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Update - Week 41, 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

Should elderly statin users get preventive herpes zoster vaccination?
Despite the overwhelming evidence of statin safety, the >300 million world-wide statin users create a significant number of patients, that despite low risk, do present with adverse responses. One problem that can confront statin users, is re-activation of latent herpes varicella; herpes zoster infections. In this meta-analysis the authors evaluated publications of clinical trials registries that collected HZ infections in statin users. Querying the established literature registries from inception to 2018, they included 5 large studies, published between 2014 and 2018. The heterogeneity of the studies and limited number of specific patient and/or statin characteristics makes it virtually impossible to draw definite conclusions. Overall statin use was associated with an increase of reported HZ infections. In one study a significant 25% risk increase was reported, but only in patients aged 70 year or older. Effects of statin duration were contradictory. In all studies diabetic patients participated; diabetes by itself increase the risk of HZ, however only one trial was able to show a significant 18% increased risk of HZ in diabetic statin users vs patients that were not taking statins. One of the included studies estimated that ± 20,000 cases of HZ, out of 628,000 HZ infections per year, could be attributable to statin use in Americans aged >50 years. Although the observed findings of this meta-analysis can only be considered preliminary, a raised awareness of statin related HZ should prompt for more focused research, exploring the mechanisms as well as HZ incidence and effects of preventive strategies such as vaccinations. Of note is the potential diminished anti-body response in patients that participated in influenza and HZ vaccinations program. Zatelli G, L'Erario R et al. Herpes zoster infection and statins: which implications in clinical practice? European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30298219
 
Lp(a) associated with residual risk in statin treated patient
One lipoprotein fraction that is gaining notoriety as an important CV risk factor is Lp(a). Studies of large registries as well as mendelian randomization studies have unequivocally branded this LDL type particle as an important independent risk factor. Although Statins do not seem to effect plasma concentration of Lp(a), in 7 major clinical endpoint trials, Lp(a) was measured at baseline and at the end of the study. These studies were included in this meta-analysis of patient level data. The aim was to evaluate the residual risk of increased Lp(a) plasma concentrations in statin treated patients. Overall 29 069 patients were included, mean age 62 years and 28% females. Baseline and on-statin treatment Lp(a) concentrations showed a linear relationship with CVD risk. Baseline lipoprotein(a) plasma concentrations, compared to <15mg/dl revealed a HR 1·04 (0·91–1·18) for 15 mg/dL to <30 mg/dL, 1·11 (1·00–1·22) for 30 mg/dL to <50 mg/dL and 1·31 (1·08–1·58)  >50 mg/.  Respective HR’s for on-statin lipoprotein(a) lelves were 0·94 (0·81–1·10), 1·06 (0·94–1·21), and 1·43 (1·15–1·76) respectively. HR remained similar in numerous subgroup analyses. The risk associated with Lp(a) seemed stronger in the placebo treated patients (interaction p=0.010) and was more pronounced in younger patients (interaction p=0.008). The author concluded that in statin treated patients, elevated baseline and on treatment Lp(a) plasma concentrations showed a strong linear association with CVD risk. The results of this meta-analysis support measuring as well as potentially treating elevated  Lp(a) with new treatment modalities such as Apo A siRNA.
Willeit P, Ridker PM, Nestel PJ et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30293769
 
Genetic variants of KIF6 predict statin response
The individual response to statins varies and to some extent, depend on metabolic characteristics of the recipient. Genetic markers of proteins that influence statins LDL-c lowering properties have been shown to predict statin response. These so called pharmacogenetic determinants of the LDL-c lowering effects of statins have been reported for the SLCO1B1, HMGCR and Cyp450 3A4 genes. The authors of this study evaluated the c.2155T>c variants of the KIF6 gene and response to simvastatin (N=106), atorvastatin (N=114) and rosuvastatin (N=30), in a multi-center observational prospective follow-up study that included 252 patients. Patients with the CC variant showed a reduced LDL-c lowering effect of 7.0% (P=0.015) compared to the TT and TC variants. Patients that used rosuvastatin and carried the CC variant showed 21.9% less HDL-c increase compared to TT and CT carriers. No effect on LDL-c lowering were observed in rosuvastatin users when C and T variants were compared, but this could be related to the relatively small number of patients that used rosuvastatin, 30/250 (12%). The mechanism by which the KIF6 protein effects statin response is not well understood and was not explored in this study. The authors concluded that the CC variant of the KIF6 gene negatively affected treatment response to simvastatin, atorvastatin and rosuvastatin, the clinical consequences of this finding deserve further exploration but could ultimately lead to alternative choices to optimally treat patient with a high risk of CVD and carriers of the KIF6 c.2155T>C genotype.
Ruiz-Iruela C, Padro-Miquel A, Pinto-Sala X et al. KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment. PLoS One 2018; 13:e0205430. http://www.ncbi.nlm.nih.gov/pubmed/?term=30304062
 
