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Update - Week 22, 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

Statin related new onset diabetes modifiable by fitness
New onset diabetes (NOD) is one of the important factors that potentially hampers initiation and adherence to statins in patient with a high CVD risk. The authors of this paper aimed to evaluate the benefits of cardio-respiratory fitness and NOD in dyslipidemic patients of a Veterans Affairs medical center in Washington DC and Palo Alto California. All had a normal exercise test between 1986 and 2014. Statin use was observed in 4 092 patients, mean age 58.8 years (±10.9). No diabetes was present at time of statin prescription. The group was divided in 4 fitness categories: Least-, low-, moderate- and high-fit. Controls were the 3 001 non-statin users, age 57.2 years (±11.2). Overall the statin-users were more likely to develop DM2, an increase of 24% between users and not users. The degree of fitness was strongly associated with this unwanted side-effect. When comparing the high-fit patients with the least-fit group their risk was 34% lower (HR: 0.66; 95% - CI 0.53-0.82; p<0.001). Only in the least-fit and the low-fit group was there a significant increased risk of developing NOD compared with the no-statin control group, with a HR of 1.5 (95% - CI 1.3-1.73; p<0.001) and a HR of 1.22 (95% - CI 1.06-1.41; p=0.006), respectively. The authors concluded that cardio respiratory fitness was an important (modifiable) factor in patients that developed NOD while using statins.
Kokkinos P, Faselis C, Narayan P et al. Cardiorespiratory Fitness and Incidence of Type 2 Diabetes in United States Veterans on Statin Therapy. Am J Med 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28552431
Atorvastatin 20 mg + ezetimibe 10 mg superior to atorvastatin 40 mg in post ACS patients
Combining simvastatin with ezetimibe proved a safe and effective strategy in post ACS patients as demonstrated in the IMPROVE-IT study. In this small open label prospective follow-up study, conducted in Tbilisi - Georgia, 323 patients hospitalized for an ACS were treated with atorvastatin 20 mg. If after 28 days patients had an LDL-C > 1.81 mmol/l, they would be randomized to co-administration of Ezetimibe 10 mg (N=136) or doubling of the atorvastatin dosage (N=127). Overall 228 patients were randomized and evaluated for major cardiovascular endpoints after 16 weeks. Event free survival was observed in 88.1% of the patients on combinations treatment vs. 77.0% in patients that doubled their atorvastatin dosage; reflected by a HR of 2.1 (95% CI 1.165-3.781; p=0.014). No difference was observed between male and female participants. The observed results showed the benefit of the addition of Ezetimibe10 mg  to a standard dosage of 20 mg atorvastatin, compared to doubling the dosages of atorvastatin to 40 mg. This was reflected in improved event free survival as well as lower LDL-C levels achieved of 1.60 mmol/l vs 1.91 mmol/l respectively. No difference between males and females could be determined, but the number of participants was small. As in IMPROVE-IT atorvastatin 20 mg + ezetimibe 10 mg showed better survival compared to 40 mg of atorvastatin after, a short 16-week evaluation period. The improved outcome is most likely related to the lower LDL-C achieved in patients using the combination of atorvastatin 20 mg + ezetimibe 10 mg.  Japaridze L, Sadunishvili M. The short term effect of atorvastatin plus ezetimibe therapy vs. atorvastatin monotherapy on clinical outcome in the acute coronary syndrome patients by gender. Kardiol Pol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28553847
In hemodialysis patients statins could reduce ESA hypo-responsiveness
Japanese investigators evaluated the effects of statins on erythropoiesis-stimulating agent (ESA) hypo-responsiveness. The retrospectively analyzed data of 3 602 hemodialysis patients that were receiving dialysis in 60 Japanese dialysis centers. Patients participated in the Japan Dialysis Outcomes and Practice Patterns Study phases 3–5 (2005–2015). Baseline statin use was observed in 585 (16.2%) of the patients; 12.8% were classified as having ESA hypo-responsiveness after 4 months of follow-up. There was a non-significant difference with an OR of 0.87 (95% CI 0.66-1.15) and a significant reduced ESA resistance index (ERI) ; OR 0.94 (95% CI 0.89-0.99). The Authors concluded that their results support the hypothesis that statins may reduce ESA hypo-responsiveness in HD patients, but the magnitude of the adjusted association was small and that further investigations are needed in different populations.  
