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Update - Week 01,  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

Potential statin side effects how to recognize and prevent
In this practical review center stage is reserved for statin drug interactions. A concise overview discusses the potential harms that clinicians should be aware of when prescribing statins, but more importantly the difference between statins, pertaining to their metabolic pathways and lipo/hydrophilicity. Although the risk for statin toxicity is very low, having knowledge about statins metabolism including absorption, metabolism, and statin clearance is important.  Key point is that the statin plasma concentrations are pivotal in many of the experienced adverse effects. Dosing of statins should be adjusted in patients with a high probability of potential side effects e.g. age, co-morbidities, genetic disposition and last but not least co-medications. Knowledge regarding the enzymes that are responsible for statin degradation, and that are used by other pharmacological interventions, are important as well. Cytochrome P450 3A4 is associated with simvastatin, lovastatin (high risk) and atorvastatin (moderate risk). Fluvastatin, pitavastatin, rosuvastatin, and pravastatin pose the least risk for interaction with drugs metabolized by CYP 3A4. Cytochrome P450 2E9 is targeted by different concomitant drugs and here fluvastatin, pitavastatin and rosuvastatin are the statins to be aware of. Alternatively, statin transporters such as OATP1B1, OATP1B3, Pgp-1 can impact plasma concentrations as well. The authors include a downloadable table that provides an overview of potential interactions between specific statins and concomitant drugs that a patient potentially could be using simultaneously. The information provided in this concise review and the downloadable tables, can aid healthcare providers in safely prescribing statins.
Wooten JM. A Brief Drug Class Review: Considerations for Statin Use, Toxicity, and Drug Interactions. Southern medical journal 2018; 111:39-44. http://www.ncbi.nlm.nih.gov/pubmed/?term=29298368
 
Statin “Fake News” rebuttal by ESC
The term ‘fake news’ has become a household term in the context of politics, but this label is quite fitting as well when browsing through the numerous anti-statin (social) media reports. In this brief EHJ comment two authors, that are part of the ESC media committee, provide a powerful rebuttal against the recent ARTE broadcast Entitled “The Great Bluff” In this televised program physicians and patients are encouraged to interrupt lipid-lowering treatments and statins. They point out that the “scientific approximations” presented in this aired segement can have serious consequences; not only by undermining the trust of doctor – patient relationship; but could even prompt patients to stop taking their prescribed medications, subsequently increasing their risk for an MI, stroke and even death. Referring to the recent EHJ publication by Nordestgaard and Nielsen that showed the impact of negative statin-related news stories on increased statin discontinuations; OR 1.09 (1.06-1.12) and among those who discontinued statins, increased risk of MI and CVD death; HR 1.26 (1.21–1.30) and 1.18 (1.14–1.23), respectively. Information on prevention and management of cardiovascular disease should be a privileged collaboration between professional organizations like the ESC and public media channels, in order to provide reliable and balanced information on issues that can have potential catastrophic consequences when presented out of context.
Schiele F, Kristensen SD. The anti-statin lobby strikes again: time to set the record straight. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29300911
 
Which CVD- statin guideline should I use?
What is the “real-life” utility of the recently updated CVD prevention guidelines in terms of number of patients (potentially) eligible for statin therapy and which guideline has the largest impact on preventing CVD complications and saving life’s? In this analysis, the authors compared the 5 most recent published guidelines: The ACC/AHA (2013), NICE (2014), CCS (2016), USPSTF (2016,) ESC/EAS (2106). By implementing their recommendations on participants of the Danish Copenhagen Population Study. This registry collected clinical data of almost 50 000 Danes aged 40-75 years without CVD and who did not use statins at baseline. This study was designed as an observational analysis of actual events over a 10-year follow-up period and modelled on the 5 different statin treatment guidelines. The percentage of Danish patients eligible for statins were 44% (CCS); 42% (ACC/AHA); 40% (NICE); 31% (USPSTF) and 15% (ESC/EAS). If eligible patients would have used statins for 10 years, based on the different guideline recommendations, the percentage of ASCVD events would have been reduced by -34% (CCS); -34% (ACC/AHA); -31% (NICW), -27% (USPSTF) and -13% (EAS/EAS). The authors concluded that the percentage of reduced events is directly related to the percentage that would be eligible for statin therapy. Based on  the well-documented safety and low cost of statins, these results favour the CCS, ACC/AHA, and NICE strategies as preferable because of a superior effect on event reduction.
Mortensen MB, Nordestgaard BG. Comparison of Five Major Guidelines for Statin Use in Primary Prevention in a Contemporary General Population. Annals of internal medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29297004
 
