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Update - Week 45,  2017 
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

Measuring LDL-C stimulates reaching targets!
Correct outpatient evaluation and follow-up after a CAD diagnosis, increases the odds of patients reaching guideline dictated LDL-C targets. The observational INTERCATH study, conducted at the University hospital in Hamburg, enrolled patients that underwent a coronary angiography. The study, started in 2015, and a sub-cohort of 200 newly diagnosed CAD patients were included for this evaluation. Patients were monitored after discharge and had a follow-up of ≥6-months. Lipid lowering medication laboratory and lipid measurements were evaluated at baseline and follow-up visits. In 34.5% of the newly diagnosed CAD patients no lipid measurement was performed at a scheduled outpatient visit. No differences were observed at baseline, between the patients with or without lipid measurements. Patient who had a lipid profile measurement were more likely to have their lipid lowering drugs up-titrated 23.6% vs 4.3%; P<0.001. Patients that had >3 lipid measurements achieved lower LDL-C plasma concentrations (mean 81 mg/dl) and LDL-C targets < 70 mg/dl were reached in a significant greater number of patients, 44.7%. In patients that had one measurement, mean LDL-C was 95mg/dl and 21.8% reached this target. With two measurements mean LDL-C reached 91 mg/dl and 28.9% could achieve the LDL-C goal. The authors concluded that performing, as well as frequency of LDL-C measurements play an important role in treatment intensification to reach LDL-C guideline dictated targets in patients that have been newly diagnosed with CAD. LDL-C measurements should be recommended to improve lipid management in secondary prevention.
Waldeyer C, Seiffert M, Staebe N et al. Lipid Management After First Diagnosis of Coronary Artery Disease: Contemporary Results From an Observational Cohort Study. Clinical therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29103665
Careful when combining statins with…..
In last week’s literature update a case report suggestion potential drug-drug interaction between atorvastatin and ticagrelor (Beavers JC. Elevated Creatine Kinase due to Potential Drug Interaction With Ticagrelor and Atorvastatin. Journal of pharmacy practice 2017:897190017740282. http://www.ncbi.nlm.nih.gov/pubmed/?term=29096571). A new report in this week’s update presents a 49-year-old African American female with a past medical history of hypertension, diabetes mellitus, discoid lupus, remote history of post-streptococcal glomerulonephritis with complete recovery, and multi-vessel disease with drug-eluting stent placement with rhabdomyolysis and acute renal failure. Peak CK levels reached 338,601 IU/ml. on day 2 after ICU admission. Although rosuvastatin is not metabolized by the CYP450A-3/A4, the enzyme partly inhibited by ticagrelor, dosages need to be adjusted if renal function is impaired. Ticagrelor can reduce renal clearance although the exact mechanism is unknown and dose adjustment is not necessary. Patient was switched to clopidogrel and rosuvastatin was discontinued. Within days renal function improved significantly and patient was discharged with clopidogrel + aspirin and the advice to re-evaluate restarting (rosuva)statin after renal function completely recovered.
Another commonly used drug, fusidic acid if combined with (atorva)statin can potentiate the risk for severe myositis and even rhabdomyolysis + acute renal failure. In this case report a 79-year-old women that started with fusidic acid to treat her MSSA positive dermatitis. Two weeks after adding fusidic acid (250 mg 4 x per day) and clindamycin (300 mg 3 x per day) to her medication regimen that include atorvastatin 20 mg she developed limb weakness, myalgia and inability to walk or even stand. After discontinuation of antibiotics and statin her symptoms subsided and abnormal lab tests recovered within 10 days. Although CYP450 3A4 is inhibited by fusidic acid, an inhibitory effect of fusidic acid on the BCRP and OATP1B1 mediated liver and intestinal uptake as well inhibiting hepatic metabolism of statins. Overall 9 studies reported similar deleterious effects of combining statins with fusidic acid. In the majority of the reports atorvastatin was used, but also pravastatin, simvastatin and rosuvastatin were implicated.
These three-separate case-reports illustrate that statins, despite an impressive safety profile, can pose a serious risk for patients that need add on treatment. Drugs that potentiate statin plasma concentrations and trigger life-threatening muscle/renal complications, need to be carefully monitored; patients instructed on specific signs – symptoms and how to respond. 
