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Update - Week 43, 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

Pharmacist can address the statin treatment gap in diabetic patients
To bridge the gap of optimally treating risk factors in patients with DM2, innovative approaches are explored. Pharmacists can play a more direct role in the management of diabetic patients by actively intervening in therapeutic strategies of inadequately treated diabetic patients. Absence of statin prescriptions was observed in 38% of the participants of the US PINNACLE registry. The authors share an approach by the US state of Idaho that allowed pharmacists to initiate statin prescription in statin eligible diabetic patients, starting July 1st, 2018. Following strict criteria, statins can be only initiated diabetic patients (40-75 years) without contraindications or exclusion or cautionary criteria specified in guidelines. Pharmacists need to collect relevant clinical information as well as a patient-specific follow-up care and monitoring plan in accordance with clinical guidelines. The patient’s health care provider will be informed of changes in the therapeutic portfolio, adding statins, within 5 business days, to reduce fragmentation and ensure continuity of care. The authors suggest that the Idaho approach could be implemented in other US states or non-US healthcare settings.
Vanderholm T, Renner HM, Stolpe SF, Adams AJ. An Innovative Approach to Improving the Proposed CMS Star Rating "Statin Use in Persons with Diabetes". Journal of managed care & specialty pharmacy 2018; 24:1126-1129. http://www.ncbi.nlm.nih.gov/pubmed/?term=30362914
 
The essence of Statin safety by Collins and Peto
In this updated review of Collins and Peto the benefits of statins are given a fresh perspective using existing clinical trial data that consistently and convincingly re-affirms not only benefits but safety of this drug class as well. In this new effort to refute the claims of so called “statin sceptics”, they succeed in providing sold scientific evidence from large randomized clinical trials and contrast this with the unfounded claims of statin harms mostly based on non-randomized observational findings. Explaining in simple terms why evidence-based medicine relies on data from RCT’s to prompt for reliable clinical decisions, supported by hard proof of efficacy as well as safety for our clinical therapeutic strategies, ultimately translated into practice guidelines. They report the finding of 11 large (> 1000 patients) clinical outcome trials using statins. Systematically asked questions as well as initial run-in period are compared and highlighted in trials that included these options and trials that did not. Studies where patients were asked detailed questions regarding muscle related side effects did show an increase of muscle based complains but failed to show bigger contrast between statin or placebo users. Similar observations in trials that included a so called “run-in” phase, failing to show increased reported side effects in statin users versus patients using a placebo. Overall, 9 trials that included > 10 000 patients, muscle related symptoms were observed in 11.7% of the active drug users vs 11.4% in the placebo group, so a difference of 0.3% (SE 0.2%) and not statistically significant. IN their final comment the emphasize the need for better communicating the well proven benefits of statins, and the very small risk of harm observed in RCT using statins.
Peto R, Collins R. Trust the Blinded Randomized Evidence That Statin Therapy Rarely Causes Symptomatic Side Effects. Circulation 2018; 138:1499-1501. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354509
 
Can statins reduce mortality in sceptic/bacteremic patients?
The effects of statins on inflammation and infection are re-surfacing in publications quite regularly. Not exclusively in the cardiovascular disease arena but in communicable diseases as well. Recent reports on potential anti-microbial properties is an example of surprising non-LDL- c lowering effects. In this article, the authors highlight that continued statin use, in bacteremic patients, have potential benefits to promote survival. In this retrospective analysis of 633 bacteremic patients that were cared for in a single US center between October 2009 and March 2013, available electronic patient data was queried. Patients were selected if they used antibiotics at least 2 days during the first 3 days of their hospital stay and were adherent to statins ≥90 days prior to admission as well as ≥5 days after admission (N=232); vs those not continuing statins during their hospital stay (N=401). The statins used were simvastatin (53.2%) and atorvastatin (33.8%). Based on a propensity score-adjusted Cox proportional hazards regression analysis, statin continuations resulted in significantly better survival. The percentage of patients that died during admission were 2.59% vs 10.97% respectively; HR: 0.25 (0.08-0.79; p=0.0002). length of stay was higher in statin users as well; median 6.0, interquartile range (IQR) 5.0– 9.0 vs 5.0 days, IQR 3.0–9.0 (p < 0.0001). The conflicting and confusing evidence on statin use in septicemic/bacteremic patients, as well as the obvious limitations of this observational study, ensure that this dilemma is not resolved. However, the impressive results of this study are in line with earlier findings, do warrant for more robust studies in septicemic/bacteremic patients and the role that statins could play in reducing their very high mortality risk.