LDL-c lowering of ezetimibe add-on compared to doubling statin dose
The position of ezetimibe as add on to statins therapy has become more prominent, after the initial negative results of the poorly designed ENHANCE trial. In this meta-analysis the aim was to compare the LDL-c lowering response of up-titrating simvastatin, atorvastatin or rosuvastatin mono-therapy to adding ezetimibe. Overall 35 RCT’s were identified that included hypercholesterolemic, high risk patients and treated with a statin.  The authors performed a Bayesian network meta-analysis (NMA) within each statin population. The primary outcome was LDL-C change (%) from baseline. In patients that started with simvastatin the add-on of ezetimibe resulted in a mean LDL-c difference (MD) of − 13.62% (−19.99 - −6.91) compared to doubling the starting dose of simvastatin. Patients that started with atorvastatin and in whom ezetimibe was added a MD in LDL-C of − 14.71% (−16.46 - −12.95), compared to doubling the starting dose of atorvastatin, was observed. Adding ezetimibe to rosuvastatin resulted in an MD in LDL-C of − 14.96% (−17.79 - −12.11), compared to doubling the starting dose of rosuvastatin. Numerous permutations of not only doubling but also quadrupling statins dosages as well as adding ezetimibe to increased dosage are shown in the article. The authors concluded that regardless of the initial statin, adding ezetimibe resulted in a statistically greater LDL-c reduction compared to doubling statin dose or switching to an equal dose of higher-potency rosuvastatin. Although the benefits of LDL-c on of CV outcomes have been unequivocally shown for almost any type of cholesterol lowering therapy, and reaching guideline dictated goals are very important. One unresolved issue remains, if the observed benefits of statins are solely dependent on the LDL-c lowering or if other, so called pleiotropic cardio-protective benefits, are clinically relevant. If ezetimibe is on par with statins in the full spectrum of ASCVD risk can only be determined by a properly designed RCT that compares the two treatments strategies on major cardiovascular outcomes.
Lorenzi M, Ambegaonkar B, Baxter CA et al. Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy. Clinical research in cardiology : official journal of the German Cardiac Society 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30302558
 
NSTEMI’s on the rise but proper preventive treatment strategies are lagging
The observed improved survival of patients admitted for ACS over the last 2-30 year has been very impressive, reflecting not only improved acute care but better management of the major modifiable CVD risk factors as well. The type of AMI’s is changing and studies have reported  decreases in STEMI’s plus increases in NSTEMI’s. In this analysis the authors used data collected in the Taiwan National Health Insurance Research Database between 2009 ad 2015. Individual patient data of 100 570 patient hospitalized for AMI where studied and temporal changes in AMI incidence were observed. No changes in the incidence of AMI, 49.8% in 2009 and 50.7% in 2015. But worrying trends were observed in young men and young women; AMI incidence increased by 30.3% and 29.4% respectively. No changes or even reduced incidences were observed in the older groups. The ratio of STEMI vs NSTEMI increased from 1.93 in 2009 to 2.47 in 2015. NSTEMI’s increased by 49.8% in young men (<55 years). Dyslipidemia was the most common risk factor in young AMI patients. Treatments for secondary preventions including PCI, dual antiplatelets, ACEi/ARB’s, β blockers and statins were less frequently prescribed in NSTEMI patients compared to STEMI patients. In-hospital mortality improved between 2013 and 2015; 8.6% and 7.6% respectively. This trend was not observed in NSTEMI patients with in-hospital mortality of 13.3% and 13.5% respectively. The authors concluded that in Taiwan similar changing patterns of AMI were observed, with lower STEMI rates vs increased incidence of NSTEMI’s in young Taiwanese. In-hospital mortality remained unchanged for NSTEMI patients and less frequent use of guideline dictated pharmacological interventions could play an important role and warrants a more intensive therapeutic/preventive focus in (Taiwanese) NSTEMI patients.
Lee CH, Fang CC, Tsai LM et al. Patterns of Acute Myocardial Infarction in Taiwan from 2009 to 2015. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30301543
 