Do we need statins for primary prevention in (very) elderly?
Lipid management of elderly is still a controversial topic, one of the reasons; the lack of designated randomized clinical hard-endpoint statin trials of elderly participants. In this review, the authors underline the importance of coming up with clear recommendations for these, age related, high risk patients. When aiming for “Healthy Aging” reducing the risk for ASCVD events in this rapidly expanding population becomes a priority. Unfortunately the recommendations of the 5 most recent statin guidelines (ACC/AHA, NICE, CCS, USPSTF and EAS/EAS) provide no clear cut and sometimes even contradictory directives. The life expectancy of 65 year olds, in high-income countries, is estimated to be >20 years in women and >17 years in men. These demographic changes will have a dramatic impact on CVD burden. US estimates predict a 43% increase in the number of CVD patients with exploding health care cost of +198% or approximately 70 billion US dollars. To curb the predicted spiraling costs urgent actions and changes are needed. Appropriate guideline recommendations are pivotal to disseminate and effectuate early effective, safe and affordable therapeutic strategies such as statins for elderly patients. The authors review the different recommendations of the 5 guidelines by focusing on 3 different age population: A. middle aged (40-65 years), B. elderly (66-75 years) and C. very elderly (>75 years), with emphasis on the 66-75 years age group. The most commonly used risk calculators are reviewed, in the context of treatment recommendations: the US Pooled Cohort Risk Equation, Framingham, QRISK2 and SCORE. The article provides a concise overview of all statin trials that did include elderly patients such as ALLHAT-LLT, PROSPER, ASCOT-LLA, CARDS, MEGA, JUPITER and HOPE-3. Despite the lack of RCT trials there is meaningful evidence to support statin therapy in the elderly and that this intervention could provide substantial benefit both for the individual patient and society. To fill-in this gap in our knowledge, the STAREE (STAtins for Reducing Events in the Elderly) trial has been initiated. This is a primary prevention study designed to determine efficacy and safety of statins in individuals >70 years of age.
Mortensen MB, Falk E. Primary Prevention With Statins in the Elderly. J Am Coll Cardiol 2018; 71:85-94. http://www.ncbi.nlm.nih.gov/pubmed/?term=29301631
 
Statins lower (central) blood pressure independently from LDL-c
Using a provocative study design, the authors show that there is a direct effect of LDL-C and statins on blood pressure but that there is a statin mediated effects, un-related to LDL-C as well. This new evidence adds weight to the pleiotropic claims of statins. For their analysis, the CARTAGeNE registry was used. The CARTaGENE cohort consisted of randomly recruited 20 004 individuals (40 to 70 years; July 2009 and October 2010) in major urban regions of Quebec. The aim of this registry was to investigate social, environmental, and medical- determinants of chronic diseases. Central blood pressure measurements were performed in 16 507 participants. The authors used a mediation statistical analysis to distinguish if BP changes were related to plasma LDL-c or statin use, independent of the LDL-c. The measured LDL-c levels showed a positive correlation with central BP (diastolic and systolic) in nonusers (β=0.077 and 0.106; P<0.001), in participants with statins for primary (β=0.086 and 0.114; P<0.001) and secondary prevention (β=0.120 and 0.194; P<0.003). Primary prevention statin users had a lower central systolic, diastolic, and pulse pressures (−3.0, −1.6, and −1.3 mm Hg; P<0.001). Based on mediation analysis the authors showed that LDL-c contributed approximately 15% of the observed central systolic BP, 44% central diastolic BP and 22% central pulse pressure, reductions. For the brachial BP components, similar results were observed. LDL-C seemed to have an effect on the steady (diastolic) components of BP. Vascular tone is one of its major determinants, a reduced endothelial function would have a negative effect. Increased LDL-c has detrimental effects on endothelial function. The pulsatile BP components (systolic and pulse pressures) are related to arterial stiffness. Oxidative stress and endothelial AT II receptors are postulated to be improved by statin related pleiotropic mechanisms, thereby explaining observed BP improvements. Lamarche F, Agharazii M, Nadeau-Fredette AC et al. Central and Brachial Blood Pressures, Statins, and Low-Density Lipoprotein Cholesterol: A Mediation Analysis. Hypertension 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29295849
 
