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Update - Week 52, 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

How to predict and avoid non-adherence – in Chinese patients
The reasons why patients stop taking statins are different depending on geographical location and ethnicity. In this Chinese study statin adherence as well as the CV consequences of not taking the prescribed lipid lowering medication, were studied. Conducted in a single academic hospital in Chonqing (February 1st and October 31st, 2013). Participating patients had a confirmed CHD diagnosis and used statins. All 732 patients were followed for 4-8 months. For the final analysis data on 615 patients was available. The two factors that with the biggest impact on non-compliances were coronary artery stenosis <75%; OR: 3.4 (2.2-5.4, P<0.001) and adverse events, OR: 2.5 (1.3-4.9, P=0.005). The major personal reasons for non-adherence to statin therapy (15.9% of patients), were: lack of knowledge about CHD (36.7%), doctor’s advice (19.4%), difficulty obtaining statins (12.2%), using traditional Chinese medicine (9.2%), economics (6.1%), adverse effects (5.1%) and other (11.2%). CV adverse events showed an clear correlation with non-adherence, OR:1.7 (1.04-2.9, P=0.037). The results underline the short-term impact of statin non-adherence. The study provides important pointers on which patients are more likely to stop statins as well as reasons for non-compliance  that can be addressed at hospital discharge or during outpatient consultations.
Yu G, Zhang Y, Wang Y et al. Factors that contribute to poor adherence to statin therapy in coronary heart disease patients from Chongqing and measures to improve their therapeutic outcomes. Genes & diseases 2018; 5:335-341. http://www.ncbi.nlm.nih.gov/pubmed/?term=30591935
 
Statins protect renal function in Korean ICU patients
How renal function is affected by statins could be different for certain patient categories. In this retrospective observational study, the focus was on critically ill patients, admitted to an ICU for advanced care. Pre-admission statin users, taking statin >1 month prior to admission, were compared to patients that did not use a statin. The primary endpoint of this evaluation was the incidence of acute kidney injury (AKI) <72 hrs. after admission, and if pre-admission eGFR had an impact on AKI. Electronic data was collected from patients admitted to the ICU in a single Korean University hospital between January 2012 and December 2017. Data from 21 236 patients; 5 756 (27.1%) pre-admission statin users and 15 480 (72.9%) non-users were analyzed. Statin use prior to admission was associated with a significant (-31%) reduced risk for AKI <72hr post-admission, resulting in an OR of 0.69 (0.61-0.79, P<0.001). Patients that had started with a baseline e-GFR< 30 ml/min-1 1.73 m2 were not protected, (P>0.05). The authors suggested that pleiotropic immunomodulatory effects might play a role in the observed benefits. Of note, the patients using statins were significantly older and sicker; more patients with impaired renal function, diabetes mellitus, IHD and cerebrovascular disease. Statins used by patients that developed a critical illness and needed ICU care, did not compromise their renal function but prevented serious and life-threatening AKI.
Oh TK, Song IA, Cho YJ et al. Preadmission Statin Therapy Is Associated with a Lower Incidence of Acute Kidney Injury in Critically Ill Patients: A Retrospective Observational Study. Journal of clinical medicine 2018; 8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30585236
 
Statin safety - Scientific statement of the AHA
The safety of statins is a very controversial topic frequently exploited by statin sceptics to convince patients to stop statins. This update review/scientific statement of the AHA, provides clinicians with an in-depth overview on reported safety as well as tolerability issues as reported in the (large) statin trials as well as observational cohort studies. The review is focused on the general population but also informs clinicians on what they can expect in certain demographic subgroups. Elderly, children, pregnant women and East Asians. Treating patients with underlying disorders such as CKD, chronic liver disease, HIV, and organ transplants. Serious complications remain rhabdomyolysis and serious hepatoxicity they are observed rarely, <0.1% and ≈0.001% respectively. Myopathy, without CK elevations was observed in <1% of patients, and < 0.1% in patients that stopped their statin because of muscle related complaints. Newly diagnosed diabetes is associated with statin use, ≈0.2%/year, however the presence of pre-diabetes characteristics increases this risk. The risk of developing a hemorrhagic stroke in patients with cerebrovascular disease is small and remains controversial. The observed reduced ASCVD risk in patients using statins clearly outweighs the bleeding risk. The authors found no evidence that statin use could increase the odds for cancer, cataracts, cognitive decline, peripheral neuropathy, erectile dysfunction or tendonitis. This 44-page article with 369 references, is a must read for health care professionals that prescribe statins and frequently have to defend their use to patients that have encountered critical views in the traditional media or on-line. After 40 years and > 300 000 000 patients using statin worldwide, it is remarkable that no new serious safety and/or tolerability issues surfaced in this updated review, they remain quite similar to earlier reports and reviews.
Newman CB, Preiss D, Tobert JA et al. Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2018:Atv0000000000000073. http://www.ncbi.nlm.nih.gov/pubmed/?term=30580575
 
