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Update - Week 31,  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

Substantial residual CVD risk despite statin treatment
Despite the risk reducing effects of high dose statins, residual risk in statin users remains an uncharted challenge. Using data from the (Multi-Ethnic Study of Atherosclerosis) MESA registry, 1014 statin treated adults, free of CAD at baseline, were followed for 11 ±2.8 years (median 12.0 years). ASCVD events were recorded and corrected using standard risk factors as well as biomarkers and AS evaluations. Moderate and high intensity statins were used in 67.7% and 4.8% of the participants. Patients were categorized as having a low (5.3%), intermediate (12.2%), high (60.3%) or very high (22.2%) baseline risk. Age and ethnic background corrected ASCVD event rates (per 1000 person-years) were calculated for men and women separately. Events were recorded in 173 participants (17.1%). The number of events amounted to 4.9 (males and females) in the low as well as the moderate risk category; 19.1 and 14.2 in the males and females respectively, of the high-risk group. In the very high-risk category 35.6 males and 26.7 females suffered an ASCVD event. independent predictors of residual risk were current smoking, family history, diabetes, high-sensitivity C-reactive protein, low-density lipoprotein particle number, carotid intimal medial thickness and Ca-score. Patients who received a moderate or high intensity statin at baseline had a 39% lower risk, compared to low intensity statin users. Increasing the baseline statin dose during follow up resulted in a 62% reduced risk (P<0.01). The authors concluded that residual risk in statin treated patients remains high. Evaluating risk factors, biomarkers and sub-clinical atherosclerosis helps to identify these individuals.
Wong ND, Zhao Y, Quek RGW et al. Residual atherosclerotic cardiovascular disease risk in statin-treated adults: The Multi-Ethnic Study of Atherosclerosis. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28754224
 
Are hepatitis B/C patients protected from cirrhosis by statins?
The effects that statins have on liver cells has changed from damaging to protective. In this meta-analysis, the authors evaluated 6 cohort studies (4 high quality – 2 medium quality) that included 263 573 patients with hepatitis B/C and 38 951 cirrhosis cases. Statin use was associated with a 42% reduction of cirrhosis risk. Asians were more likely to experience these protective effects. There was an accumulative statin dosage effect response whereby every 50-cumulative defined daily dosages (cDDD) decreased the risk of cirrhosis by 11%; OR 0.89 (0.86-0.93; p=0.001). More robust data needs to be generated to confirm these impressive results, but if validated the role of statin in patients with infectious hepatitis will become more prominent and result in the incorporation in practice guidelines for managing patients with chronic hepatitis B and C.
Wang Y, Xiong J, Niu M et al. Statins and the risk of cirrhosis in hepatitis B or C patients: a systematic review and dose-response meta-analysis of observational studies. Oncotarget 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28777739
 
Can statin prevent diabetic foot infections?
Diabetic patients showed reduced diabetic foot infection after using Atorvastatin
In this Iranian case control study 110 diabetic patients with a history of diabetic foot infections (DFI) were matched with 123 diabetic patients without a DFI. There were important differences between the DFI and control group. Smoking was observed in 12.73% of the DFI patients and 3.25% in the control group; P<0.007. Duration of diabetes in the DFI patients amounted to 14.7 ±8.1 years vs 8.2 ±6.8 years in the controls. Atorvastatin was used in 49.1% of the DFI patients and 66.7% of the control group; P=0.007. duration of atorvastatin use was not statistically different (P=0.065) 3.0 ±2.3 years vs 3.7 ±2.6. the primary endpoint, the risk of developing DFI was significantly reduced in the participants that used atorvastatin; OR 0.36 (0.19-0.71; p=0.003). Other factors associated with a statistical significant difference of developing DFI were duration of diabetes (P<0.001) and smoking (P<0.008). Bone involvement, need for surgical intervention and rate of severe DFI were observed less frequently in atorvastatin users but this difference was not statistically significant. Despite the limitations of the observational nature of this study, the results are intriguing and deserve a more detailed exploration in properly designed RCT’s.