Samuel G, Atanda AC, Onyemeh A et al. A Unique Case of Drug Interaction between Ticagrelor and Statin Leading to Acute Renal Failure. Cureus 2017; 9:e1633. http://www.ncbi.nlm.nih.gov/pubmed/?term=29104841
Patoulias D, Michailidis T, Papatolios T et al. Rhabdomyolysis Induced by Coadministration of Fusidic Acid and Atorvastatin: A Case Report and Comprehensive Review of the Literature. Case Rep Nephrol 2017; 2017:2187264. http://www.ncbi.nlm.nih.gov/pubmed/?term=29119029
Additional lipid lowering needed before carotid artery stent placement?
Although complete regression of existing atherosclerotic lesions is unrealistic, plaque stabilizing effects of the existing lesions is an achievable aim with intensive lipid lowering regimens. In this single center Japanese study, patients that received a carotid artery stent (CAS) were followed post-operatively to determine if additional aggressive lipid lowering treatment would reduce the occurrence of new ischemic lesions on diffusion-weighted imaging (DWI). This is a complication that can be observed regularly, after a CAS deployment. Patients that had a CAS procedure between April 2013 and August 2016 were evaluated and out of 187, 60 patients were diagnosed with symptomatic artery-to-artery embolism from carotid plaques. DWI lesions were more frequently observed in patients with increased baseline triglycerides. This was confirmed in 17 (28%) of the 187 patients. Additional lipid lowering (ALL) was started in patients with baseline LDL-C > 120 mg/dl, or >100mg/dl if CAD was present. The add on therapy was started on average 15 days before the scheduled CAS procedure. In total 26 patients started with ALL, 8 used evolocumab. In patients that initiated ALL, new lesions occurred in 11.5%; those not treated with ALL had DWI incidence of 41.2%; P=0.029. The authors suggested that a treatment strategy that aims for >50% LDL-C reduction, seems to be superior than a treat-to-target approach to improve prognosis after CAS. 
Mizobe T, Nakamura M, Motooka Y et al. Impact of Additional Lipid-Lowering Therapy on New Ischemic Lesions of Diffusion-Weighted Imaging in Carotid Artery Stenting. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29103862
Do elderly patients benefit from statins? Women do!
The lipid management of (very) elderly patients has been insufficiently addressed in the large randomized clinical endpoint trials. Data from observational studies is the source of growing number publications seeking to aid clinicians in their quest for reliable evidence how to manage this increasing category of patients. This study used a retrospective analysis of data collected in a tertiary medical center of elderly patients (>80years) admitted to the dept. of internal medicine for 1 year. Total 3-year mortality and survival years after hospital admissions were the targeted endpoints of this study. There were 216 patients included in this study: 122(56.5%) women, aged 85.3. Overall 66 (53.2%) of the women and 58 (46.8%) of the men used statins for ≥3 years after hospital admission. Over the 3 years of the study 48 (39.3%) of the women and 48 (51.1%) of the men died. Statins were observed to be protective in the women only. Of the women not using statins 57.1% died vs 24.2% of those that did use statins. RR 0.2 (0.1-0.5; p<0.0001). Women that used statins for primary prevention or secondary preventions the P values were P<0.0001 and P=0.014 respectively. For elderly men, no benefits could be observed, one possible reason for this intriguing difference is the higher life expectancy in women compared to men, as suggested by the authors.