Do Statins increase risk for ICH? Not in Korean patients!
In Asia (Korea) the risk of getting an intra-cerebral bleed (ICH) is high compared to western countries. To determine if Korean patients are exposed to an increased bleeding risk when using statins, the authors queried the large Korean National Health Insurance Service–National Sample Cohort (NHIS-NSC) database from 2002-2015. This registry was started in 1977, and from 1989 onward covered the entire Korean population (+50 million). Out of the initially selected 313 368 patients 21 797 statin users and the same number of individuals not using statins were compared, using a propensity score matching model. After a mean follow-up period of 6.4 years, the primary endpoint, ICH, occurred in 456 of the 43 594 (1.05%) patients. statin use was associated with a significantly reduced ICH risk, HR 0.78 (0.65-0.94). The secondary endpoints were less likely to occur in statin users as well; all-cause mortality, HR 0.61 (0.57-0.64); cardiovascular and cerebrovascular disease related mortality, HR 0.75 (0.65-0.85) as well as stroke related mortality, HR 0.69 (0.54-0,88). When comparing both groups for recurrence or mortality after an ICH event, no difference were noted. The authors concluded that the use of statins seemed not to be associated with worse outcomes in patients that developed an ICH. First occurrence of ICH as well as other cardio- cerebrovascular events were observed less frequently in Korean patients that used statins. Despite the obvious limitations of observational studies, large scale administrative registries offer a unique opportunity for long term safety assessment of medical interventions.
Jung M, Lee S. Effects of Statin Therapy on the Risk of Intracerebral Hemorrhage in Korean Patients with Hyperlipidemia. Pharmacotherapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30585646
 
