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Update - Week 17, 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

The effects of Vitamin D supplementation on statin adherence
The effects of vitamin D supplementation in improving adherence to statins was explored in a secondary analysis of the long-term statin therapy in the Vitamin D Assessment (VIDA) study. A large population-based placebo controlled randomized trial to evaluate the effects of monthly vitamin D (100 000 IU) supplementation on cardiovascular disease and other health outcomes. The trial lasted from 2011 until 2015 and 2494 out of the 5110 participants were on long term statin therapy. Adherence (proportion of days covered by prescriptions >80%)and persistence (non-discontinuation of the statin therapy following an allowed 30 days gap between refills). Overall no effects on compliance were observed (RR 1.01; p=0.62) but improved persistence (RR: 1.15; p<0.02) was noted. Simvastatin users did show improved adherence as well, at 6-months (RR 1.10; p<0.01), 12-months (RR 1.09; p=0.05), and 24- months (RR 1.09; p=0.04). The authors concluded that vitamin D supplementation could increase compliance and persistence to statins, especially for simvastatin users; additional long-term studies are needed to confirm these preliminary findings.
Wu Z, Camargo CA, Jr., Khaw KT et al. Effects of vitamin D supplementation on adherence to and persistence with long-term statin therapy: Secondary analysis from the randomized, double-blind, placebo-controlled ViDA study. Atherosclerosis 2018; 273:59-66. http://www.ncbi.nlm.nih.gov/pubmed/?term=29684661
Friedewald formula update?
Determining precise LDL-c levels is important to determine statin initiation as well as determining dosage selection. In many laboratories LDL-c is calculated using the Friedewald formula: LDL-c = Tc – HDL-c – Tg/5 (in mg/dL). The authors evaluated the accuracy of the Friedewald method with a novel formula (LDL-Cc= TC –HDL-c – TG/adjustable factor) to determine statin eligibility according to the 2013 ACC/AHA guidelines. Using data collected in the NHANES (2005–2014) cohort, 5302 US adults aged between 40 and 75 years and without history of atherosclerotic cardiovascular disease 0.2% (0.0-0.8) and 0.4% (0.3-0.6) would no longer qualify or be newly eligible for statin treatment. In patients with TG’s ≥150 mg/dl and LDL-c ≤70 mg/dl (based on the Friedewald formula) 11.6% (4.0–29.3) would become newly eligible for the statin treatment. The authors suggested that reassessment with the novel LDL-c calculating method, would lead to a small net increase for statin eligibility in patients with TG’s ≥150 mg/dl and LDL-c ≤70 mg/dl.
Shin D, Bohra C, Kongpakpaisarn K. Novel method versus the Friedewald method for estimating low-density lipoprotein cholesterol in determination of the eligibility for statin treatment for primary prevention in the United States. Medicine (Baltimore) 2018; 97:e0612. http://www.ncbi.nlm.nih.gov/pubmed/?term=29703063
BP improvements independent of statin type or dosage

Blood pressure (BP) reductions have been observed in trials/registries where statins were evaluated. Between 2007 and 2017 the effects of different statins on BP was studied in this observational, cross sectional analysis of 987 hypertensive Italian outpatients. They were all managed in a single hypertension unit, were using statins and had a 24-hour ambulatory blood pressures recording. Patients were allocated to 4 groups: 291 (29.5%) on simvastatin 10-80 mg/d, 341 (34.5%) on atorvastatin 10-80 mg/d, 187 (18.9%) on rosuvastatin 5-40 mg/d, and 168 (17.0%) on other statins. All patients showed similar BP reducing effects, except for superior “in Clinic” (P=0.007) and “daytime“ (P=0.13) diastolic blood pressures values of the patients using simvastatin or atorvastatin compared to the individuals taking other statins. The authors suggest that the BP lowering effects of statins is a class effect, not related to either statin type or the dosage, however additional research is warranted to confirm these observational findings.