Nassaji M, Ghorbani R, Saboori Shkofte H. Previous Atorvastatin Treatment and Risk of Diabetic Foot Infection in Adult Patients: A Case-control Study. Wounds : a compendium of clinical research and practice 2017; 29:196-201. http://www.ncbi.nlm.nih.gov/pubmed/?term=28762948
 
Non-adherent statin users show increased risk of recurrent stroke
Based on the Taiwan National Health Insurance Research Database, Chinese stroke patients discharged with a statin were followed for 1-year to explore the effects of statin discontinuation on stroke recurrence. Overall 45 151 patients were discharged with a statin within 90 days after their qualifying ischemic stroke, between 2001 and 2012. Three categories of patients were evaluated separately; those that discontinued their statin, patients where their statin dose was reduced and individuals that continued their statin as prescribed at discharge. Compared to patients that continued their statins, those that stopped (18%) and those that lowered the original statin (7.0%) dose, their risk of a recurrence increased HR 1.42 (1.28-1.57) and remained the same 0.94 (0.78-1.14) respectively. The authors concluded that stopping statins 3 and 6 months after an ischemic stroke showed an increased risk of recurrence within one year after the initial stroke. Of note no statistical significant increase in hemorrhagic strokes was observed in the patients that continued their statin although there was a numerical decrease of recurrences in patients that lowered their original statin dose and a numerical increase in patients that stopped their statins.
Lee M, Saver JL, Wu YL et al. Utilization of Statins Beyond the Initial Period After Stroke and 1-Year Risk of Recurrent Stroke. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28768645
 
How to treat SAMS; metformin?
Despite the unparalleled success of statins to reduce the risk for ASCVD, a major therapeutic hurdle remains; the statin associated muscle symptoms (SAMS). The authors of this article postulated that the pathophysiological basis of SAMS could be related to mitochondrial dysfunction and activation of muscle specific E3 ubiquitin ligase, atrogin-1. Activation of AMP-activated protein kinase (AMPK) could stimulate atrogin-1 as well. Another mechanism implicated is the Forkhead box protein (FOXO1 and FOXO3a). Alterations in the FOXO pathway are implicated in the increase of new onset of diabetes (NODM), as observed in statin treated patients. Metformin stimulates PPAR-Gamma co-activator 1-alpha and this increases mitochondrial production. It alters the FOXO pathway, but in an antagonistic sense as compared to statins. Combining statins with metformin could theoretically increase mitochondrial function and reduce SAMS and mitigate the increased incidence of NODM. PubMed, MEDLINE, and Scopus were searched for randomized-controlled trials, meta-analyses, and reviews to identify relevant literature related to “statin myopathy”, “AMPK”, “mitochondrial dysfunction”, and “metformin. This resulted in 786 hits. After careful evaluation 32 studies were included in this systematic review. Despite the fact that collective research suggests a potential benefit of metformin on SAMS, no studies or observations could be found to confirm this in a clinical setting. Studies aimed at exploring the potential benefits of combining statins with metformin on the incidence SAMS are needed. Additionally, metformin activates AMPK. This results in an established anti-diabetic, as well as cholesterol lowering effect. The authors conclude that based on their review, studies were statins are combined with metformin are urgently needed to explore the benefits of this complementary pharmacological combination.
Elsaid O, Taylor B, Zaleski A et al. Rationale for investigating metformin as a protectant against statin-associated muscle symptoms. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28764958
 
How many patients need ezetimibe or PCSK9ab to get to target?
This study used a large administrative database of US medical and pharma claims, and included 105 269 patients with ASCVD between January 1, 2012 and December 31, 2013. Patients with LDL-C >70 mg/dl were entered in a simulation model. Patients not on a statin started with atorvastatin 20 mg, they were subsequently up titrated to Atorvastatin 80 mg; add on ezetimibe 10 mg; add-on alirocumab 75 mg and add-on alirocumab 150 mg. Evolocumab was included in the sensitivity analysis. Efficacy data from published studies was used and incorporated at patient-level variation. Data were analyzed from December 2015 to May 2017. Included patients were 57.2% male and had a mean age of 65.1 (12.1) years. The simulation model cohort comprised 1 million patients, 54.8% male and mean age 66.4 (12.2) years. At baseline 51.5% used statin monotherapy; 1.75% used ezetimibe add-on therapy; only 25.2% achieved a target LDL-C of <70mg/dl. Simulation of treatment intensification resulted in 99.3% achieving LDL-C targets; 67.3% with statin monotherapy, 18.7% with statins plus ezetimibe, and 14% with add-on PCSK9 inhibitor. Based on this simulation model estimations, 99.3% of patients could achieve an LDL-C targets <70 mg/dl; 67.3% with statin monotherapy; 18.7% with ezetimibe addition and a modest 14% with PCSK9ab ad-on. The authors concluded that currently only a small percentage CHD patients are achieving guideline dictated LDL-C targets. In the simulation model, full adherence was assumed. Intensification of oral lipid lowering drugs could achieve secondary prevention guideline targets in the majority of patients and only a modest percentage required the addition of a PCSK9ab.