Residual risk explained
The concept of residual risk is used to indicate risk factors beyond the traditional, treatable risk factors e.g. LDL-cholesterol and blood-pressure. Despite optimal RF control, patients with progressive ASCVD need additional evaluations to fine tune their therapies. In this updated review the authors share their insights into the residual risk related biomarkers, that have shown promising results in terms of modulating CVD risk. When abnormal levels are present, lower LDL-c targets might be appropriate or perhaps novel treatments, targeting these risk factors could reduce the increased CV risk. The 4 candidate residual risk markers reviewed in this paper are triglyceride rich lipoproteins (TRL’s) and their remnants; High density Lipoproteins (HDL), Lp(a) and the non-lipid risk factor inflammation, e.g. hsCRP. The authors point out that a full understanding of residual risk remains challenging, but basic – and clinical research efforts will help clinicians to effectively use a precision medicine approach to improve the management of their high CVD-risk patients.
 Matsuura Y, Kanter JE, Bornfeldt KE. Highlighting Residual Atherosclerotic Cardiovascular Disease Risk. Arterioscler Thromb Vasc Biol 2019; 39:e1-e9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30586334
Relevant publications
  1. Soska V, Kyselak O. Some causes of poor adherence to long-term statin therapy and their solution. Vnitr Lek 2018; 64:923-927. http://www.ncbi.nlm.nih.gov/pubmed/?term=30590938
  2. Wilson PWF, Polonsky TS, Miedema MD et al. Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation 2018:Cir0000000000000626. http://www.ncbi.nlm.nih.gov/pubmed/?term=30586775
  3. Lloyd-Jones DM, Braun LT, Ndumele CE et al. Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease. Circulation 2018:Cir0000000000000638. http://www.ncbi.nlm.nih.gov/pubmed/?term=30586766
  4. Lan NSR, Martin AC, Brett T et al. Improving the detection of familial hypercholesterolaemia. Pathology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30579649
  5. Katzmann JL, Mahfoud F, Bohm M et al. Association of medication adherence and depression with the control of low-density lipoprotein cholesterol and blood pressure in patients at high cardiovascular risk. Patient preference and adherence 2019; 13:9-19. http://www.ncbi.nlm.nih.gov/pubmed/?term=30587940
  6. Hochhauser M, Avoros O, Perman V et al. Survey of family doctors' attitudes towards statin treatment in patients with type 2 diabetes. Diabetes Res Clin Pract 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30583035
  7. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation 2018:Cir0000000000000625. http://www.ncbi.nlm.nih.gov/pubmed/?term=30586774
  8. Chien SC, Chen PS, Huang YH et al. 2019 Taiwan Society of Lipids and Atherosclerosis expert consensus statement on statin intolerance. Journal of the Formosan Medical Association = Taiwan yi zhi 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30584005
  9. Chen Y, Li LB, Zhang J et al. Simvastatin, but not pravastatin, inhibits the proliferation of esophageal adenocarcinoma and squamous cell carcinoma cells: a cell-molecular study. Lipids Health Dis 2018; 17:290. http://www.ncbi.nlm.nih.gov/pubmed/?term=30579354
  10. Burke AC, Telford DE, Huff MW. Bempedoic acid: effects on lipoprotein metabolism and atherosclerosis. Curr Opin Lipidol 2019; 30:1-9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30586346
  11. Ma Y, Xiang C, Zhang B. Efficacy Evaluation of High-Dose Atorvastatin Pretreatment in Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials. Medical science monitor : international medical journal of experimental and clinical research 2018; 24:9354-9363. http://www.ncbi.nlm.nih.gov/pubmed/?term=30580373
  12. Pagano D, Oliva E, Khouzam S et al. The addition of simvastatin administration to cold storage solution of explanted whole liver grafts for facing ischemia/reperfusion injury in an area with a low rate of deceased donation: a monocentric randomized controlled double-blinded phase 2 study. BMC surgery 2018; 18:122. http://www.ncbi.nlm.nih.gov/pubmed/?term=30587165
  13. Otake H, Sugizaki Y, Toba T et al. Efficacy of alirocumab for reducing plaque vulnerability: Study protocol for ALTAIR, a randomized controlled trial in Japanese patients with coronary artery disease receiving rosuvastatin. J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30579806
  14. Nidorf SM, Thompson PL. Why Colchicine Should Be Considered for Secondary Prevention of Atherosclerosis: An Overview. Clinical therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30591286
  15. Mann A, Esse TW, Serna O et al. Effectiveness of mailed letters to improve medication adherence among Medicare Advantage Plan participants with chronic conditions. Patient preference and adherence 2019; 13:37-46. http://www.ncbi.nlm.nih.gov/pubmed/?term=30587942
  16. Lima WG, Alves-Nascimento LA, Andrade JT et al. Are the Statins promising antifungal agents against invasive candidiasis? Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 111:270-281. http://www.ncbi.nlm.nih.gov/pubmed/?term=30590315
  17. Li G, Zhao M, Qiu F et al. Pharmacokinetic interactions and tolerability of berberine chloride with simvastatin and fenofibrate: an open-label, randomized, parallel study in healthy Chinese subjects. Drug design, development and therapy 2019; 13:129-139. http://www.ncbi.nlm.nih.gov/pubmed/?term=30587933
  18. Doll JA, Hellkamp AS, Thomas L et al. The association of pre- and posthospital medication adherence in myocardial infarction patients. Am Heart J 2018; 208:74-80. http://www.ncbi.nlm.nih.gov/pubmed/?term=30580129
  19. Chen CC, Rane PB, Hines DM et al. Low-density lipoprotein cholesterol outcomes post-non-PCSK9i lipid-lowering therapies in atherosclerotic cardiovascular disease and probable heterozygous familial hypercholesterolemia patients. Therapeutics and clinical risk management 2018; 14:2425-2435. http://www.ncbi.nlm.nih.gov/pubmed/?term=30587999
Miscellaneous publications
 
 
  1. Snarska A, Wysocka D, Rytel L et al. Simvastatin-induced Changes in the Leukocytic System of Porcine Bone Marrow. Journal of veterinary research 2018; 62:329-333. http://www.ncbi.nlm.nih.gov/pubmed/?term=30584612
  2. Niu M, Feng X, Zhou L. The role of the ERK1/2 pathway in simvastatin-loaded nanomicelles and simvastatin in regulating the osteogenic effect in MG63 cells. International journal of nanomedicine 2018; 13:8165-8178. http://www.ncbi.nlm.nih.gov/pubmed/?term=30584296
  3. Matsunaga N, Ufuk A, Morse BL et al. Hepatic OATP-mediated clearance in the Beagle dog: assessing in vitro-in vivo relationships and applying cross species empirical scaling factors to improve prediction of human clearance. Drug metabolism and disposition: the biological fate of chemicals 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30593544
  4. Balaz M, Becker AS, Balazova L et al. Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation. Cell Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30581121
  5. Danielak D, Gorzycka P, Kruszyna L et al. Development of an LC-MS/MS method for simultaneous determination of ticagrelor and its active metabolite during concomitant treatment with atorvastatin. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2018; 1105:113-119. http://www.ncbi.nlm.nih.gov/pubmed/?term=30580183
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This activity is supported by an educational grant from Pfizer.