Hasegawa T, Zhao J, Fuller DS et al. Erythropoietin Hyporesponsiveness in Dialysis Patients: Possible Role of Statins. Am J Nephrol 2017; 46:11-17. http://www.ncbi.nlm.nih.gov/pubmed/?term=28564644
Dyslipidemic NAFLD patients using statins improved biochemical as well as histological markers
NAFLD is gaining momentum in terms of numbers of affected patients. Obesity and type 2 diabetes are contributing factors related to this rising incidence. Statins in general and atorvastatin in particular are emerging as a potential treatment for condition. In this paper, the authors compared the effect of atorvastatin 20 mg, in 57 dyslipidemic patients vs pentoxifylline 800 mg in 41 non-dyslipidemic patients). All patients were diagnosed with histological confirmed NAFLD and followed for ± 8 months. In the Atorvastatin group significant reductions of ALT, AST, GGT, TC, AP and TG levels (P<0.0001) were achieved, as well as the extent of steatosis. Histologically, no changes in fibrosis and necro-inflammation could be detected. For the non-dyslipidemic patients using pentoxifylline, similar improvements were noted for ALT, AST and GGT (P<0.05), but not for AP, TC and TG. Improvement of one or more components of the NAS score were only observed in the atorvastatin group, and attenuation of fibrosis was not realized in either group. The necro-inflammation score improved only in the Pentoxifylline patients. The overall NAS score improvement was highly significant in the atorvastatin group (P=0.00007), but borderline significant in the Pentoxifylline patients (p=0.04073). The authors concluded that statins may have potential to improve some of the histological features of NAFLD.
Cioboata R, Gaman A, Trasca D et al. Pharmacological management of non-alcoholic fatty liver disease: Atorvastatin versus pentoxifylline. Experimental and therapeutic medicine 2017; 13:2375-2381. http://www.ncbi.nlm.nih.gov/pubmed/?term=28565851
Starting statins in patients with pre-diabetes/T2DM + NASH did not result in worsening of liver pathology or insulin resistance
To evaluate the safety of statins in pre-diabetic patients the authors performed a post-hoc analysis of a trial that evaluated the effects of pioglitazone vs placebo in patients with NASH. A total of 101 subjects (86 on statins) with biopsy proven NASH and pre-diabetes/T2DM were followed for 36 months. At 18 and 36 months patients had an oral glucose tolerance test and percutaneous liver biopsy.  A liver 1HMRS and euglycemic insulin clamp with measurement of glucose turnover were performed at baseline and after 18 months. Statins use was observed in only 37% of these high-risk patients! No worsening of liver histology or hepatic insulin resistance was observed in the patients that started statin therapy plus placebo during the main RCT with Pioglitazone. The authors concluded that statin use did not contribute to any detrimental effects in patients with NASH and pre-diabetes/T2DM.
Bril F, Portillo Sanchez P, Lomonaco R et al. Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic Steatohepatitis: Post-hoc Analysis of a Randomized Trial. J Clin Endocrinol Metab 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28575232

Relevant publications
  1. Sinning D, Landmesser U. [Update Dyslipidaemias - Comments on the 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias]. Deutsche medizinische Wochenschrift (1946) 2017; 142:816-820. http://www.ncbi.nlm.nih.gov/pubmed/?term=28564733
  2. Sehra D, Sehra S, Sehra ST. Cardiovascular pleiotropic effects of statins and new onset diabetes: is there a common link: do we need to evaluate the role of KATP Channels? Expert opinion on drug safety 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28571494
  3. Sbrana F, Dal Pino B, Bigazzi F et al. Statin intolerance in heterozygous familial hypercolesterolemia with cardiovascular disease: After PCSK-9 antibodies what else? Eur J Prev Cardiol 2017:2047487317712419. http://www.ncbi.nlm.nih.gov/pubmed/?term=28555526
  4. Raphael J, Collins SR, Wang XQ et al. Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28552627
  5. Pandey AS, Bajaj HS, Garg V et al. The emerging role of proprotein convertase subtilisin/kexin type-9 inhibition in secondary prevention: from clinical trials to real-world experience. Current opinion in cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28557865
  6. Lin H, Zhang YM. The effect of Ezetimibe and Simvastatin Combination Therapy on percutaneous coronary intervention patients. Int J Cardiol 2016. http://www.ncbi.nlm.nih.gov/pubmed/?term=28550977
  7. Hennig M, Brandt A, Bautembach-Minkowska J et al. When do paediatric patients with familial hypercholesterolemia need statin therapy? Developmental period medicine 2017; 21:43-50. http://www.ncbi.nlm.nih.gov/pubmed/?term=28551692
  8. Cohen JD, Cziraky MJ, Jacobson TA et al. Barriers to PCSK9 inhibitor prescriptions for patients with high cardiovascular risk: Results of a healthcare provider survey conducted by the National Lipid Association. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28550993
  9. Whayne TF, Jr. Is There an Ideal Low-Density Lipoprotein Cholesterol Level? Confusion regarding Lipid Guidelines, Low-Density Lipoprotein Cholesterol Targets, and Medical Management. Int J Angiol 2017; 26:73-77. http://www.ncbi.nlm.nih.gov/pubmed/?term=28566931
  10. Bedi P, Chalmers JD, Graham C et al. A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study. Chest 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28554732