Cannon CP, Khan I, Klimchak AC et al. Simulation of Lipid-Lowering Therapy Intensification in a Population With Atherosclerotic Cardiovascular Disease. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28768335
Relevant publications
  1. Ramachandran R, Wierzbicki AS. Statins, Muscle Disease and Mitochondria. Journal of clinical medicine 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28757597
  2. Paricahua LI, Goncalves AFO, Pacheco S, Pacheco FJ. Sepsis Mortality in Critical Care and Prior Statin Therapy: A Retrospective Cohort Study in Central Argentina. J Clin Diagn Res 2017; 11:Oc17-oc21. http://www.ncbi.nlm.nih.gov/pubmed/?term=28764218
  3. Naraoka M, Matsuda N, Shimamura N et al. Long-acting statin for aneurysmal subarachnoid hemorrhage: A randomized, double-blind, placebo-controlled trial. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2017:271678x17724682. http://www.ncbi.nlm.nih.gov/pubmed/?term=28762878
  4. Kent ST, Rosenson RS, Avery CL et al. PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. Circ Cardiovasc Genet 2017; 10:e001632. http://www.ncbi.nlm.nih.gov/pubmed/?term=28768753
  5. Han Y, Yang CK, Gao CY et al. Association between the ApoB/A1 ratio and the vulnerability of LMCA plaque in the patients with stable angina pectoris. Zhonghua yi xue za zhi 2017; 97:2101-2106. http://www.ncbi.nlm.nih.gov/pubmed/?term=28763883
  6. Albright KC, Howard VJ, Howard G et al. Age and Sex Disparities in Discharge Statin Prescribing in the Stroke Belt: Evidence From the Reasons for Geographic and Racial Differences in Stroke Study. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28768644
  7. Zinellu A, Sotgia S, Sotgiu E et al. Cholesterol lowering treatment restores blood global DNA methylation in chronic kidney disease (CKD) patients. Nutrition, metabolism, and cardiovascular diseases : NMCD 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28755807
  8. Teramoto T, Kiyosue A, Iimura T et al. Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With Atorvastatin in Japanese Patients With Primary Hypercholesterolemia. Circulation journal : official journal of the Japanese Circulation Society 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28768921
  9. Nelson KL, Stenehjem D, Driscoll M, Gilcrease GW. Fatal Statin-Induced Rhabdomyolysis by Possible Interaction with Palbociclib. Frontiers in oncology 2017; 7:150. http://www.ncbi.nlm.nih.gov/pubmed/?term=28770167
  10. Murtola TJ, Peltomaa AI, Talala K et al. Statin Use and Prostate Cancer Survival in the Finnish Randomized Study of Screening for Prostate Cancer. European urology focus 2016. http://www.ncbi.nlm.nih.gov/pubmed/?term=28753762
  11. Michaelsson K, Lohmander LS, Turkiewicz A et al. Association between statin use and consultation or surgery for osteoarthritis of the hip or knee: a pooled analysis of four cohort studies. Osteoarthritis and cartilage 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28756279
  12. Konstantinov VO. The Role of non-Statin Therapy for Lowering the Concentration of low-Density Lipoprotein Cholesterol and Reducing the Risk of Developing Atherosclerotic Cardiovascular Complications. Kardiologiia 2017; 57:68-72. http://www.ncbi.nlm.nih.gov/pubmed/?term=28762924
  13. Koh KK, Sakuma I, Shimada K et al. Combining Potent Statin Therapy with Other Drugs to Optimize Simultaneous Cardiovascular and Metabolic Benefits while Minimizing Adverse Events. Korean Circ J 2017; 47:432-439. http://www.ncbi.nlm.nih.gov/pubmed/?term=28765731
  14. Harshman LC, Werner L, Tripathi A et al. The impact of statin use on the efficacy of abiraterone acetate in patients with castration-resistant prostate cancer. Prostate 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28762529
  15. Hamilton RJ. Making Sense of the Statin-Prostate Cancer Relationship: Is It Time for a Randomized Controlled Trial? European urology focus 2016. http://www.ncbi.nlm.nih.gov/pubmed/?term=28753767
  16. Garza L, Dols J, Gillespie M. An initiative to improve primary prevention of cardiovascular disease in adults with type II diabetes based on the ACC/AHA (2013) and ADA (2016)
  17. Roberts R. A Breakthrough in Genetics and Prevention of Coronary Artery Disease and its Relevance to Prevention in LMIC. Global heart 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28756179
