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Update - Week 45, 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

Cost-effectiveness analysis of using statins in Chinese T2D patients
Type 2 diabetes T2D is rapidly becoming one of the world’s major health care challenges. Not only in developed but also in developing countries the rapidly expanding numbers of T2D patients is taking its toll on existing health care facilities, financially as well as available resources. Strategies to reduce the burden of T2D associated ASCVD complications need to be implemented and costs + cost effectiveness evaluated. In this Chinese analysis, the impact of atorvastatin prescription in Chinese T2D primary prevention patients was evaluated. Quality Adjusted Life Years (QALY) and Incremental Cost-Effectiveness Ratio (ICER) was calculated based on using atorvastatin 10 mg in newly diagnosed T2D patients and lifelong treatment. Estimated to add 0.08 Qualys, at an incremental cost of $1676, compared to no statins. This would amount to $21 924 per QALY gained. The willingness to pay threshold was $ 27 351 per QALY gained. Age of T2D diagnosis and expected length of life were the most relevant modifying parameters. Implementing this strategy would have an 80% probability of being cost-effective compared to control, no statin therapy. The authors supported the tested strategy as a cost-effective way to reduce CVD burden in newly diagnosed T2D patients.
Li T, Wan X, Ma J, Wu B. Cost-Effectiveness of Primary Prevention with Statin Treatment for Chinese Patients with Type 2 Diabetes. Adv Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30390239
EMPATHY per protocol post hoc analysis confirms “lower is better”!
The Japanese EMPATHY trial evaluated the safety and efficacy in reducing CV events of pitavastatin in T2D patients with hyperlipidemia and retinopathy. The aim was to achieve an LDL-c <70 mg/dl in patients with intensive therapy vs an LDL-c of ≥100 mg/dl but ≤ 120 mg/dl in the control arm of the study. After 3 years and using an intention to treat analysis (ITT) the LDL-C contrast was only 27.7 mg/dl and less than 50% of the participating patients in the intensive treatment arm managed to reach the designated LDL-c target. In this post-hoc analysis patients that did reach the target of an LDL-c ≤ 70 mg/dl (N=703) were compared to the patients that received standard care (N=1206). The LDL-C at le 36 months reached 59.7±11.6 mg/dL in the intensive group vs 107.1±17.8 mg/dL in the standard group (P< 0.05). The composite Endpoints of CV events or deaths related to CV events was significantly lower in the intensive than the standard group, HR: 0.48 (0.28−0.82; P= .007). Based on this post-hoc analysis diabetic + retinopathy patients had reduced CVD events related to intensive LDL-c treatment using pitavastatin. These results reaffirm that the “lower is better” strategy is valid for Japanese diabetic patients as well.  
Itoh H, Komuro I, Takeuchi M et al. Achieving LDL-C target levels less than 70 mg/dL may provide extra cardiovascular protection in high-risk patients: exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients With Hypercholesterolemia and Diabetic Retinopathy Study. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30393955
Slowing down renal function decline
The large randomized controlled 4D and AURORA trials did not show unequivocal CVD benefit of using statins in patients with advanced renal disease. Apart from these findings the potential protective or harmful effects of statins in patients with chronic kidney disease (CKD) remains controversial and new, sometimes conflicting data keeps fueling debates. Since no large RCT’s are expected, almost all data is generated from observational registries, systematic reviews, and meta-analyses. This most recent retrospective, observational study, examined the harms and benefits of statin use in 3 441 Chinese CKD patients. Patients were selected by querying the Taiwanese National Health Insurance Database as well as the Multicenter CKD Cohort. Patients were divided into two groups, based on statin use. Overall 825 patients used a statin ≥90-day within 180 days of the index date.  The endpoints were renal function decline as reflected by an annual eGFR decline of >5ml/min/1.73m2 or progressing to dialysis. The OR for CKD progression, after adjustment for baseline characteristics, was 0.80 (0.63-1.16). Factors as age, sex, Charlson score and statin use ware associated with CKD progression. In patients with CKD stage 1-3A there was a small, but non-significant trend toward better renal function preservation in statin users, OR 0.97 (0.68-1.38). Patients with more advanced renal disease, stage 3B-5, did show a significantly reduced renal function decline, OR 0.68 (0.48-0,95). On a similar note a note, non-significant trend toward accelerated progression was seen in statin users with proteinuria <1 gram/day, OR 1.02 (0.74-1.141). In patients with >1gram/day proteinuria statin use slowed down the progression of renal decline, OR 0.63 (0.43-0.92). Based on these findings the authors suggest the statin prescription in patients with stage 3b-5 and /or proteinuria >1gram/day could slow down renal function decline. What remains to be explored are differences in statin dosages as well as statin type.