Presta V, Figliuzzi I, Citoni B et al. Effects of different statin types and dosages on systolic/diastolic blood pressure: Retrospective analysis of 24-hour ambulatory blood pressure database. Journal of clinical hypertension (Greenwich, Conn.) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29683251
Meta-analysis on statins and liver safety or transaminase increases?
The title of this systematic review and meta-analysis is confusing because no information on liver disease of liver complications were presented. The authors did analyze the effects of statin on transaminase increases. Of note no trials with rosuvastatin and only one relatively small trial with atorvastatin was included in this analysis. What they observed is that based on the 16 included studies and 74 078 patients that participated in these clinical trials, transaminases increased and that there was a borderline dose dependent statistical significant effect. OR: 1.18 (1.01-1.93; p=0.04). Intriguingly most robust, and again of borderline significance, effects were observed for Fluvastatin; OR: 3.50 (1.07-11.53; p=0.04). Higher statin dosages (≥40 mg/day) also showed a more pronounced, but not unexpected, impact; OR: 3.62 (1.52-8.65; p=0.004). Recently the detrimental effects of transaminase increases, frequently observed in patients using statins, have been questioned. The reports of serious liver diseases related to statin use are scant and an accumulating numbers studies show improved hepatic outcomes in patients with liver disease that use HMG-CoA reductase inhibitors. The title suggests that statins can compromise liver safety, this seems incorrect as no data is presented in the article to support this. The interpretation of the title and the manner how the results are discussed could persuade doctors to limit statin use in patients with elevated transaminases, as to prevent liver damage. However the inflicted harm of not prescribing statins in (very) high risk patients, because of increased transaminase levels (e.g. DM2/MS + NAFLD/NASH), could have serious consequences in terms an increased risk of fatal and non-fatal ASCVD complications, that far outweigh the risk of serious liver damage.
 Liang X, He Q, Zhao Q. Effect of Stains on LDL Reduction and Liver Safety: A Systematic Review and Meta-Analysis. BioMed research international 2018; 2018:7092414. http://www.ncbi.nlm.nih.gov/pubmed/?term=29693013
Simple, effective strategies to improve statin adherence
In this qualitive review, German GP’s were interviewed to share their experience on statin adherence. In the article barriers, as well as approaches to improve long term statin adherence are presented. Socio-demographic characteristics such as low educational level and older age were seen as important hurdles for adherence by all participants. Although patients with a higher educational level were more likely to continue using taking their statins, they were more concerned about statin benefits as well. Fears of (muscle) related side effects and the effect this could have on their quality of life . GP’s were inclined not to discuss side effects with anxious patients, and as a consequence they were less frequently quizzed about complaints. However, all GP’s were convinced that less informed patients would be more vulnerable to negative media attention and non-expert opinions, factors that could not only affect statin adherence, but the doctor-patient relationship as well. A small number of GP’s were concerned that for primary prevention statins would be a substitute for lifestyle changes and were inclined to stop statins on patient’s requests. The most successful methods to improve adherence, were repeated motivation through patient education as well as patient-centered care. Some GP’s employed specific tools or strategies, such as printed therapy plans, frequently measuring LDL-c levels, checking prescription refill records.  All GP’s stressed the importance of a long term therapeutic relationship to achieve guideline recommended LDL-c targets. Using a person centered approach to overcome concerns and resistance as well as to properly address perceived sided effects, were recommendations that all GP’s agreed on. This would include individual risk assessment combined with shared decision-making. The simple, straightforward advice shared in this review is helpful for clinicians managing patients where statins are indicated.