Can pharmacies predict statin persistence and adherence?
After finding the right patient and initiating the right statin in the right dosage, the remaining, and biggest challenge, is to ensure statin persistence and adherence. The University of Groningen pharmacy database (www.IADB.nl) is a registry that contains drug dispensing data, from 60 community pharmacies in the Netherlands, covering approximately 600,000 people. Based on a retrospective analysis of this data, the authors showed that 20.0% of 12 741 patients that started using statins were non-persistent in the 1st year; 9.0% in the 2nd year and 7.5% in the 3rd year. Of the initially persistent patients, 13.4%  were non-adherent in the 1st year, 15.6% in the 2nd year and this increased to 18.1% in the 3rd year. Predictors of non-persistence were:  female gender; HR:1.10 (1.01-1.19), older age; HR:1.52 (1.31-1.75), primary prevention; HR:1.10 (1.00-1.20), initiating on low-dose; HR:1.44 (1.07-1.94) or standard-dose; HR:1.56(1.16-2.10), and no cardiovascular co-medication; HR:1.19 (1.07-1.33). Patients with ≥4 medications were more likely to be persistent. Non-adherence was more frequently observed in patients <50 years; OR:1.47 (1.22-1.77), low socioeconomic status; OR:1.27 (1.12-1.45), and in primary prevention; OR:1.21 1.07-1.38). This contrasted with females, who were more likely to be adherent; OR:0.87 (0.77-0.98. The authors concluded that non-persistence was more frequently observed in the 1st year after statin initiation, while non-adherence increased in the 2nd and 3rd year. Predictors of persistence, and adherence in initially persistent patient, were different. The authors suggested that the observed predictors could aid pharmacists in identifying patients that need support to improve medication use.   Alfian SD, Worawutputtapong P, Schuiling-Veninga CC et al. Pharmacy-based predictors of non-persistence and non-adherence to statin treatment among patients on oral diabetes medication in the Netherlands. Current medical research and opinion 2018:1-17. http://www.ncbi.nlm.nih.gov/pubmed/?term=29292657
 
 
Relevant publications
  1. Zheng-Lin B, Ortiz A. Lipid Management in Chronic Kidney Disease: Systematic Review of PCSK9 Targeting. Drugs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29299849
  2. Canepa M, Artom N, Ameri P et al. Short-term effect of rosuvastatin treatment on arterial stiffness in individuals with newly-diagnosed heterozygous familial hypercholesterolemia. Int J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29290422
  3. Angelini S, Rosticci M, Massimo G et al. Relationship between Lipid Phenotypes, Overweight, Lipid Lowering Drug Response and KIF6 and HMG-CoA Genotypes in a Subset of the Brisighella Heart Study Population. Int J Mol Sci 2017; 19. http://www.ncbi.nlm.nih.gov/pubmed/?term=29295555
  4. Koi C, Izumi H, Kurita T et al. Lovastatin induced Kruppel like factor 2 (KLF2), Kruppel like factor 6 (KLF6) and Ras homolog family member B (RHOB) genes and preferentially led to viability reduction of Cisplatin-resistant cells. Oncotarget 2017; 8:106429-106442. http://www.ncbi.nlm.nih.gov/pubmed/?term=29290960
  5. Dai YY, Huang ZX, Liu XT, Wang QZ. [Risk factors for recurrence of large atherosclerotic cerebral infarction]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2017; 37:1678-1682. http://www.ncbi.nlm.nih.gov/pubmed/?term=29292265
  6. Chen IC, Tseng WK, Li YH et al. Effect of cilostazol on plasma levels of proprotein convertase subtilisin/kexin type 9. Oncotarget 2017; 8:108042-108053. http://www.ncbi.nlm.nih.gov/pubmed/?term=29296222
  7. Cacabelos R, Meyyazhagan A, Carril JC et al. Pharmacogenetics of Vascular Risk Factors in Alzheimer's Disease. Journal of personalized medicine 2018; 8. http://www.ncbi.nlm.nih.gov/pubmed/?term=29301387
Miscellaneous publications
  1. Vogt K, Mahajan-Thakur S, Wolf R et al. Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins. Thrombosis and haemostasis 2018; 118:132-142. http://www.ncbi.nlm.nih.gov/pubmed/?term=29304533
  2. Soares DG, Zhang Z, Mohamed F et al. Simvastatin and nanofibrous poly(l-lactic acid) scaffolds to promote the odontogenic potential of dental pulp cells in an inflammatory environment. Acta biomaterialia 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29294374
  3. Jiang S, Venners SA, Li K et al. Effect modification by region in the associations of LEP G2548A and LEPR Q223R polymorphisms with statin-induced CK elevation. Oncotarget 2017; 8:107565-107576. http://www.ncbi.nlm.nih.gov/pubmed/?term=29296187
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This activity is supported by an educational grant from Pfizer.