Pawar AM, LaPlante KL, Timbrook TT, Caffrey AR. Improved survival with the continuation of statins in bacteremic patients. SAGE open medicine 2018; 6:2050312118801707. http://www.ncbi.nlm.nih.gov/pubmed/?term=30364748
 
The Rule of 6 confirmed in “Real World” patient data
The expected LDL-c lowering response was formulated over a decade ago by Scott Grundy as “The Rule of 6”  (or 7). Based on randomized clinical trial data an additional 6% lower LDL-c was observed with every doubling of the statin dosage, independent of the type of statin used. In this “Real World” study of statin users, based on the Kaiser Permanent Genetic Epidemiology Research on Adult Health and Aging registry (N=33 139), a more up-to-date robust analysis of statin response was conducted. A log linear relationship of a defined daily dosage (DDD) and LDL-c response was observed (β, −6.17; SE, 0.09; P<10–300) after adjusting for covariates the response remained almost unchanged (adjusted β, −5.59; SE, 0.12; P<10–300). Independent and significant predictors of statin response were: Statin type, sex, age, smoking status, diabetes mellitus, and East Asian race/ethnicity. Using data collected of at least 1 first-degree statin using relative (N=1036) the heritability of statin use was estimated at 11.7% (SE, 8.6%; P=0.087). These findings re-affirmed that the RCT based “rule of 6” was reliable when analyzing statin response in a “Real World” population. LDL-c lowering was affected by a number of clinical and demographic predictors, however, heritability of statin effects was not that strong. The authors suggest that their findings re-affirm that electronic patient data can be used as a robust source of phenotypes to conduct pharmacogenetic studies as well as precision medicine for statin-based lipid management.
Oni-Orisan A, Hoffmann TJ, Ranatunga D et al. Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort. Circulation. Genomic and precision medicine 2018; 11:e002043. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354326
 
Starting statin + aspirin in patients with MN renal disease, no time to lose!
The use of statin in patients with renal disease is a complicated one and a “one size fits all” is unfortunately not the strategy to follow. This single-center New Zealand study, focused on patients affected by primary membranous nephropathy (MN). Data were collected of 204, biopsied proven, MN patients between 2003 and 2013 (clinical events were retrospectively reviewed until November 2016). Follow up data were available of 166 patients, of which 31 patients had a major cardiovascular event (18.6%), 19 patients suffered an AMI and 12 a stroke. Almost half of these events (38%) occurred in the 1st year after the diagnosis was confirmed. The risk was higher in males, older, and diabetics as well as in patients not using statins. The latter increased the risk 2.6-fold (1.3-5.2; p=0.0047). Only 40% of the NM patients used a statin and, despite their increased thrombotic risk, only 42% used an anti-thrombotic agent. The observed dyslipidemia e.g. increases in LDL-c, triglycerides, Lp(a) and lower HDL-c warrants rapid and intensive lipid control by statins, this is suggested by the Kidney Disease Improvement Global Outcomes (KDIGO) guidelines as well, recommending statin use in patients with glomerular disease and dyslipidemia. The authors concluded that the observed very high CVD and thrombotic risk in MN patients warrants the use of statins and aspirin. The rapid onset of complications observed in the 1st year after diagnoses underline that starting these medications as soon as their diagnosis is confirmed is crucial.