Kruger K, Leppkes N, Gehrke-Beck S et al. Improving long-term adherence to statin therapy: a qualitative study of GPs' experiences in primary care. Br J Gen Pract 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29686133
Relevant publications
  1. Hashiguchi M, Hakamata J, Shimizu M et al. Risk factors for rhabdomyolysis with HMG-CoA reductase inhibitors identified using a postmarketing surveillance database in Japan. International journal of clinical pharmacology and therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29701171
  2. Yamashita M, Iwata A, Kato Y et al. Impact of the triglyceride level on coronary plaque components in female patients with coronary artery disease treated with statins. Heart Vessels 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29696358
  3. Wei WQ, Li X, Feng Q et al. LPA Variants are Associated with Residual Cardiovascular Risk in Patients Receiving Statins. Circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29703846
  4. Wang K, Chen L, Liu L et al. The effects of atorvastatin on IL-6, CRP, blood lipid and myocardial protection of interventional therapy in patients with acute myocardial infarction. Minerva medica 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29696937
  5. Takata K, Kataoka Y, Andrews J et al. Triglyceride-to-High-Density Lipoprotein Cholesterol Ratio and Vulnerable Plaque Features With Statin Therapy in Diabetic Patients With Coronary Artery Disease: Frequency-Domain Optical Coherence Tomography Analysis. JACC. Cardiovascular imaging 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29680344
  6. Schol-Gelok S, van der Hulle T, Biedermann JS et al. Clinical effects of antiplatelet drugs and statins on D-dimer levels. European journal of clinical investigation 2018:e12944. http://www.ncbi.nlm.nih.gov/pubmed/?term=29682728
  7. Ridker PM, Rose LM, Kastelein JJP et al. Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29685591
  8. Nutman A, Chodick G, Shalev V. The Potential Effects of Implementing the 2013 ACC/AHA Cholesterol Guidelines on the Use of Statins in a Large Health Maintenance Organization in Israel. Value in health regional issues 2015; 7:22-26. http://www.ncbi.nlm.nih.gov/pubmed/?term=29698148
  9. Liang E, Rastegar M. Immune-mediated necrotising myopathy: a rare cause of hyperCKaemia. BMJ case reports 2018; 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29691272
  10. Kim H, Choi HY, Kim YH et al. Pharmacokinetic interactions and tolerability of rosuvastatin and ezetimibe: an open-label, randomized, multiple-dose, crossover study in healthy male volunteers. Drug design, development and therapy 2018; 12:815-821. http://www.ncbi.nlm.nih.gov/pubmed/?term=29692602
  11. Jonnalagadda VG, Shaik A. Statin on insulin and adiponectin levels: true or false prophecy? Diabetes, metabolic syndrome and obesity : targets and therapy 2018; 11:131. http://www.ncbi.nlm.nih.gov/pubmed/?term=29697702
  12. Haddad C, Hallit S, Salhab M et al. Association Between Adherence to Statins, Illness Perception, Treatment Satisfaction, and Quality of Life among Lebanese patients. Journal of cardiovascular pharmacology and therapeutics 2018:1074248418769635. http://www.ncbi.nlm.nih.gov/pubmed/?term=29683005
  13. Gauthier MS, Awan Z, Bouchard A et al. Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29699916
  14. Gant CM, Binnenmars SH, Harmelink M et al. Real-life achievement of lipid-lowering treatment targets in the DIAbetes and LifEstyle Cohort Twente: systemic assessment of pharmacological and nutritional factors. Nutrition & diabetes 2018; 8:24. http://www.ncbi.nlm.nih.gov/pubmed/?term=29695715
  15. DeJonckheere M, Robinson CH, Evans L et al. Designing for Clinical Change: Creating an Intervention to Implement New Statin Guidelines in a Primary Care Clinic. JMIR human factors 2018; 5:e19. http://www.ncbi.nlm.nih.gov/pubmed/?term=29691206
  16. Arinze N, Farber A, Sachs T et al. The effect of statin use and intensity on stroke and myocardial infarction after carotid endarterectomy. Journal of vascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29685507
