlm.nih.gov/pubmed/?term=30046679
  11. Bobrovitz N, Heneghan C, Onakpoya I et al. Medications that reduce emergency hospital admissions: an overview of systematic reviews and prioritisation of treatments. BMC Med 2018; 16:115. http://www.ncbi.nlm.nih.gov/pubmed/?term=30045724
  12. Potluri R, Carter PR, Lavu D, Bainey KR. The interplay between cholesterol and breast cancer: is there a potential role for statin therapy? Future oncology (London, England) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30051723
  13. Mora S, Wenger NK, Cook NR et al. Evaluation of the Pooled Cohort Risk Equations for Cardiovascular Risk Prediction in a Multiethnic Cohort From the Women's Health Initiative. JAMA Intern Med 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30039172
  14. Karsanidze A, Antelava N, Gorgasledze N et al. STATIN-ASSOCIATED INTOLERANCE AND ITS PREVENTION. Georgian medical news 2018:155-161. http://www.ncbi.nlm.nih.gov/pubmed/?term=30035739
  15. Fukumoto Y. Impact of statin-ezetimibe combination in chronic kidney disease. Int J Cardiol 2018; 268:36-37. http://www.ncbi.nlm.nih.gov/pubmed/?term=30041796
  16. Camacho L, Zabala-Letona A, Carracedo A. Re-evaluating statin activity in cancer. Aging 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30036187
  17. Badescu C, Rezus E, Badescu L et al. New Drugs for Lowering LDL-Cholesterol. Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi 2016; 120:485-490. http://www.ncbi.nlm.nih.gov/pubmed/?term=30044561
Miscellaneous publications
 
 
  1. Zhou J, Gao X, Huang S et al. Simvastatin Improves the Jaw Bone Microstructural Defect Induced by High Cholesterol Diet in Rats by Regulating Autophagic Flux. BioMed research international 2018; 2018:4147932. http://www.ncbi.nlm.nih.gov/pubmed/?term=30050930
  2. Tripathi DM, Vilaseca M, Lafoz E et al. Simvastatin Prevents Progression of Acute on Chronic Liver Failure in Rats With Cirrhosis and Portal Hypertension. Gastroenterology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30055171
  3. Lu YW, Zhu YC, Zhang L et al. Ilexgenin A enhances the effects of simvastatin on non-alcoholic fatty liver disease without changes in simvastatin pharmacokinetics. Chinese journal of natural medicines 2018; 16:436-445. http://www.ncbi.nlm.nih.gov/pubmed/?term=30047465
  4. Ishikawa T, Hosaka YZ, Beckwitt C et al. Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics. Oncotarget 2018; 9:29304-29315. http://www.ncbi.nlm.nih.gov/pubmed/?term=30034619
  5. Ho YR, Lin CH, Kuo CY. The protective effect of simvastatin against ultraviolet B-induced corneal endothelial cell death. Indian journal of ophthalmology 2018; 66:1080-1083. http://www.ncbi.nlm.nih.gov/pubmed/?term=30038146
  6. Abdanipour A, Deheshjo F, Sohrabi D et al. Neuroprotective effect of lovastatin through down-regulation of pro-apoptotic Mst1 gene expression in rat model pilocarpine epilepsy. Neurol Res 2018:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30048231
  7. Veerabrahma K, Katla VM. Improvement of anti-hyperlipidemic activity and oral bioavailability of Fluvastatin via solid self-microemulsifying systems and comparative with liquisolid formulation. Current drug delivery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30033871
  8. Subhan M, Faryal R, Macreadie I. Statin resistance in Candida glabrata. Biotechnology letters 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30054755
  9. Li J, Yang M, Xu W. Development of novel rosuvastatin nanostructured lipid carriers for oral delivery in an animal model. Drug design, development and therapy 2018; 12:2241-2248. http://www.ncbi.nlm.nih.gov/pubmed/?term=30050285
  10. Kong R, Zhu X, Meteleva ES et al. Atorvastatin calcium inclusion complexation with polysaccharide arabinogalactan and saponin disodium glycyrrhizate for increasing of solubility and bioavailability. Drug delivery and translational research 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30039497
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