 
Relevant publications
  1. Sakamoto A, Virmani R, Finn AV. Coronary artery calcification: recent developments in our understanding of its pathologic and clinical significance. Current opinion in cardiology 2018; 33:645-652. http://www.ncbi.nlm.nih.gov/pubmed/?term=30307412
  2. Penson PE, Mancini GBJ, Toth PP et al. Introducing the 'Drucebo' effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions. Journal of cachexia, sarcopenia and muscle 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30311434
  3. Goh CC, Koh KH, Goh S et al. Achieving triple treatment goals in multi-ethnic Asian patients with type 2 diabetes mellitus in primary care. Malaysian family physician : the official journal of the Academy of Family Physicians of Malaysia 2018; 13:10-18. http://www.ncbi.nlm.nih.gov/pubmed/?term=30302178
  4. Bodde MC, Hermans MPJ, Jukema JW et al. Apolipoproteins A1, B, and apoB/apoA1 ratio are associated with first ST-segment elevation myocardial infarction but not with recurrent events during long-term follow-up. Clinical research in cardiology : official journal of the German Cardiac Society 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30298424
  5. Parra-Virto A, Torres do Rego A, Demelo-Rodriguez P et al. Usefulness of compounds with monacolin K in a case of statins intolerance. Clin Investig Arterioscler 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30309697
  6. Parhofer KG. CONTROVERSIAL ISSUES IN THE TREATMENT OF DYSLIPIDEMIAS IN PATIENTS WITH DIABETES MELLITUS. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion 2018; 70:237-243. http://www.ncbi.nlm.nih.gov/pubmed/?term=30307445
  7. Mollazadeh H, Atkin SL, Butler AE et al. The effect of statin therapy on endoplasmic reticulum stress. Pharmacol Res 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30312664
  8. Magdy YM, El-Kharashi OA, El-Waseef DAA et al. Insights into hepatic and renal FXR/DDAH-1/eNOS pathway and its role in the potential benefit of rosuvastatin and silymarin in hepatic nephropathy. Experimental and molecular pathology 2018; 105:293-310. http://www.ncbi.nlm.nih.gov/pubmed/?term=30308196
  9. Lorenzatti A, Servato ML. Role of Anti-inflammatory Interventions in Coronary Artery Disease: Understanding the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). European cardiology 2018; 13:38-41. http://www.ncbi.nlm.nih.gov/pubmed/?term=30310469
  10. Lee BC, Lin CL, Tsai HH, Kao CH. Statin and the Risk of Ischemic Stroke or Transient Ischemic Attack in Head and Neck Cancer Patients with Radiotherapy. J Stroke 2018; 20:413-414. http://www.ncbi.nlm.nih.gov/pubmed/?term=30309238
  11. He Y, Li X, Gasevic D et al. Statins and Multiple Noncardiovascular Outcomes: Umbrella Review of Meta-analyses of Observational Studies and Randomized Controlled Trials. Annals of internal medicine 2018; 169:543-553. http://www.ncbi.nlm.nih.gov/pubmed/?term=30304368
  12. Franczyk B, Gluba-Brzozka A, Jurkiewicz L et al. Embracing the polypill as a cardiovascular therapeutic: is this the best strategy? Expert Opin Pharmacother 2018:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30295098
  13. Dohlmann TL, Morville T, Kuhlman AB et al. Statin treatment decreases mitochondrial respiration but muscle coenzyme Q10 levels are unaltered: The LIFESTAT study. J Clin Endocrinol Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30299473
  14. Deseive S, Straub R, Kupke M et al. Impact of diabetes on coronary artery plaque volume by coronary CT angiography and subsequent adverse cardiac events. Journal of cardiovascular computed tomography 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30293793
  15. Derosa G, Maffioli P. Nutraceuticals for the treatment of metabolic diseases: evidence from clinical practice. Expert review of endocrinology & metabolism 2015; 10:297-304. http://www.ncbi.nlm.nih.gov/pubmed/?term=30298772
  16. Chasioti D, Yao X, Zhang P et al. Mining directional drug interaction effects on myopathy using the FAERS database. IEEE journal of biomedical and health informatics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30296244
  17. Boyle AK, Rinaldi SF, Rossi AG et al. Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2018:fj201801104R. http://www.ncbi.nlm.nih.gov/pubmed/?term=30312114
  18. Barkate H, Patel P, Shah D, Vyas F. Comparison of Efficacy and Safety of Fixed Dose Combination of Rosuvastatin and Choline Fenofibrate to Fixed Dose Combination of Rosuvastatin and Fenofibrate in Patients of Mixed Dyslipidemia: A Randomized, Open-label, Multicentre Clinical Trial in Indian Population. Indian journal of endocrinology and metabolism 2018; 22:627-631. http://www.ncbi.nlm.nih.gov/pubmed/?term=30294571
  19. Balk EM, Adams GP, Langberg V et al. Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review. Evidence report/technology assessment 2016:1-1252. http://www.ncbi.nlm.nih.gov/pubmed/?term=30307737
  20. Athyros VG, Katsiki N, Dimakopoulou A et al. Drugs that mimic the effect of gene mutations for the prevention or the treatment of atherosclerotic disease: from PCSK9 inhibition to ANGPTL3 inactivation. Current pharmaceutical design 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30306859
  21. Warraich HJ, Rana JS. Diabetic Dyslipidemia: Epidemiology and Prevention of Cardiovascular Disease and Implications of Newer Therapies. Current cardiology reports 2018; 20:125. http://www.ncbi.nlm.nih.gov/pubmed/?term=30311078
  22. Sorber R, Lehman A, Alshaikh HN et al. Metabolic syndrome is associated with increased cardiac morbidity after infrainguinal bypass surgery irrespective of the use of cardiovascular risk-modifying agents. Journal of vascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30292611
  23. Pitts RN, Eckel RH. The Emerging Role of PCSK9 Inhibitors in Preventive Cardiology. European cardiology 2014; 9:65-70. http://www.ncbi.nlm.nih.gov/pubmed/?term=30310488
  24. Lambert CT, Sandesara P, Isiadinso I et al. Current Treatment of Familial Hypercholesterolaemia. European cardiology 2014; 9:76-81. http://www.ncbi.nlm.nih.gov/pubmed/?term=30310490
  25. Korani S, Korani M, Bahrami S et al. Application of nanotechnology to improve the therapeutic benefits of statins. Drug discovery today 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30292917
  26. Ederhy S, Ancedy Y, Soulat-Dufour L et al. [Is cancer a factor or a marker of cardiovascular risk in women?]. Presse medicale (Paris, France : 1983) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30293849
  27. Cifkova R. Antiplatelet and Lipid-lowering Drugs in Hypertension. European cardiology 2014; 9:16-20. http://www.ncbi.nlm.nih.gov/pubmed/?term=30310480
  28. Carrillo-Ibarra S, Miranda-Diaz AG, Sifuentes-Franco S et al. Effect of statins on oxidative DNA damage in diabetic polyneuropathy. Journal of circulating biomarkers 2018; 7:1849454418804099. http://www.ncbi.nlm.nih.gov/pubmed/?term=30302131
  29. Cainzos-Achirica M, Enjuanes C, Greenland P et al. The prognostic value of interleukin 6 in multiple chronic diseases and all-cause death: The Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2018; 278:217-225. http://www.ncbi.nlm.nih.gov/pubmed/?term=30312930
  30. Barnett S, Ogungbenro K, Menochet K et al. Comprehensive evaluation of the utility of 20 endogenous molecules as biomarkers of OATP1B inhibition compared to rosuvastatin and coproporphyrin I. J Pharmacol Exp Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30314992
  31. Archibugi L, Arcidiacono PG, Capurso G. Statin use is associated to a reduced risk of pancreatic cancer: A meta-analysis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30314951
  32. Abdullah K, Rohatgi A. Statins: Practical Considerations - A Review. European cardiology 2014; 9:71-75. http://www.ncbi.nlm.nih.gov/pubmed/?term=30310489
  33. Abdollahimajd F, Rajabi F, Shahidi-Dadras M et al. Pachyonychia congenita: A case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation. Br J Dermatol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30307612
Miscellaneous publications
 
