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Update - Week 32, 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

Statins use in ACS patients with very low baseline LDL-c; is it worth it?
The benefits of statins in ACS patients with baseline LDL-c below guideline targets are not well documented and remain controversial. A low LDL-c is not an uncommon finding in Asian patients. The large Chinese ACS registry (CPACS - Clinical Pathways for Acute Coronary Syndromes) was used for this analysis and 16% of the included patients had a baseline LDL-c < 70 mg/dl.  Chinese ACS patients with LDL-c <70 mg were included, comparing patients that used a statin with patients that did not. They were matched using an extensive propensity score modeling. Patients were diagnosed with STEMI (34,53%), NSTEMI (13.16%) and UA (52,31%). Of the total 3374 patients, 2879 (85%) used a statin. Mean LDL-c was 55.61 mg/dl in the statin group and 54.57 mg/dl in patient that did not use a statin. Atorvastatin 20 mg was the most prescribed statin and <3% used atorvastatin ≥40 mg. Mace rates as well as cardiac deaths and all-cause mortality were significantly higher in the patients that were not prescribed statins. The HR for MACE in statin users vs non users was 0.61 (0.40-0.94). The HR’s of patients using the equivalent of 5-10 mg atorvastatin and patients using ≥20 mg was 0.61(0.40-0.94) and 0.53(0.34-0.84) respectively. The authors concluded that using low to moderate dose statin in Chinese ACS patients resulted in significant lower MACE ‘s and total mortality, 12 months after the initiating event. To build and expand this observational evidence larger randomized trials, that include the use of higher statin dosages, need to be designed and executed.
Sun Y, Xie G, Patel A et al. Prescription of statins at discharge and one-year risk of major clinical outcomes among ACS patients with extremely low LDL-c in CPACS studies. Clin Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30084224
The future of personalized lipid management of CKD patients
In this updated review on the use of statins in chronic kidney disease patients (CKD), the authors discuss the dilemma’s that clinicians face when caring for patients with impaired renal function. Although 4 large studies, the 4 D study and the AURORA trial failed to show benefits in end stage CKD/hemodialysis patients, benefits have been observed in less advanced CKD patients as well an increased risk of harm or improved outcomes in patients with specific genetic, ethnic or metabolomic characteristics. Potential options to personalize the use of statins in certain CKD patients reviewed. Meta-analysis of statin trials and subgroups in the large clinical outcome trials like JUPITER, SHARP and IMPROVE-IT showed improved outcomes in sub groups of patients that were treated with statins or statin + ezetimibe. Co-morbidities, including impaired renal function, and/or concomitant medication, increase the risk for statin related side effects. The same was found for specific genetic polymorphisms of proteins involved in statin metabolism and/or trans-membrane transport of a broad range of molecules including statins. Racial related factors have gained importance in relationship to statin plasma concentration and related side effects. Asian ancestry increases the risk of statin side effects. African ancestry was shown to impact baseline CPK concentrations, and the observed higher CPK levels are not associated with muscle related damage. Non-statin drugs as ezetimibe, fibrates and PCSK9ab reduced CVD risk in subgroups of patients with impaired renal function. Future targets such as improving HDL efflux and other functional indices are being explored. Oxidative stress reflected by MPO concentrations is another attractive new target to reduce CVD risk in CKD patients. Finally metabolomics are suggested as a innovative and promising technique to personalize risk estimation and response to lipid lowering drugs in the future.
Streja E, Streja DA, Soohoo M et al. Precision Medicine and Personalized Management of Lipoprotein and Lipid Disorders in Chronic and End-Stage Kidney Disease. Seminars in nephrology 2018; 38:369-382. http://www.ncbi.nlm.nih.gov/pubmed/?term=30082057
For primary prevention which patients benefit from using a statin and who don’t?