Hu PJ, Wu MY, Lin TC et al. Effect of Statins on Renal Function in Chronic Kidney Disease Patients. Scientific reports 2018; 8:16276. http://www.ncbi.nlm.nih.gov/pubmed/?term=30390007
The gap between the real-world practice and guideline directives
The practice of evidence-based medicine using guideline formulated targets is considered a benchmark in modern medical practice. In the arena of cholesterol management, the European ESC/EAS guidelines, as well as the recently updated AHA/ACC practice guidelines, are embraced by guideline committees as a framework for local practice decrees or, in the absence of national guidelines, clinicians use these international recommendations. In this Turkish review of real-world practice, 500 dyslipidemic patients at risk for ASCVD; LDL-c management was evaluated based on their individual risk score. Following the European SCORE charts, no less than 231 (46%) were assigned to the very-high/high-risk category and roughly half (45.9%) were able to reach an LDL-c target of <100 mg/dl. In the moderate risk category 156/210 patients (74.3%) reached <115 mg/dl. Almost all remaining (N=55) low-risk patients reached an LDL-c target of <155 mg/dl (93.2%). An inverse correlation between LDL-c levels as well as the presence of CAD and reaching European dictated LDL-c targets was observed (P<0.001 for both). These findings illustrate the embarrassing gap between simple, evidence-based and well-accepted lipid management guidelines and the practical implementation of these directives.
Guntekin U, Gumrukcuoglu HA, Yaman M et al. Compliance With Dyslipidemia Guidelines in Daily Practice: How Effective Is Cardiovascular Risk Prevention? Clinical therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30392816
Extreme high risk, not an uncommon; IMPROVE-IT!
The risk category of extreme risk is becoming a new, but well-accepted risk category where standard treatments seem to be insufficient to adequately reduce ASCVD risk. Defining this new Risk category is based on combining CVD risks factors or disease manifestations and projecting the expected risk associated with these combinations. In this sub-analysis of the IMPROVE-IT study, an attempt was made to calculate the impact of multiple risk factors in the trial participants that that not only presented with the trial inclusion criterium of an ACS event but exhibited diabetes, poly vascular disease or both as well. In the IMPROVE-IT study 18 144 ACS patients were assigned to simvastatin 40 mg + placebo or simvastatin 40 mg + ezetimibe 10 mg for a period of approximately 6 years. At baseline, peripheral artery disease was observed in 1005 (6%) patients and 1071 (6%) suffered a TIA or stroke. Diabetes as a concomitant diagnosis was found in 388 (39%) and 409 (38%) patients respectively. After a mean follow-up period of 7 years, similar primary endpoints rates were observed in 38.5% and 39.9% respectively. In contrast patients with no poly-vascular disease or diabetes, experienced ASCVD related endpoints in 29.6% of the participants. Patients with diabetes as well as the poly-vascular disease had the worst prognosis with almost 2/3 (60.0%) that suffered from renewed ASCVD complications or death, this resulted in an HR of 1.60 (1.38-1.85; P<0.0001). The addition of ezetimibe to simvastatin 40 mg consistently reduced cardiovascular risk in all groups but with greater numerical absolute risk reductions in patients allocated to the highest-risk subgroups. The results of this subanalysis highlight the impressive ASCVD risk in patients with poly-vascular disease and even more pronounced when diabetes is present as an additional risk factor. Stringent aggressive LDL-cholesterol reduction with the addition of Ezetimibe and potentially with novel therapeutic modalities such as PCSK9ab would result in an improved outcome of these patients as was observed over a mean period of 6-7 years in the IMPROVE-IT study.
Bonaca MP, Gutierrez JA, Cannon C et al. Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial. The lancet. Diabetes & endocrinology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30396865
Relevant publications
  1. Zhiqiang Z, Niu X, Dong Z et al. Upstream therapeutic strategies of Valsartan and Fluvastatin on Hypertensive patients with non-permanent Atrial Fibrillation (VF-HT-AF). Cardiovasc Ther 2018:e12478. http://www.ncbi.nlm.nih.gov/pubmed/?term=30390409
  2. Tabesh M, Magliano DJ, Tanamas SK et al. Cardiovascular disease management in people with diabetes outside North America and Western Europe in 2006 and 2015. Diabetic medicine : a journal of the British Diabetic Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30402961
  3. Rigobon AV, Kalia S, Nichols J et al. Impact of the Diabetes Canada Guideline Dissemination Strategy on the Prescription of Vascular Protective Medications: A Retrospective Cohort Study, 2010-2015. Diabetes Care 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30389671
  4. Guedeney P, Baber U, Claessen B et al. Temporal trends, determinants, and impact of high-intensity statin prescriptions after percutaneous coronary intervention: Results from a large single-center prospective registry. Am Heart J 2018; 207:10-18. http://www.ncbi.nlm.nih.gov/pubmed/?term=30404046
