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Update - Week 39,  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

Can Co-Q10 reverse statin induced mitochondrial dysfunction?
The statin related muscle side effects have been linked to impaired mitochondrial function caused by a depletion of downstream metabolites in the cholesterol synthesis pathway. In this experimental design study healthy volunteers were treated with simvastatin 40 mg for 8 weeks. After 4 weeks subjects were randomized to ubiquinol (Co-enzyme Q10) 300mg/day. Mitochondrial (dys)function was evaluated by measuring phosphocreatine recovery time (τ-PCr) using phosphorous Magnetic Resonance Spectroscopy (31PMRS) after in-magnet exercise. All participants showed a mean increase in τ-PCr of 15.2% (2.5–29.4%; P = 0.018), compared to baseline. At study completion the τ-PCr further increased in the placebo group: 37.27 s; a mean increase of 18.5% (1.1–38.9%; P = 0.037). In the ubiquinol group there was an attenuated increase in τ-PCr of 33.81 s; a mean increase of 9.1% (−7.9 to 29.2%; P = 0.31). In the placebo group the τ-PCr was significantly different from baseline at 8 weeks. No difference between baseline and 8 weeks measurements in the active treatment arm. The observed τ-PCr difference between the two groups was not statistical significant, 8.2% (−14.5 to 37.0%; P = 0.51). The authors concluded that simvastatin treatment can impair mitochondrial function even in healthy subjects and this attenuation can be partly reversed by ubiquinone 300 mg/day treatment.
van Diemen MPJ, Berends CL, Akram N et al. Validation of a pharmacological model for mitochondrial dysfunction in healthy subjects using simvastatin: A randomized placebo-controlled proof-of-pharmacology study. Eur J Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28943100
 
Do statins protect high risk Japanese patients with low plasma LDL-c?
Using data collected in the Japanese National Health and Nutrition Examination Survey 1999−2010, 1 500 high CVD-risk patients with LDL-c levels < 120 mg/dl (mean LDL-c 88.7 mg/dl) were evaluated. Using a Cox proportional hazards models unadjusted and multivariable-adjusted hazard ratios were calculated. There was a significant lower risk in patients using statins for all-cause mortality; HR: 0.62 (0.45-0.85; P=0.004). Patients with LDL-c <100 mg/dl the risk for total mortality was significantly reduced as well; HR: 0.50 (0.34-0.74; P=0.001). In patients with LDL-c <70mg/dl no significant difference was observed when compared to patients with LDL-c 70-120 mg/dl; HR 1.27 (0.72-2.10; P=0.35). Patients with moderately to high risk of CVD showed similar outcomes. Despite the limitations of the observational design of this study, the robustness of the collected data and the use of various statistical analyses makes a good case for initiating statin treatment in patients with an LDL-C <120 mg/dl but moderate to high CVD risk. Therefore, the authors emphasized the need for of large-scale and long-term follow-up studies and RCTs to confirm the results of the present study.
Tsujimoto T, Kajio H, Sugiyama T. Statin Therapy in Patients With Low Serum Levels of Low-Density Lipoprotein Cholesterol. Am J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28951019
 
The comeback of the new kid on the block: hsCRP
The role of hsCRP as a risk predictor has been controversial with a greater acceptance in North America and more skepticism in Europe. The recently published CANTOS trial rekindled the debate on the role of hsCRP in CVD risk. In this article the role of hsCRP not only as a risk marker but its association with health status is examined in 3 410 post AMI patients. Using data collected in two large prospective US - AMI registries, TRIUMPH (N=1301) and VIRGO (N=2109). Patients with elevated hsCRP (>2 mg/dl) were compared with those that had a low hsCRP (<2mg/dl). The 30-day hsCRP levels were compared with the 1-year health status (based on 3 validated questionnaires). Most patients (92%) were using statins after hospital discharge and the median 30-day hs CRP levels was 2.6 mg/dl (25th and 95th percentile: 1.1-6.1 mg/dl). In the un-adjusted and partly-adjusted models (based on co-morbidities) the 30-day hsCRP> 2mg/dl was inversely related to 1-year health status. No significant difference was observed in the fully-adjusted model. Based on this finding the authors concluded that hs-CRP is a marker of co-morbidities associated with worse health status one year after AMI. If reduction of hs-CRP – inflammation will improve health status needs to be evaluated in trials that exclusively target inflammation like the CANTOS study and ongoing studies that are using low dose methotrexate and colchicine.