The use of statins in a primary prevention setting is less clear as in patients who suffered CVD complications. Baseline risk estimation is needed to distinguish those were statins could reduce risk and those were benefits might be counter balanced by statin associated harms e.g. DM type 2. In this retrospective observational analysis of the Israeli Maccabi Healthcare Services (MHS), medical data of >2 million patients was re-evaluated. For this analysis the authors selected 265 414 patients not using statins, and without CVD or DM, at least 2 year prior to the index date of 2010 and that had at least one statin prescription between January 1st, 2010 and December 31st, 2014. Individual CVD risk was calculated using the ESC based SCORE risk tables. Patients were stratified into 3 cohorts: low risk: ≤1% intermediate risk: 1-5% and high risk ≥5%. Statins were used by 17.9% of the selected individuals. Between 2010 and 2014, 5157 (1.9%) patients had a CVD event and 11 637 (4.4%) patients developed diabetes. Those that used low-intensity statin, with over 50% adherence, were more likely to develop diabetes if their CVD risk was low or intermediate. This was not the case for patients in the high CVD risk category. No CVD benefit was observed in the low risk category; their number needed to harm (NNH; incident DM) was 40. For the intermediate and high-risk categories, the NNH were 50 and 200 respectively while the NNT were 125 and 29. The authors concluded that based on their 4-year observational period, prescribing low dose statins to patients at low CVD risk was not associated with benefit and increased risk of harm. Patient that were categorized as high CVD risk benefitted from the use of low dose statins. In the intermediate risk category individualizing treatment choices were in line with current guideline recommendations.
Porath A, Arbelle JE, Fund N et al. Statin Therapy: Diabetes Mellitus Risk and Cardiovascular Benefit in Primary Prevention. The Israel Medical Association journal : IMAJ 2018; 20:480-485. http://www.ncbi.nlm.nih.gov/pubmed/?term=30084572
Elevated TG, a high price to pay!
Addressing risk or risk factors beyond LDL-c is becoming the next challenge when we aim to further reduce CVD risk in statin treated patients. Triglycerides have re-surfaced not only as an important predictive CVD risk factor but also a lipid fraction that can be effectively reduced. The authors of this study re-analyzed data collected in the US Kaiser Permanente registries accessing almost 5 million patients. The selected patients were 45 years or older received statin mon-therapy, had and LDL-c 40-100 mg/dl, triglycerides < 500 mg/dl and a medical history of MI, stroke, ACS or PAD. Patients were divided in two groups: TG 200-499 mg/dl (N= 2 702) and TG <150 mg/dl (N= 14 481). Starting point of the first measurement was 2010 and patients were followed until December 2016, with a maximum follow-up period of 6.5 years. Total medical costs were calculated using proprietary data and validated methods. Adjustments were made for numerous relevant factors such as age, gender, ethnicity, study site etc. Patients with high TG were more frequently admitted to hospital for complications or care; Overall 13% more admissions (P<0.001). Outpatient costs were 5% higher (P=0.035) even after adjusting for co-morbidities such as diabetes and CKD. Emergency care cost were 6% greater as well and hospital ambulatory costs increased 25% in the high TG group. This translated in an annual cost increment of $964 per patient, per year.  For the complete cohort of 2 702 patients, the total extra costs accrued to $2.6 million per year and to $13.5 million covering the total mean follow up of 5.2 years. The authors concluded that their results illustrate how relevant moderately elevated triglycerides are and that (new) therapies, able to effectively and safely reduce TG’s could lead to improved outcomes and potential cost savings as well.
Nichols GA, Philip S, Reynolds K et al. Comparison of Medical Care Utilization and Costs Among Patients With Statin-Controlled Low-Density Lipoprotein Cholesterol With Versus Without Hypertriglyceridemia. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30086877
Statins prevent amputations and deaths in PAD patients
Risks for mortality and rapid progression existing peripheral artery disease are high in patients that need revascularization for chronic limb threatening ischemia (CLTI). In this analysis of the Swedish National Registry for Vascular Surgery (Swedvasc)   combined with a number of other National Swedish medical registries, patients revascularized for CLTI were evaluated for ensuing medical complications, including death, as well as co-morbidities and medications. Median follow up in this cohort was 1.6 years. The most important independent predictors for amputation and death were male gender HR 1.20 (1.09-1.33) renal insufficiency HR 1.57 (1.32-
1.87); diabetes HR 1.45 (1.32-1.60) and heart failure HR 1.17 (1.05-1.31). Reduced amputation rates were observed in patients using statins HR 0.71 (CI 0.64-0.78) and low dose acetylsalicylic acid HR 0.77, (0.70-0.86). The combined endpoint of amputation or death showed similar trends of risks; male sex HR 1.25 (1.18-1.32); renal insufficiency HR 1.94 (1.75-2.14), heart failure HR 1.50 (1.40-1.60) and diabetes HR 1.31 (1.23-1.38). Lower rates were observed when patients used statins HR 0.74 (0.67-0.82) and low dose aspirin HR 0.82 (0.77-0.88). The authors concluded that renal insufficiency is the most important risk factor for amputation and amputation/death, followed by diabetes and heart failure. Male patients with CLTI did worse than their female counterparts. And the improved outcomes in patients treated with statins and aspirin emphasize the importance of these CVD risk reducing medications in these very high risk patients.