  5. Qvist I, Sogaard R, Lindholt JS et al. Adherence to Prescribed Drugs Among 65-74 Year Old Men Diagnosed with Abdominal Aortic Aneurysm or Peripheral Arterial Disease in a Screening Trial: A VIVA Substudy. 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=30393062
  6. Ofori-Asenso R, Ilomaki J, Tacey M et al. Predictors of first-year nonadherence and discontinuation of statins among older adults: a retrospective cohort study. Br J Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30402916
  7. Mitchell JD, Fergestrom N, Gage BF et al. Impact of Statins on Cardiovascular Outcomes Following Coronary Artery Calcium Scoring. J Am Coll Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30409567
  8. Laleman N, Henrard S, van den Akker M et al. Time trends in statin use and incidence of recurrent cardiovascular events in secondary prevention between 1999 and 2013: a registry-based study. BMC Cardiovasc Disord 2018; 18:209. http://www.ncbi.nlm.nih.gov/pubmed/?term=30400778
  9. Hansen M, Kuhlman ACB, Sahl RE et al. Inflammatory biomarkers in patients in Simvastatin treatment: No effect of co-enzyme Q10 supplementation. Cytokine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30389229
  10. Barale C, Frascaroli C, Senkeev R et al. Simvastatin Effects on Inflammation and Platelet Activation Markers in Hypercholesterolemia. BioMed research international 2018; 2018:6508709. http://www.ncbi.nlm.nih.gov/pubmed/?term=30402489
  11. Azhar W, Buczkowski B, Smith C, Onambele-Pearson G. Impact of Circulating Triglycerides Concentration on Atherosclerotic Disease Status in Middle-Aged Saudi Arabian Dwellers. Nutrients 2018; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=30400262
  12. Soko ND, Masimirembwa C, Dandara C. Rosuvastatin pharmacogenetics in African populations. Pharmacogenomics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30398065
  13. Shah SC, Glass J, Giustino G et al. Statin Exposure Is Not Associated with Reduced Prevalence of Colorectal Neoplasia in patients with Inflammatory Bowel Disease. Gut Liver 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30400722
  14. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Medical hypotheses 2018; 121:60-63. http://www.ncbi.nlm.nih.gov/pubmed/?term=30396495
  15. Halandras PM. Vascular Surgery and Geriatric Patients. Clinics in geriatric medicine 2019; 35:93-101. http://www.ncbi.nlm.nih.gov/pubmed/?term=30390986
Miscellaneous publications
  1. Zhao J, Cheng Q, Liu Y et al. Atorvastatin alleviates early hypertensive renal damage in spontaneously hypertensive rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 109:602-609. http://www.ncbi.nlm.nih.gov/pubmed/?term=30399597
  2. Yin E, Hara M, Uchiyama M, Niimi M. Graft Protective Effect of HMG-CoA Reductase Inhibitor Pravastatin in Murine Cardiac Allograft Transplantation. Transplantation proceedings 2018; 50:2804-2806. http://www.ncbi.nlm.nih.gov/pubmed/?term=30401401
  3. Matusewicz L, Podkalicka J, Sikorski AF. Immunoliposomes with Simvastatin as a Potential Therapeutic in Treatment of Breast Cancer Cells Overexpressing HER2-An In Vitro Study. Cancers 2018; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=30388834
  4. Li T, Yao W. Therapeutic effect of irbesartan combined with atorvastatin calcium in the treatment of rats with coronary heart disease. Experimental and therapeutic medicine 2018; 16:4119-4123. http://www.ncbi.nlm.nih.gov/pubmed/?term=30402154
  5. Hassan SMS, Rizk A, Thomann C et al. Preconditioning with atorvastatin against renal ischemic-reperfusion injury in non-diabetic versus diabetic rats. Canadian journal of physiology and pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30412424
  6. Fawzy Fahim V, Wadie W, Shafik AN, Ishak Attallah M. Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia. Brain research bulletin 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30395886
  7. Beckwitt CH, Clark AM, Ma B et al. Statins attenuate outgrowth of breast cancer metastases. Br J Cancer 2018; 119:1094-1105. http://www.ncbi.nlm.nih.gov/pubmed/?term=30401978
  8. Soliman NA, Keshk WA, Rizk FH, Ibrahim MAA. The possible ameliorative effect of simvastatin versus sulfasalazine on acetic acid induced ulcerative colitis in adult rats. Chemico-biological interactions 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30408459
  9. Liu P, Liu Y, Li P et al. Rosuvastatin- and Heparin-Loaded Poly(L-Lactide-Co-Caprolactone) Nanofibre Aneurysm Stent Promotes Endothelialization via Vascular Endothelial Growth Factor Type A Modulation. ACS applied materials & interfaces 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30403126
  10. Kim AR, Kim JH, Kim A et al. Simvastatin attenuates tibial bone loss in rats with type 1 diabetes and periodontitis. Journal of translational medicine 2018; 16:306. http://www.ncbi.nlm.nih.gov/pubmed/?term=30413166
  11. Itoh H, Matsui M, Miyamura Y et al. Biosynthesis of Novel Statins by Combining Heterologous Genes from Xylaria and Aspergillus. ACS synthetic biology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30403849
  12. El-Zailik A, Cheung LK, Wang Y et al. Simultaneous LC-MS/MS analysis of simvastatin, atorvastatin, rosuvastatin and their active metabolites for plasma samples of obese patients underwent gastric bypass surgery. Journal of pharmaceutical and biomedical analysis 2018; 164:258-267. http://www.ncbi.nlm.nih.gov/pubmed/?term=30396053
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