 
  1. Sedki M, Khalil IA, El-Sherbiny IM. Hybrid nanocarrier system for guiding and augmenting simvastatin cytotoxic activity against prostate cancer. Artificial cells, nanomedicine, and biotechnology 2018:1-10. http://www.ncbi.nlm.nih.gov/pubmed/?term=30295086
  2. El Sayed I, Helmy MW, El-Abhar HS. Inhibition of SRC/FAK cue: A novel pathway for the synergistic effect of rosuvastatin on the anti-cancer effect of dasatinib in hepatocellular carcinoma. Life sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30292831
  3. Deng LJ, Wu YL, He XH et al. Simvastatin delivery on PEEK for bioactivity and osteogenesis enhancements. Journal of biomaterials science. Polymer edition 2018:1-30. http://www.ncbi.nlm.nih.gov/pubmed/?term=30307376
  4. Braga Filho JAF, Abreu AG, Rios CEP et al. Prophylactic Treatment With Simvastatin Modulates the Immune Response and Increases Animal Survival Following Lethal Sepsis Infection. Frontiers in immunology 2018; 9:2137. http://www.ncbi.nlm.nih.gov/pubmed/?term=30298072
  5. Marchetti DP, Steffens L, Jacques CE et al. Oxidative Imbalance, Nitrative Stress, and Inflammation in C6 Glial Cells Exposed to Hexacosanoic Acid: Protective Effect of N-acetyl-L-cysteine, Trolox, and Rosuvastatin. Cellular and molecular neurobiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30302628
  6. Hu MB, Zhang JW, Gao JB et al. Atorvastatin induces autophagy in MDA-MB-231 breast cancer cells. Ultrastructural pathology 2018:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30300062
  7. Al-Hashimi NN, Shahin RO, Al-Hashimi AN et al. Cetyl-alcohol-reinforced hollow fiber solid/liquid phase microextraction and HPLC-DAD analysis of ezetimibe and simvastatin in human plasma and urine. Biomedical chromatography : BMC 2018:e4410. http://www.ncbi.nlm.nih.gov/pubmed/?term=30315647
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