Baubeta Fridh E, Andersson M, Thuresson M et al. Impact of Comorbidity, Medication, and Gender on Amputation Rate Following Revascularisation for Chronic Limb Threatening Ischaemia. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30093176
Relevant publications
  1. Shanbhag A, Ananthula A, Reddy Palagiri RD et al. Variation in High-Intensity Statin Use After Hospitalization for Acute Vascular Emergencies. Am J Med Sci 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30082029
  2. Rana R, Sharma R, Kumar A. Repurposing of Existing Statin drugs for treatment of Microbial Infections: How much Promising? Infectious disorders drug targets 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30081793
  3. Putra RA, Effendi JS, Permadi W et al. Role of statin as inducer of Hmox-1 system in treatment of preeclampsia. Cell Mol Biol (Noisy-le-grand) 2018; 64:1-4. http://www.ncbi.nlm.nih.gov/pubmed/?term=30084810
  4. Pasnoor M, Barohn RJ, Dimachkie MM. Toxic myopathies. Current opinion in neurology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30080718
  5. Pan ML, Hsu CC, Chen YM et al. Statin Use and the Risk of Dementia in Patients with Stroke: A Nationwide Population-Based Cohort Study. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30087076
  6. Morotti K, Lopez J, Vaupel V et al. Adherence to and Persistence With Statin Therapy in a Veteran Population. The Annals of pharmacotherapy 2018:1060028018792702. http://www.ncbi.nlm.nih.gov/pubmed/?term=30084646
  7. Mantsiou C, Tziomalos K. Strategies to achieve low-density lipoprotein cholesterol targets in high-risk patients. Current medical research and opinion 2018:1-5. http://www.ncbi.nlm.nih.gov/pubmed/?term=30086667
  8. Lee YH, Hong N, Lee CJ et al. Differential association of ezetimibe-simvastatin combination with major adverse cardiovascular events in patients with or without diabetes: a retrospective propensity score-matched cohort study. Scientific reports 2018; 8:11925. http://www.ncbi.nlm.nih.gov/pubmed/?term=30093717
  9. Khan SZ, Rivero M, Cherr GS et al. Metformin Is Associated with Improved Survival and Decreased Cardiac Events With No Impact on Patency and Limb Salvage After Revascularization for Peripheral Arterial Disease. Annals of vascular surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30081159
  10. Howard G, Schwamm LH, Donnelly JP et al. Participation in Get With the Guidelines-Stroke and Its Association With Quality of Care for Stroke. JAMA neurology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30083763
  11. Hari P, Khandelwal P, Satpathy A et al. Effect of atorvastatin on dyslipidemia and carotid intima-media thickness in children with refractory nephrotic syndrome: a randomized controlled trial. Pediatric nephrology (Berlin, Germany) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30091061
  12. Giustino G, Colantonio LD, Brown TM et al. Titration to High-Intensity Statin Therapy Following Acute Myocardial Infarction in Patients With and Without Diabetes Mellitus. Cardiovasc Drugs Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30078077
  13. Calfee CS, Delucchi KL, Sinha P et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. The lancet. Respiratory medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30078618
  14. Bajnok L. [Newer evidences and recommendations in lipidology]. Orvosi hetilap 2018; 159:1303-1309. http://www.ncbi.nlm.nih.gov/pubmed/?term=30078359
  15. Bae JC, Min KW, Kim YH et al. Efficacy and safety of fixed-dose comBination therApy with gemigLiptin (50 mg) and rosuvAstatiN (20 mg) Compared with Each monotherapy in patients with type 2 diabetes and dyslipidaemia (BALANCE): A multicentre, randomized, double-blind, controlled, phase 3 trial. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30084112