  18. Garza L, Dols J, Gillespie M. An initiative to improve primary prevention of cardiovascular disease in adults with type II diabetes based on the ACC/AHA (2013) and ADA (2016) guidelines. Journal of the American Association of Nurse Practitioners 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28772017
  19. Elam MB, Majumdar G, Mozhui K et al. Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge. PLoS One 2017; 12:e0181308. http://www.ncbi.nlm.nih.gov/pubmed/?term=28771594
  20. Di Lorenzo G, Sonpavde G, Pond G et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. European urology focus 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28753882
  21. Chamaria S, Johnson KW, Vengrenyuk Y et al. Intracoronary Imaging, Cholesterol Efflux, and Transcriptomics after Intensive Statin Treatment in Diabetes. Scientific reports 2017; 7:7001. http://www.ncbi.nlm.nih.gov/pubmed/?term=28765529
  22. Alburikan KA, Asiri RM, Alhammad AM et al. Utilization and adherence to guideline-recommended lipid-lowering therapy at an academic medical center. Annals of Saudi medicine 2017; 37:276-281. http://www.ncbi.nlm.nih.gov/pubmed/?term=28761026
Miscellaneous publications
  1. Wang ZS, Huang HR, Zhang LY et al. Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo. Biological & pharmaceutical bulletin 2017; 40:1247-1254. http://www.ncbi.nlm.nih.gov/pubmed/?term=28769006
  2. Sanfelice RA, Machado LF, Bosqui LR et al. Activity of rosuvastatin in tachyzoites of Toxoplasma gondii (RH strain) in HeLa cells. Experimental parasitology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28774497
  3. Rababa HA, Hijjawi TB, Alzoubi KH et al. The Nephroprotective Effect of N-Acetyl-L-Cysteine and Atorvastatin against Imipenem induced Nephrotoxicity. Current molecular pharmacology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28762308
  4. Peng Y, He G, Tang D et al. Lovastatin Inhibits Cancer Stem Cells and Sensitizes to Chemo- and Photodynamic Therapy in Nasopharyngeal Carcinoma. Journal of Cancer 2017; 8:1655-1664. http://www.ncbi.nlm.nih.gov/pubmed/?term=28775785
  5. Madbouly Taha N, Salah AYHA, El-Sayed SH et al. Atorvastatin repurposing for the treatment of cryptosporidiosis in experimentally immunosuppressed mice. Experimental parasitology 2017; 181:57-69. http://www.ncbi.nlm.nih.gov/pubmed/?term=28764965
  6. Ma Z, Zhu L, Liu Y et al. Lovastatin Alleviates Endothelial-to-Mesenchymal Transition in Glomeruli via Suppression of Oxidative Stress and TGF-beta1 Signaling. Frontiers in pharmacology 2017; 8:473. http://www.ncbi.nlm.nih.gov/pubmed/?term=28769803
  7. Li Y, Jiang T, Fu X et al. Atorvastatin protects cardiomyocytes against OGD/Rinduced apoptosis by inhibiting miR199a5p. Mol Med Rep 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28765953
  8. Jin R, Luo X, Luan K et al. Disorder of the mevalonate pathway inhibits calcium-induced differentiation of keratinocytes. Mol Med Rep 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28765912
  9. Ishihara N, Suzuki S, Tanaka S et al. Atorvastatin increases Fads1, Fads2 and Elovl5 gene expression via the geranylgeranyl pyrophosphate-dependent Rho kinase pathway in 3T3-L1 cells. Mol Med Rep 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28765914
  10. Hou HH, Liao YJ, Hsiao SH et al. Corrigendum: Role of phosphatase activity of soluble epoxide hydrolase in regulating simvastatin-activated endothelial nitric oxide synthase. Scientific reports 2017; 7:46877. http://www.ncbi.nlm.nih.gov/pubmed/?term=28758642
  11. Han F, Xiao QQ, Peng S et al. Atorvastatin ameliorates LPS-induced inflammatory response by autophagy via AKT/mTOR signaling pathway. Journal of cellular biochemistry 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28771872
  12. Chen B, Zhang M, Xing D, Feng Y. Atorvastatin enhances radiosensitivity of hypoxia-induced prostate cancer cells related with HIF-1alpha inhibition. Bioscience reports 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28760843
  13. Carroll JA, Race B, Phillips K et al. Statins are ineffective at reducing neuroinflammation or prolonging survival in scrapie-infected mice. The Journal of general virology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28758631
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