Alawami M, Wimalasena S, Ghashi R, Alnasrallah B. Acute Arterial Cardiovascular Events Risk in Patients with Primary Membranous Nephropathy. Internal medicine journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30346109
 
Relevant publications
  1. Tuteja S, Rader DJ. SLCO1B1 and Statin Therapy. Circulation. Genomic and precision medicine 2018; 11:e002320. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354338
  2. Teschke R. Top ranking drugs out of 3312 drug induced liver injury cases evaluated by the Roussel Uclaf Causality Assessment Method. Expert Opin Drug Metab Toxicol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354694
  3. Rea F, Calusi G, Franchi M et al. Adherence of Elderly Patients with Cardiovascular Disease to Statins and the Risk of Exacerbation of Chronic Obstructive Pulmonary Disease: Evidence from an Italian Real-World Investigation. Drugs Aging 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30361806
  4. Radaelli G, Sausen G, Cesa CC et al. Statin Treatments And Dosages In Children With Familial Hypercholesterolemia: Meta-Analysis. Arquivos brasileiros de cardiologia 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30365601
  5. Peyser B, Perry EP, Singh K et al. Effects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational Settings. Circulation. Genomic and precision medicine 2018; 11:e002228. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354330
  6. Petrov IS, Postadzhiyan AS, Tokmakova MP et al. Management of High and Very High-Risk Subjects with Familial Hypercholesterolemia: Results from an Observational Study in Bulgaria. Folia medica 2018; 60:389-396. http://www.ncbi.nlm.nih.gov/pubmed/?term=30355848
  7. Obreja E, Sequeira P, Girnita D. When Should a Patient with Statin-Induced Myopathy Be Re-challenged? A Case of Necrotizing Autoimmune Myopathy. Case Rep Rheumatol 2018; 2018:1215653. http://www.ncbi.nlm.nih.gov/pubmed/?term=30364043
  8. Nimitphong H, Mahattanapreut A, Chailurkit LO et al. More evening preference is positively associated with systemic inflammation in prediabetes and type 2 diabetes patients. Scientific reports 2018; 8:15882. http://www.ncbi.nlm.nih.gov/pubmed/?term=30367094
  9. Nehme MA, Upadhyay A. Ezetimibe in the Treatment of Patients with Metabolic Diseases. European endocrinology 2013; 9:55-60. http://www.ncbi.nlm.nih.gov/pubmed/?term=30349611
  10. Mottl AK, Buse JB, Ismail-Beigi F et al. Long-Term Effects of Intensive Glycemic and Blood Pressure Control and Fenofibrate Use on Kidney Outcomes. Clin J Am Soc Nephrol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30361335
  11. Moore N, Duret S, Grolleau A et al. Previous Drug Exposure in Patients Hospitalised for Acute Liver Injury: A Case-Population Study in the French National Healthcare Data System. Drug Saf 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30361989
  12. Lim J, Rietveld A, De Bleecker JL et al. Seronegative patients form a distinctive subgroup of immune-mediated necrotizing myopathy. Neurology(R) neuroimmunology & neuroinflammation 2019; 6:e513. http://www.ncbi.nlm.nih.gov/pubmed/?term=30345336
  13. Hermans MP, Gevaert S, Descamps O et al. Frequency and predictors of cholesterol target attainment in patients with stable coronary heart disease in Belgium: results from the Dyslipidemia International Study II (DYSIS II CHD). Acta clinica Belgica 2018:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=30355016
  14. Ge Z, Baber U, Claessen BE et al. The prevalence, predictors and outcomes of guideline-directed medical therapy in patients with acute myocardial infarction undergoing PCI, an analysis from the PROMETHEUS registry. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30351514
  15. Yan MM, Wu SS, Ying YQ et al. Safety assessment of concurrent statin treatment and evaluation of drug interactions in China. SAGE open medicine 2018; 6:2050312118798278. http://www.ncbi.nlm.nih.gov/pubmed/?term=30345053