  17. Anderson JL, Knowlton KU, May HT et al. Temporal changes in statin prescription and intensity at discharge and impact on outcomes in patients with newly diagnosed atherosclerotic cardiovascular disease-Real-world experience within a large integrated health care system: The IMPRES study. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29703626
  18. McKeand W, Baird-Bellaire S, Ermer J, Patat A. A Study of the Potential Interaction Between Bazedoxifene and Atorvastatin in Healthy Postmenopausal Women. Clinical pharmacology in drug development 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29683561
  19. Kotyla PJ. Simvastatin reduces antiphospholipid antibodies formation in patients with systemic lupus erythematosus: a preliminary study. Lupus 2018:961203318772015. http://www.ncbi.nlm.nih.gov/pubmed/?term=29699441
  20. Kato Y, Iwata A, Futami M et al. Impact of von Willebrand factor on coronary plaque burden in coronary artery disease patients treated with statins. Medicine (Baltimore) 2018; 97:e0589. http://www.ncbi.nlm.nih.gov/pubmed/?term=29703054
  21. Hua S, Ma C, Zhang J et al. Influence of APOA5 Locus on the Treatment Efficacy of Three Statins: Evidence From a Randomized Pilot Study in Chinese Subjects. Frontiers in pharmacology 2018; 9:352. http://www.ncbi.nlm.nih.gov/pubmed/?term=29695967
  22. Bajawi SM, Jafarri SA, Buraik MA et al. Pathogenesis-based therapy: Cutaneous abnormalities of CHILD syndrome successfully treated with topical simvastatin monotherapy. JAAD case reports 2018; 4:232-234. http://www.ncbi.nlm.nih.gov/pubmed/?term=29687057
Miscellaneous publications
  1. Rocha B, Rodrigues AR, Tomada I et al. Energy restriction, exercise and atorvastatin treatment improve endothelial dysfunction and inhibit miRNA-155 in the erectile tissue of the aged rat. Nutrition & metabolism 2018; 15:28. http://www.ncbi.nlm.nih.gov/pubmed/?term=29686722
  2. Min JJ, Shin BS, Lee JH et al. Effects of Pravastatin on Type 1 Diabetic Rat Heart with or without Blood Glycemic Control. Journal of diabetes research 2018; 2018:1067853. http://www.ncbi.nlm.nih.gov/pubmed/?term=29682576
  3. Liao Y, Zhang P, Yuan B et al. Pravastatin Protects Against Avascular Necrosis of Femoral Head via Autophagy. Front Physiol 2018; 9:307. http://www.ncbi.nlm.nih.gov/pubmed/?term=29686621
  4. Lee Y, Pai SB, Bellamkonda RV et al. Cerivastatin Nano-Liposome as a Potential Disease Modifying Approach for the Treatment of Pulmonary Arterial Hypertension. J Pharmacol Exp Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29695410
  5. Farrag SM, Hamzawy MA, El-Yamany MF et al. Atorvastatin in nano-particulate formulation abates muscle and liver affliction when coalesced with coenzyme Q10 and/or vitamin E in hyperlipidemic rats. Life sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29694831
  6. Zhou Y, Yang H, Zhou X et al. Lovastatin synergizes with itraconazole against planktonic cells and biofilms of Candida albicans through the regulation on ergosterol biosynthesis pathway. Applied microbiology and biotechnology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29691631
  7. Zeng X, Su W, Liu H et al. Simultaneous determination of rosuvastatin, naringin and naringenin in rat plasma by RRLC-MS/MS and its application to a pharmacokinetic drug interaction study. Journal of chromatographic science 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29701749
  8. Soares DG, Anovazzi G, Bordini EAF et al. Biological Analysis of Simvastatin-releasing Chitosan Scaffold as a Cell-free System for Pulp-dentin Regeneration. Journal of endodontics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29703618
  9. Gu F, Ning J, Fan H et al. Preparation and characterization of simvastatin/DMbetaCD complex and its pharmacokinetics in rats. Acta pharmaceutica (Zagreb, Croatia) 2018; 68:145-157. http://www.ncbi.nlm.nih.gov/pubmed/?term=29702479
  10. Garcia-Guzman P, Medina-Torres L, Calderas F et al. Characterization of hybrid microparticles/Montmorillonite composite with raspberry-like morphology for Atorvastatin controlled release. Colloids and surfaces. B, Biointerfaces 2018; 167:397-406. http://www.ncbi.nlm.nih.gov/pubmed/?term=29702471
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