Pokharel Y, Sharma PP, Qintar M et al. High-sensitivity C-reactive protein levels and health status outcomes after myocardial infarction. Atherosclerosis 2017; 266:16-23. http://www.ncbi.nlm.nih.gov/pubmed/?term=28946036
 
Taiwanese sepsis patients using statins lived longer – Observational analysis of 52 737 patients
The potential benefits of statins in serious life-threatening conditions like sepsis is discussed in this retrospective observational Taiwanese study using data collected in the National Health Insurance Research Database (2001 – 2011). Data from 53 737 of sepsis patients were appraised. Patient included were using statins >30 day prior to the sepsis admission (n=3 598) and only patients that were using atorvastatin (N=1 855), rosuvastatin (N=732) and simvastatin (N=916) were entered. Sepsis outcome was evaluated by using a Cox model and a propensity score (PS) matched model. The latter by using 1:1:1 PS matching technique. When comparing the patients not using statins with simvastatin and atorvastatin their respective HR’s for the primary endpoint of this study, the 30-day survival, improved; HR: 0.72, (0.58-0.90) and HR: 0.78 (0.68-0.90) respectively. The survival benefits at 90 days were somewhat attenuated but remained significant. This was not observed in patients using rosuvastatin; HR: 0.87 (0.73-1.04). When applying rosuvastatin as the reference population both atorvastatin: HR 0.79 (0.64-0.99) and simvastatin: HR 0.77 (0.59-0.99) showed a better survival. The authors suggest that non-lipid lowering effects of statins are responsible for the observed improved survival. In experimental, animal studies preservation of cardiac function, attenuation of inflammatory cytokines and neutrophil infiltration in the lung and inhibiting T-cell dysfunction were observed. Atorvastatin, pravastatin, rosuvastatin but particular simvastatin seem to have direct anti-microbial and anti-virulence effects as well, that could contribute and to some extend explain the observed benefits.
Lee CC, Lee MG, Hsu TC et al. A population-based cohort study on the drug specific effect of statins on sepsis outcome. Chest 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28962887
 
Expert opinion prioritizing lipid management in Asian diabetic patients
This review by one of Hong Kong’s leading diabetologists, Julia Chan aims to addresses the anticipated increase in the prevalence and incidence of DM2 in Asia. The combined cardio-renal organ complications observed in diabetics will create a tremendous strain on the health care system and will have serious health budget consequences as well. The emphasis of recent guidelines to initiate lipid lowering treatment solely based on absolute risk estimation, instead of LDL-C targets, has not been widely implemented in clinical practice. Especially in patients with diabetes, reflecting very high CVD risk, treatment strategies should facilitate starting early with guideline indicated medications. In Asian diabetic patients the risk of developing renal disease seems to be enhanced and the augmented effects on ASCVD puts an even greater emphasis on using the appropriate statin (high intensity) and (high) dose. Of note, due to the difference in drug metabolism observed in Asian patients, rosuvastatin should be prescribed in low dosages (5-10 mg) in patients of this ethnic background. The authors prioritize the use of moderate- to high-intensity statins such as simvastatin 20-40 mg and Atorvastatin 10-40 mg. Atorvastatin based on the proven safety in Asian populations plus the pleiotropic and organ protective effects, as shown in epidemiological and experimental studies as well as the recent UK NICE guidelines, is an attractive (first) choice. Having a pro-active lipid management approach in Asian diabetic patients can have a significant impact in reducing diabetes CKD and ASCVD related complications. A simple and cost-effective strategy to reduce the substantial burden of diabetes in Asia.   
Lau TW, Tan KE, Choo JC et al. Regional Evidence and International Recommendations to Guide Lipid Management in Asian Patients with Type 2 Diabetes with Special Reference to Renal Dysfunction. Journal of diabetes 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28960806
 
Statin related muscle side effects remains a riddle wrapped in a mystery inside an enigma!
In this article the authors pondered the question if statin lipophilicity as compared to hydrophilicity, could help us to better understand the statin associated muscle symptoms (SAMS) phenomenon. They conducted a meta-analysis according to the universally accepted PRISMA guidelines. From the initial 5 545 studies 135 RCT’s were included in this meta-analysis, 129 had parallel and 6 a cross-over design. Sixteen trials were not double blinded and in 86 stated that they were randomized, but the method of sequence generation for randomization was not provided. In total 192 977 patients were treated with statins and 92 546 received placebo or usual care. Adverse muscle symptoms were observed in 8 755 statin treated patients and 7 885 placebo/usual care participants. Statin use showed a small risk increase for SAMS compared to placebo RR = 1.050 (1.014–1.089; P = 0.007). No additional risk for the use of lipophilic statins compared to hydrophilic statins or high dose compared to lows dose could be determined. In the overall analysis the increased risk of SAMS in statin users were mostly observed in patients with a history of statin intolerance. The authors concluded that there was very limited evidence pointing towards an increases SAMS risk in patients using lipophilic and/or high dose as compared to hydrophilic and low dose statins.