  16. Al-Zakwani I, Zubaid M, Alsheikh-Ali AA et al. Effect of evidence-based cardiac drug therapy on mortality in patients with acute coronary syndrome: Findings from the Gulf COAST registry. Cardiovasc Ther 2018:e12463. http://www.ncbi.nlm.nih.gov/pubmed/?term=30079461
  17. Al-Kuraishy HM, Al-Gareeb AI, Al-Buhadily AK. Rosuvastatin as forthcoming antibiotic or as adjuvant additive agent: In vitro novel antibacterial study. Journal of laboratory physicians 2018; 10:271-275. http://www.ncbi.nlm.nih.gov/pubmed/?term=30078961
  18. Feng P, Zhao L, Guo F et al. The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins. Chemico-biological interactions 2018; 293:115-123. http://www.ncbi.nlm.nih.gov/pubmed/?term=30086269
  19. Choi Y, Lee S, Jang IJ, Yu KS. Pharmacokinetic interaction between fimasartan and atorvastatin in healthy male volunteers. Drug design, development and therapy 2018; 12:2301-2309. http://www.ncbi.nlm.nih.gov/pubmed/?term=30087555
  20. Brum J, Ramsey D, McRorie J et al. Meta-Analysis of Usefulness of Psyllium Fiber as Adjuvant Antilipid Therapy to Enhance Cholesterol Lowering Efficacy of Statins. Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30078477
  21. Alghofaily M, Tordik P, Romberg E et al. Healing of Apical Periodontitis after Nonsurgical Root Canal Treatment: The Role of Statin Intake. Journal of endodontics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30078575
Miscellaneous publications
  1. Xue D, Gong Z, Zhu F et al. Simvastatin increases cell viability and suppresses the expression of cytokines and vascular endothelial growth factor in inflamed human dental pulp stem cells in vitro. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30088351
  2. Wang Y, Jin Y, Yun X et al. Co-administration with simvastatin or lovastatin alters the pharmacokinetic profile of sinomenine in rats through cytochrome P450-mediated pathways. Life sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30096386
  3. McCarthy C, Lee E, Bridges JP et al. Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. Nature communications 2018; 9:3127. http://www.ncbi.nlm.nih.gov/pubmed/?term=30087322
  4. Leite GAA, Figueiredo TM, Pacheco TL et al. Reproductive outcomes in rat female offspring from male rats co-exposed to rosuvastatin and ascorbic acid during pre-puberty. Journal of toxicology and environmental health. Part A 2018:1-20. http://www.ncbi.nlm.nih.gov/pubmed/?term=30081759
  5. Lapczuk-Romanska J, Wajda A, Pius-Sadowska E et al. Effects of simvastatin on nuclear receptors, drug metabolizing enzymes and transporters expression in Human Umbilical Vein Endothelial Cells. Pharmacological reports : PR 2018; 70:875-880. http://www.ncbi.nlm.nih.gov/pubmed/?term=30092417
  6. Kong Y, Cheng L, Mao F et al. Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC). The Journal of biological chemistry 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30089652
  7. Cheng ZJ, Dai TM, Shen YY et al. Atorvastatin Pretreatment Attenuates Ischemic Brain Edema by Suppressing Aquaporin 4. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30093197
  8. Zhang N, Liang X, Gao C et al. Loading lovastatin into camptothecin-floxuridine conjugate nanocapsules for enhancing anti-metastatic efficacy of cocktail chemotherapy on triple-negative breast cancer. ACS applied materials & interfaces 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30096224
  9. Mo X, Zheng Z, He Y et al. Antiglioma via regulating oxidative stress and remodeling tumor-associated macrophage using lactoferrin-mediated biomimetic codelivery of simvastatin/fenretinide. J Control Release 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30096402
  10. Kim JH, Lee JM, Kim JH, Kim KR. Fluvastatin activates sirtuin 6 to regulate sterol regulatory element-binding proteins and AMP-activated protein kinase in HepG2 cells. Biochem Biophys Res Commun 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30078674
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