  11. Rosenson RS, Farkouh ME, Mefford M et al. Trends in Use of High-Intensity Statin Therapy After Myocardial Infarction, 2011 to 2014. J Am Coll Cardiol 2017; 69:2696-2706. http://www.ncbi.nlm.nih.gov/pubmed/?term=28571633
  12. Raparelli V, Pannitteri G, Todisco T et al. Treatment and Response to Statins: Gender-related Differences. Curr Med Chem 2016. http://www.ncbi.nlm.nih.gov/pubmed/?term=28552051
  13. Quinn AG, Schwemberger R, Stock EO et al. Moderate statin treatment reduces prebeta-1 high-density lipoprotein levels in dyslipidemic patients. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28558949
  14. Ports WC, Fayyad R, DeMicco DA et al. Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis. Clinical drug investigation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28573499
  15. Ovrakh T, Serik S, Kochubiei O. Impact of atorvastatin and rosuvastatin on residual on-clopidogrel treatment platelet reactivity in patients with ischemic heart disease and type 2 diabetes mellitus after acute coronary syndrome. Georgian medical news 2017:7-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=28574378 (Article in Russian)
  16. Marz W, Grammer TB, Delgado G, Kleber ME. [Congenital disorders of lipoprotein metabolism]. Herz 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28555288
  17. Kim TM, Kim H, Jeong YJ et al. The differences in the incidence of diabetes mellitus and prediabetes according to the type of HMG-CoA reductase inhibitors prescribed in Korean patients. Pharmacoepidemiol Drug Saf 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28556206
  18. Donzelli A, Battaggia A, Schivalocchi A. Statin use does not protect from fractures: the healthy adherer effect is a plausible explanation in observational studies. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28555283
  19. Bader AP, Barone CP, Smeds MR. Risk factor modification behaviors of practicing vascular surgeons. Annals of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28572029
  20. An T, Hao J, Sun S et al. Statin treatment and healthy adherer effects. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28555284

Miscellaneous publications
  1. Yu SF, Cheng J, Geng S, Gao S. [Effects of simvastatin on the proliferation, invasion and radiosensitivity in Lewis lung cancer cell line]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 2017; 39:245-249. http://www.ncbi.nlm.nih.gov/pubmed/?term=28550662
  2. Varga Z, Nemcekova M, Carnicka S et al. Naproxen and Diclofenac Attenuate Atorvastatin-induced Preconditioning of the Myocardium. Cureus 2017; 9:e1201. http://www.ncbi.nlm.nih.gov/pubmed/?term=28560127
  3. Peng P, Wei W, Long C, Li J. Atorvastatin augments temozolomide's efficacy in glioblastoma via prenylation-dependent inhibition of Ras signaling. Biochem Biophys Res Commun 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28554840
  4. Mouchrek Junior JCE, Macedo CG, Abdalla HB et al. Simvastatin modulates gingival cytokine and MMP production in a rat model of ligature-induced periodontitis. Clinical, cosmetic and investigational dentistry 2017; 9:33-38. http://www.ncbi.nlm.nih.gov/pubmed/?term=28553143
  5. Liu HY, Zhou J, Tong H et al. Quantitative evaluation of atherosclerotic plaques and intraplaque neovascularization using contrast-enhanced ultrasound after treatment with atorvastatin in rabbits. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2017; 92:277-284. http://www.ncbi.nlm.nih.gov/pubmed/?term=28551548
  6. Li Y, Xian M, Yang B et al. Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells. Stem cell reports 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28552603
  7. Lee SH, Kim DH, Youn YN et al. Effect of Rosuvastatin on Bovine Pericardial Aortic Tissue Valve Calcification in a Rat Subdermal Implantation Model. Korean Circ J 2017; 47:401-408. http://www.ncbi.nlm.nih.gov/pubmed/?term=28567091
  8. Kamata T, Giblett S, Pritchard C. KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment. Blood 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28550040
  9. Doi H, Matsumoto S, Odawara S et al. Pravastatin reduces radiation-induced damage in normal tissues. Experimental and therapeutic medicine 2017; 13:1765-1772. http://www.ncbi.nlm.nih.gov/pubmed/?term=28565765
  10. Whitaker EJ, Alshammari A. Bacteriostatic Effect of Simvastatin on Selected Oral Streptococci in Vitro. Contemporary clinical dentistry 2017; 8:59-63. http://www.ncbi.nlm.nih.gov/pubmed/?term=28566853
  11. Sato T, Mishima E, Mano N et al. Potential drug interactions mediated by renal organic anion transporter OATP4C1. J Pharmacol Exp Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28550055
  12. Martins AF, Frank CDS, Altissimo J et al. Determination of statin drugs in hospital effluent with dispersive liquid-liquid microextraction and quantification by liquid chromatography. Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering 2017:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=28575579
  13. Li Z, Tian L, Liu J et al. Graphene Oxide/Ag Nanoparticles Cooperated with Simvastatin as a High Sensitive X-Ray Computed Tomography Imaging Agent for Diagnosis of Renal Dysfunctions. Advanced healthcare materials 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28564489
  14. Juneja M, Kobelt D, Walther W et al. Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. PLoS biology 2017; 15:e2000784. http://www.ncbi.nlm.nih.gov/pubmed/?term=28570591
  15. Ferri N, Marchiano S, Lupo MG et al. Geranylgeraniol prevents the simvastatin-induced PCSK9 expression: role of the small G protein Rac1. Pharmacol Res 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28554582

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