Irwin JC, Khalesi S, Fenning AS, Vella RK. The effect of lipophilicity and dose on the frequency of statin-associated muscle symptoms: A systematic review and meta-analysis. Pharmacol Res 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28943224
Relevant publications
  1. Zhou Z, Albarqouni L, Breslin M et al. Statin-associated muscle symptoms (SAMS) in primary prevention for cardiovascular disease in older adults: a protocol for a systematic review and meta-analysis of randomised controlled trials. BMJ Open 2017; 7:e017587. http://www.ncbi.nlm.nih.gov/pubmed/?term=28963307
  2. Ofori-Asenso R, Jakhu A, Zomer E et al. Adherence and Persistence among Statin Users aged 65 years and over: A Systematic Review and Meta-analysis. J Gerontol A Biol Sci Med Sci 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28958039
  3. Messas N, Dube MP, Tardif JC. Pharmacogenetics of Lipid-Lowering Agents: an Update Review on Genotype-Dependent Effects of HDL-Targetingand Statin Therapies. Curr Atheroscler Rep 2017; 19:43. http://www.ncbi.nlm.nih.gov/pubmed/?term=28944433
  4. Margaritis M, Sanna F, Antoniades C. Statins and oxidative stress in the cardiovascular system. Current pharmaceutical design 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28950822
  5. Jung KY, Kim KM, Han SK et al. Effect of Rosuvastatin on Cholesterol Efflux Capacity and Endothelial Function in Type 2 Diabetes Mellitus and Dyslipidemia. Circulation journal : official journal of the Japanese Circulation Society 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28943594
  6. Filippatos TD, Kei A, Elisaf MS. Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias? Diseases (Basel, Switzerland) 2017; 5. http://www.ncbi.nlm.nih.gov/pubmed/?term=28961179
  7. Christensen JJ, Ulven SM, Retterstol K et al. Comprehensive lipid and metabolite profiling of children with and without familial hypercholesterolemia: A cross-sectional study. Atherosclerosis 2017; 266:48-57. http://www.ncbi.nlm.nih.gov/pubmed/?term=28963918
  8. Bartlett LE, Pratt N, Roughead EE. Does a fixed dose combination of amlodipine and atorvastatin improve persistence to therapy in the Australian population? Current medical research and opinion 2017:1-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=28945105
  9. Wan Q, Li L, Yang S, Chu F. Impact of Statins on Arteriovenous Fistulas Outcomes: A Meta-Analysis. Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28960860
  10. Waiyaput W, Pumipichet S, Weerakiet S et al. Effect of simvastatin on monocyte chemoattractant protein-1 expression in endometriosis patients: a randomized controlled trial. BMC women's health 2017; 17:89. http://www.ncbi.nlm.nih.gov/pubmed/?term=28950844
  11. Tokgozoglu L. [Efficacy of pitavastatin on HDL-cholesterol]. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:5-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=28952471
  12. Takahashi EA, Kallmes DF, Fleming CJ et al. Predictors and Outcomes of Postcontrast Acute Kidney Injury after Endovascular Renal Artery Intervention. Journal of vascular and interventional radiology : JVIR 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28947366
  13. Soden PA, Zettervall SL, Deery SE et al. Black patients present with more severe vascular disease and a greater burden of risk factors than white patients at time of major vascular intervention. Journal of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28951156
  14. Siriangkhawut M, Tansakul P, Uchaipichat V. Prevalence of potential drug interactions in Thai patients receiving simvastatin: The causality assessment of musculoskeletal adverse events induced by statin interaction. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 2017; 25:823-829. http://www.ncbi.nlm.nih.gov/pubmed/?term=28951665
  15. Sansoy V. [The efficacy and safety of pitavastatin]. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:1-4. http://www.ncbi.nlm.nih.gov/pubmed/?term=28952470
  16. Pichardo-Almarza C, Diaz-Zuccarini V. Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach. Frontiers in pharmacology 2017; 8:635. http://www.ncbi.nlm.nih.gov/pubmed/?term=28955237
  17. Kayikcioglu M. [Cardiovascular prevention and pitavastatin]. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:8-12. http://www.ncbi.nlm.nih.gov/pubmed/?term=28952472