Justo D, Tchernichovsky M, Kremer A et al. Gender differences in mortality among statin users aged 80 years or more. Zeitschrift fur Gerontologie und Geriatrie 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29116376
Fluctuations of plasma CETP – PCSK9 – Lp(a) concentrations in ILLUMINATE
The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial included 15,067 men and women at high cardiovascular risk, was used to evaluate the effects of lipid lowering treatment on plasma PCSK9 and Lp(a) levels and subsequent CAD risk. Patients were titrated with atorvastatin 10 – 20 - 40 and 80 mg/day, aiming for an LDL-C target < 100 mg/dl.  Subsequently patients were randomized to torcetrapib or placebo. At baseline atorvastatin use was associated with a dose dependent increase PCSK9 and Lp(a) levels. Diabetic patients had a significant higher PCSK9 (357 ± 123 vs 338 ±115 ng/mL, P = 0.0012) and lower LP(a) (28 ± 32 vs 32 ± 33 mg/dL, P =0.0005) plasma concentrations. In a similar fashion torcetrapib lightly increased PCSK9 (+13.1 ± 125.3 ng/mL [+3.7%], P < 0.005) and reduced Lp(a) (-3.4 ± 10.7 mg/dL [-11.1%], P < 0.0001). The mechanism of statin mediated PCSK9 increased have been elucidated but the dose dependent LP(a) rise remain elusive. Observed decrease of Lp(a) and increase of PCSK9 in diabetic patients are not well understood either.  The authors concluded that physiological link(s) between glycemic parameters, PCSK9, LDL receptor function, and Lp(a) metabolism clearly needs to be addressed in future studies.
Arsenault BJ, Petrides F, Tabet F et al. Effect of atorvastatin, cholesterol ester transfer protein inhibition, and diabetes mellitus on circulating proprotein subtilisin kexin type 9 and lipoprotein(a) levels in patients at high cardiovascular risk. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29103916
Relevant publications
  1. Thompson GR, Blom DJ, Marais AD et al. Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29106543
  2. Michos ED, Blaha MJ, Blumenthal RS. Use of the Coronary Artery Calcium Score in Discussion of Initiation of Statin Therapy in Primary Prevention. Mayo Clinic proceedings 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29108840
  3. Lee MG, Lee CC, Lai CC et al. Preadmission statin use improves the outcome of less severe sepsis patients - a population-based propensity score matched cohort study. British journal of anaesthesia 2017; 119:645-654. http://www.ncbi.nlm.nih.gov/pubmed/?term=29121292
  4. Labos C, Brophy JM, Smith GD et al. Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression. Arterioscler Thromb Vasc Biol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29122815
  5. Kim KM, Jung KY, Yun HM et al. Effect of rosuvastatin on fasting and postprandial endothelial biomarker levels and microvascular reactivity in patients with type 2 diabetes and dyslipidemia: a preliminary report. Cardiovascular diabetology 2017; 16:146. http://www.ncbi.nlm.nih.gov/pubmed/?term=29121934
  6. Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study. J Hepatol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29107150
  7. Giugliano RP, Keech A, Murphy SA et al. Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29117276
  8. Gencer B, Koskinas KC, Raber L et al. Eligibility for PCSK9 Inhibitors According to American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines After Acute Coronary Syndromes. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29122809
  9. Burstein B, Altobelli KK, Williams K et al. Impact of Heart Outcomes Prevention Evaluation Trial on Statin Eligibility for the Primary Prevention of Cardiovascular Disease: Insights from the National Health and Nutrition Examination Survey. Circulation 2017; 136:1860-1862. http://www.ncbi.nlm.nih.gov/pubmed/?term=29109198
  10. Brennan MB, Huang ES, Lobo JM et al. Longitudinal trends and predictors of statin use among patients with diabetes. Journal of diabetes and its complications 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29107453
  11. Wada S, Koga M, Toyoda K et al. Factors Associated with Intima-Media Complex Thickness of the Common Carotid Artery in Japanese Noncardioembolic Stroke Patients with Hyperlipidemia: The J-STARS Echo Study. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29118311
  12. Soska V, Kyselak O. [Is it possible to improve long-term compliance of patients to statin therapy?]. Vnitr Lek 2017; 63:663-666. http://www.ncbi.nlm.nih.gov/pubmed/?term=29127749
  13. Sandesara PB, Ramjee V, Ghasemzadeh N et al. Circulating progenitor cells in patients with familial hypercholesterolemia. Journal of clinical apheresis 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29114919