  16. Di Bartolo BA, Psaltis PJ, Bursill CA, Nicholls SJ. Translating Evidence of HDL and Plaque Regression. Arterioscler Thromb Vasc Biol 2018; 38:1961-1968. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354261
  17. Chyzhyk V, Kozmic S, Brown AS et al. Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30352774
  18. Chung PW, Yoon BW, Lee YB et al. Medication Adherence of Statin Users after Acute Ischemic Stroke. European neurology 2018; 80:106-114. http://www.ncbi.nlm.nih.gov/pubmed/?term=30347393
  19. Boulmpou A, Kartas A, Farmakis I et al. Motivational Interviewing to Support LDL-C Therapeutic Goals and Lipid-Lowering Therapy compliance in patients with Acute Coronary Syndromes (IDEAL-LDL) Study: Rationale and design. Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30352291
  20. Yeh JJ, Lin CL, Hsu CY et al. Statin for Tuberculosis and Pneumonia in Patients with Asthma(-)Chronic Pulmonary Disease Overlap Syndrome: A Time-Dependent Population-Based Cohort Study. Journal of clinical medicine 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30355982
  21. Xiang Q, Zhang X, Ma L et al. The association between the SLCO1B1, apolipoprotein E, and CYP2C9 genes and lipid response to fluvastatin: a meta-analysis. Pharmacogenetics and genomics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30363031
  22. Verma S, Leiter LA, Mazer CD et al. Liraglutide Reduces Cardiovascular Events and Mortality in Type 2 Diabetes Mellitus Independently of Baseline Low-Density Lipoprotein Cholesterol Levels and Statin Use. Circulation 2018; 138:1605-1607. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354517
  23. Vassy JL, Brunette CA, Majahalme N et al. The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study: Protocol for a point-of-care randomized controlled trial of statin pharmacogenetics in primary care. Contemporary clinical trials 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30367991
  24. Slomski A. Benefits May Persist After Antihypertensive and Statin Treatment. Jama 2018; 320:1631. http://www.ncbi.nlm.nih.gov/pubmed/?term=30357296
  25. Lin JH, Lin YF, Wang WJ et al. Plasma Aldosterone Concentration as a Determinant for Statin Use among Middle-Aged Hypertensive Patients for Atherosclerotic Cardiovascular Disease. Journal of clinical medicine 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30355992
  26. Langballe R, Cronin-Fenton D, Dehlendorff C et al. Statin use and risk of contralateral breast cancer: a nationwide cohort study. Br J Cancer 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30353047
  27. Kumamaru H, Lee MP, Choudhry NK et al. Using Previous Medication Adherence to Predict Future Adherence. Journal of managed care & specialty pharmacy 2018; 24:1146-1155. http://www.ncbi.nlm.nih.gov/pubmed/?term=30362915
  28. Krysiak R, Szkrobka W, Okopien B. Atorvastatin potentiates the effect of selenomethionine on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis. Current medical research and opinion 2018:1-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354702
  29. Koh KK. Letter by Koh Regarding Article, "Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)". Circulation 2018; 138:1914-1915. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354661
  30. Itoh H, Ueshima K, Komuro I. Response to Comment on Itoh et al. Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. Diabetes Care 2018;41:1275-1284. Diabetes Care 2018; 41:e145-e146. http://www.ncbi.nlm.nih.gov/pubmed/?term=30348847
  31. Elsby R, Hare V, Neal H et al. Mechanistic in vitro studies indicate that the clinical drug-drug interaction between telithromycin and simvastatin acid is driven by time-dependent inhibition of CYP3A4 with minimal effect on OATP1B1. Drug metabolism and disposition: the biological fate of chemicals 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30348903