  18. Janic M, Lunder M, France Stiglic A et al. Sub-therapeutic doses of fluvastatin and valsartan are more effective than therapeutic doses in providing beneficial cardiovascular pleiotropic effects in rats: A proof of concept study. Vascul Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28951255
  19. Elena C, Cristina C, Salvatore T et al. A severe myopathy case in aged patient treated with high statin dosage. Toxicology reports 2017; 4:438-440. http://www.ncbi.nlm.nih.gov/pubmed/?term=28959671
  20. Cherkas Y, McMillian MK, Amaratunga D et al. ABC gene-ranking for prediction of drug-induced cholestasis in rats. Toxicology reports 2016; 3:252-261. http://www.ncbi.nlm.nih.gov/pubmed/?term=28959545
  21. Carmo M, Barbetta I, Bissacco D et al. Development and validation of a score to predict life expectancy after carotid endarterectomy in asymptomatic patients. Journal of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28943008
  22. Beyaz S, Ukinc K. [Pitavastatin and new diabetes development]. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:13-15. http://www.ncbi.nlm.nih.gov/pubmed/?term=28952473
  23. Anand K, Sketris I, Zhang Y et al. The Impact of US FDA and Health Canada Warnings Related to the Safety of High-dose Simvastatin. Drugs - real world outcomes 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28956294
  24. Alburikan KA, Nazer RI. Use of the guidelines directed medical therapy after coronary artery bypass graft surgery in Saudi Arabia. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 2017; 25:819-822. http://www.ncbi.nlm.nih.gov/pubmed/?term=28951664
Miscellaneous publications
  1. Zhou Q, Luo A, Kummerow FA. Lovastatin reversed the enhanced sphingomyelin caused by 27-hydroxycholesterol in cultured vascular endothelial cells. Biochemistry and biophysics reports 2016; 5:127-133. http://www.ncbi.nlm.nih.gov/pubmed/?term=28955814
  2. Zandl-Lang M, Fanaee-Danesh E, Sun Y et al. Regulatory effects of simvastatin and apoJ on APP processing and amyloid-beta clearance in blood-brain barrier endothelial cells. Biochim Biophys Acta 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28941799
  3. Tse DY, Kim SJ, Chung I et al. The ocular toxicity and pharmacokinetics of simvastatin following intravitreal injection in mice. International journal of ophthalmology 2017; 10:1361-1369. http://www.ncbi.nlm.nih.gov/pubmed/?term=28944193
  4. Nasoohi S, Simani L, Khodagholi F et al. Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin. Nutritional neuroscience 2017:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=28946820
  5. Gouda A, Helal E, Ali S et al. Maxillary sinus lift using osteoinductive simvastatin combined with beta-TCP versus beta-TCP - a comparative pilot study to evaluate simvastatin enhanced and accelerated bone formation. Acta odontologica Scandinavica 2017:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=28952824
  6. Zhao W, Li J, He X et al. In vitro steatosis hepatic cell model to compare the lipid-lowering effects of pomegranate peel polyphenols with several other plant polyphenols as well as its related cholesterol efflux mechanisms. Toxicology reports 2014; 1:945-954. http://www.ncbi.nlm.nih.gov/pubmed/?term=28962306
  7. Zaid AN, Shtayah R, Qadumi A et al. Stability of extemporaneously prepared rosuvastatin oral suspension. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 2017; 74:1579-1583. http://www.ncbi.nlm.nih.gov/pubmed/?term=28947528
  8. Nurullahoglu-Atalik KE, Kutlu S, Solak H, Koca RO. Cilostazol enhances atorvastatin-induced vasodilation of female rat aorta during aging. Physiology international 2017; 104:226-234. http://www.ncbi.nlm.nih.gov/pubmed/?term=28956637
  9. Leone G, Consumi M, Pepi S et al. Alginate-gelatin formulation to modify lovastatin release profile from red yeast rice for hypercholesterolemia therapy. Therapeutic delivery 2017; 8:843-854. http://www.ncbi.nlm.nih.gov/pubmed/?term=28944737
  10. Guo JE, Mi SB, Yan XC et al. [Effects of Gualou Xiebai Banxia decoction on blood lipid content, oxidative stress and ox-LDL/Lox-1 pathway in ApoE-/- mice]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 2017; 42:752-757. http://www.ncbi.nlm.nih.gov/pubmed/?term=28959848
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This activity is supported by an educational grant from Pfizer.