  14. Saasouh W, Leung S, Yilmaz HO et al. Are perioperative therapeutic doses of statins associated with postoperative pain and opioid consumption after hip surgery under spinal anaesthesia? British journal of anaesthesia 2017; 119:803-811. http://www.ncbi.nlm.nih.gov/pubmed/?term=29121296
  15. Parikh KH, Kirtane AJ. Should We Up the Intensity of Statin Therapy After Placing a Drug-eluting Stent. Rev Esp Cardiol (Engl Ed) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29104001
  16. Lumu W, Kampiire L, Akabwai GP et al. Dyslipidaemia in a Black African diabetic population: burden, pattern and predictors. BMC research notes 2017; 10:587. http://www.ncbi.nlm.nih.gov/pubmed/?term=29121994
  17. Krysiak R, Szkrobka W, Okopien B. The Effect of Hypolipidemic Agents on Thyroid Autoimmunity in Women with Hashimoto's Thyroiditis Treated with Levothyroxine and Selenomethionine. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29117614
  18. Gnjidic D, Du W, Pearson SA et al. Ascertainment of self-reported prescription medication use compared with pharmaceutical claims data. Public health research & practice 2017; 27. http://www.ncbi.nlm.nih.gov/pubmed/?term=29114718
  19. Ganz P, Amarenco P, Goldstein LB et al. Association of Osteopontin, Neopterin, and Myeloperoxidase With Stroke Risk in Patients With Prior Stroke or Transient Ischemic Attacks: Results of an Analysis of 13 Biomarkers From the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trial. Stroke 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29114094
  20. Ercan E. Statin treatment in dialysis patients after acute myocardial infarction improves overall mortality. Atherosclerosis 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29111224
  21. Cheng-Lai A, Snead J, Ng C et al. Comparison of Adherence to the 2013 ACC/AHA Cholesterol Guideline in a Teaching Versus Nonteaching Outpatient Clinic. The Annals of pharmacotherapy 2017:1060028017739325. http://www.ncbi.nlm.nih.gov/pubmed/?term=29103310
  22. Akram Z, Vohra F, Javed F. Efficacy of statin delivery as an adjunct to scaling and root planing in the treatment of chronic periodontitis: A meta-analysis. Journal of investigative and clinical dentistry 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29119729
  23. Correction: Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. BMJ open diabetes research & care 2017; 5:e000438corr000431. http://www.ncbi.nlm.nih.gov/pubmed/?term=29119974
Miscellaneous publications
  1. Nozu T, Miyagishi S, Kumei S et al. Lovastatin inhibits visceral allodynia and increased colonic permeability induced by lipopolysaccharide or repeated water avoidance stress in rats. Eur J Pharmacol 2017; 818:228-234. http://www.ncbi.nlm.nih.gov/pubmed/?term=29107672
  2. Hoeke G, Wang Y, van Dam AD et al. Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis. Atherosclerosis 2017; 267:116-126. http://www.ncbi.nlm.nih.gov/pubmed/?term=29121499
  3. Chang Y, Li Y, Ye N et al. Atorvastatin protects the proliferative ability of human umbilical vein endothelial cells inhibited by angiotensin II by changing mitochondrial energy metabolism. International journal of molecular medicine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29115384
  4. Buranrat B, Suwannaloet W, Naowaboot J. Simvastatin potentiates doxorubicin activity against MCF-7 breast cancer cells. Oncology letters 2017; 14:6243-6250. http://www.ncbi.nlm.nih.gov/pubmed/?term=29113274
  5. Sarfraz RM, Ahmad M, Mahmood A et al. Development of beta-cyclodextrin-based hydrogel microparticles for solubility enhancement of rosuvastatin: an in vitro and in vivo evaluation. Drug design, development and therapy 2017; 11:3083-3096. http://www.ncbi.nlm.nih.gov/pubmed/?term=29123380
  6. Salama AH, Basha M, El Awdan S. Experimentally designed lyophilized dry emulsion tablets for enhancing the antihyperlipidemic activity of atorvastatin calcium: Preparation, in-vitro evaluation and in-vivo assessment. Eur J Pharm Sci 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29117504
  7. Lee JY, Kim MS, Ju JE et al. Simvastatin enhances the radiosensitivity of p53deficient cells via inhibition of mouse double minute 2 homolog. International journal of oncology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29115437
  8. Chang WL, Jackson C, Riel S et al. Differential preventive activity of sulindac and atorvastatin in Apc+/Min-FCCCmice with or without colorectal adenomas. Gut 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29122850
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