  32. Donzelli A, Schivalocchi A, Giudicatti G, Battaggia A. Comment on Itoh et al. Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. Diabetes Care 2018;41:1275-1284. Diabetes Care 2018; 41:e143-e144. http://www.ncbi.nlm.nih.gov/pubmed/?term=30348846
  33. Donzelli A, Schivalocchi A, Giudicatti G. Letter by Donzelli et al Regarding Article, "Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)". Circulation 2018; 138:1912-1913. http://www.ncbi.nlm.nih.gov/pubmed/?term=30354663
  34. Chidwick K, Strongman H, Matthews A et al. Statin use in cancer survivors versus the general population: cohort study using primary care data from the UK clinical practice research datalink. BMC Cancer 2018; 18:1018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30348123
  35. Bergstrom H, Branvall E, Helde-Frankling M, Bjorkhem-Bergman L. Differences in discontinuation of statin treatment in women and men with advanced cancer disease. Biology of sex differences 2018; 9:47. http://www.ncbi.nlm.nih.gov/pubmed/?term=30342545
  36. Aminsharifi A, Howard LE, Amling CL et al. Statins are Associated With Increased Biochemical Recurrence After Radical Prostatectomy in Diabetic Men but no Association was Seen in Men also Taking Metformin: Results From the SEARCH Database. Clinical genitourinary cancer 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30366879
Miscellaneous publications
 
 
  1. Yu P, Yang X, Qi Z. Letter to the editor: The sole and combined effect of simvastatin and platelet rich fibrin as a filling material in induced bone defect in tibia of albino rats. Bone 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30366110
  2. Spiridon AM, Neamtu J, Belu I et al. Simultaneous Analysis of Clopidogrel Bisulfate, Acetylsalicylic Acid and Atorvastatin calcium in Tablets by HPLC Method. Current health sciences journal 2015; 41:172-178. http://www.ncbi.nlm.nih.gov/pubmed/?term=30364896
  3. Pei WN, Hu HJ, Liu F et al. C-reactive protein aggravates myocardial ischemia/reperfusion injury through activation of extracellular-signal-regulated kinase 1/2. Journal of geriatric cardiology : JGC 2018; 15:492-503. http://www.ncbi.nlm.nih.gov/pubmed/?term=30364730
  4. Liu J, Huang H, Shi S et al. Atorvastatin upregulates apolipoprotein M expression via attenuating LXRalpha expression in hyperlipidemic apoE-deficient mice. Experimental and therapeutic medicine 2018; 16:3785-3792. http://www.ncbi.nlm.nih.gov/pubmed/?term=30344653
  5. Fahmy UA. Augmentation of Fluvastatin Cytotoxicity Against Prostate Carcinoma PC3 Cell Line Utilizing Alpha Lipoic-Ellagic Acid Nanostructured Lipid Carrier Formula. AAPS PharmSciTech 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30350252
  6. Dourado PMM. Rosuvastatin Decreases the Formation of Neointima by Increasing Apo J, Reducing Restenosis after Balloon Injury in Rats. Arquivos brasileiros de cardiologia 2018; 111:569-570. http://www.ncbi.nlm.nih.gov/pubmed/?term=30365679
  7. Zapata-Catzin GA, Bonilla-Hernandez M, Vargas-Coronado RF et al. Effect of the rigid segment content on the properties of segmented polyurethanes conjugated with atorvastatin as chain extender. Journal of materials science. Materials in medicine 2018; 29:161. http://www.ncbi.nlm.nih.gov/pubmed/?term=30357534
  8. Yan S, Ren J, Jian Y et al. Injectable maltodextrin based micelle/ hydrogel composites for simvastatin controlled release. Biomacromolecules 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30350597
  9. Verma M, Nanda A, Kumar Y. Self-Emulsifying Drug Delivery System of Simvastatin: Formulation Development, Optimization by Box- Behnken Design, In-Vitro and In-Situ Single-Pass Intestinal Perfusion (SPIP) Studies. Recent patents on drug delivery & formulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30345934
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