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Update - Week 03, 2019
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

Statin toxicity – updated review
Statin prescribers and statin skeptics get into heated debates regarding risks and benefits for this class of cholesterol-lowering drugs. Benefits of statins have been reviewed extensively and their use in patients at high CVD risk is and remains firmly established. Managing patients in whom statin is indicated, awareness and knowledge of statin-related adverse effects is essential. The authors of this article provide broad and in-depth insights about the potential risks and harms of statin therapy as well as practical pointers on how to deal with most commonly reported side effects. It includes a review of the mechanisms of action, including pharmacokinetics and dynamics of the different statins. Statin-associated muscle symptoms (SAMS) are explored extensively and provides a better understanding of the possible causes and different types of SAMS, including clinical presentations. Prevalence and risk factors for developing SAMS as well as intrinsic mechanisms that are considered to elicit the symptoms of pain and muscle cramps are explained. Metabolic changes triggered by statins, cellular and subcellular, e.g. mitochondrial toxicity and calcium channel signaling are discussed. Pharmacogenetic targets, such as SLCO1B1 gene, new onset type 2 diabetes, neurological neurocognitive (including dementia and Alzheimer disease), hepatoxicity, renal toxicity and of target statin side effects are appraised as well. The article is “open access”, a free article that provides interested health care providers not only with an elaborate 23-page statin toxicity review but allow those that are exploring specific topics to do so by assessing 195 referenced publications as well.
Ward NC, Watts GF, Eckel RH. Statin Toxicity. Circulation research 2019; 124:328-350. http://www.ncbi.nlm.nih.gov/pubmed/?term=30653440
The potential side effects of long term PCSK9ab use
The latest addition to our LDL-c lowering armamentarium, the PCSK9ab have proven to be not only highly efficacious but safe and very well tolerated as well. The limited clinical experience spanning ± 5 years provides limited re-assurance on long term safety. One well-recognized statin side-effect, new onset diabetes (NODM), has not surfaced in the two largest PCSK9ab clinical trials the ODYSSEY Outcome and FOURIER studies. The authors of this article explored the effects of a genetic variant (T allele of rs1159147), in the PCSK9 gene, associated with a loss of function phenotype. Using data collected in 479 522 participants of the UK Biobank, they observed an association with T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The association of the PCSK9 T allele with T2DM was independent of BMI and central obesity, this contrasted with diastolic blood pressure where this association remained robust. The T allele was also associated with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism. Based on these observations, long term use of PCSK9ab could be associated with NODM, similar like statins, and alertness for other potential side effects in patients that use PCSK9ab for a prolonged period of time, such as (young) FH patients, is warranted.  
Nelson CP, Lai FY, Nath M et al. Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors. Circulation. Genomic and precision medicine 2019; 12:e002196. http://www.ncbi.nlm.nih.gov/pubmed/?term=30645167
Fish-oils what is there to know?
Managing LDL-c plasma levels with statins and add on LDL-c lowering drugs such as ezetimibe and PCSK9ab has proven to be unequivocally successful. Despite reaching very low LDL-c levels a significant number of patients continue to experience CV complications. From this perspective addressing the residual risk is gaining importance in managing patients prone to ASCVD. In this review, the potential benefits of using omega-3 fatty acids as an add-on to statins in high risk (hypertriglyceridemic) patients are discussed. Despite the failure of earlier trials in establishing benefits of fish oils, the recent REDUCE-IT trial, using eicosapentaenoic acid (EPA) in a high dose (4 gr/day) was associated with an impressive 25% reduction of CV-events in patients with CVD or DM2. In this updated review the mechanisms of action beyond TG lowering are highlighted, improving endothelial function, reducing oxidative stress of various ApoB-containing lipoprotein particles, increasing the functionality of HDL, inhibiting inflammation & plaque as well as stabilizing plaques. An intriguing mechanism, suggested as unique for EPA, is the inhibition of glucose-induced cholesterol crystalline domain formation as to preserve normal membrane structure, lipid organization as well as membrane lipid oxidation. These properties are not observed with docosahexaenoic acid (DHA) or other TG lowering drugs. The author suggests that certain benefits are markedly enhanced when EPA is combined with statins. The three large still ongoing trials will help increase the understanding of the role of Omega-3 fatty acids in managing residual risk in statin-treated patients. Positive outcomes would establish the use of EPA and/or DHA as a valuable add on therapy in patients that use statins to lower their (residual) CVD risk.
Preston Mason R. New Insights into Mechanisms of Action for Omega-3 Fatty Acids in Atherothrombotic Cardiovascular Disease. Curr Atheroscler Rep 2019; 21:2. http://www.ncbi.nlm.nih.gov/pubmed/?term=30637567
Reduced mortality when starting statins before dialysis
In dialysis patients starting statin are not recommended based on the negative results of two large clinical outcome trials. Guidelines do advice to continue statins when started before dialysis. In this retrospective analysis of US veterans (2007 – 2014) effects of continuing statins initiated > 12 months before starting dialysis and survived at least 1 year of dialysis. The primary outcome 12-month all-cause mortality and CV mortality. Mean age 71 (SD:10) years majority were male (96.7%), African American (21.3%). Diabetes was diagnosed in 74.6% of the participants. After 1-year statin use was associated with lower all-cause and CV mortality. Reported deaths per 100 person-years were 21.9 (20.9-22.8) and 8.1 (7.5-8.6) in statin continuers vs 30.3 (27.8-32.8) and 9.8 (8.3-11.2) in statin discontinuers. After adjusted Cox proportional hazard regression analysis, the benefits in statin users persisted and resulted in an HR of 0.72 (0.66-0.79) and 0.82 (0.69-0.96) respectively. When corrected for age, race and diabetes status results remained the same. The authors suggested that based on the observed rapid and significant benefits of pre-dialysis statin use in ultimately dialysis-dependent patients, future studies are needed to confirm the observed benefits.
Streja E, Gosmanova EO, Molnar MZ et al. Association of Continuation of Statin Therapy Initiated Before Transition to Chronic Dialysis Therapy With Mortality After Dialysis Initiation. JAMA network open 2018; 1:e182311. http://www.ncbi.nlm.nih.gov/pubmed/?term=30646217
CVD outcomes relate to statin intensity + adherence in a large UK primary care cohort
Observational analysis of large National registries can provide important and relevant insights on the effects of CVD preventive disease management strategies. To evaluate the effects of statin adherence as well as statin intensity on clinical outcomes the authors used the UK primary cared Clinical Practice Research Datalink from January 2010 through February 2016. Three groups of patients were selected: Patients with CVD, patients with DM2 and no CVD or chronic kidney disease (CKD) and patients with CKD but no CVD. Included were patients that started with statins and/or ezetimibe between 2010 – 2013 and had prescriptions during the following year. Statin intensity was defined as low intensity (< 30% LDL-c lowering), moderate intensity (30-50% LDL-c lowering) and high intensity (>50% LDL-c Lowering). Patients were considered adherent if >80% of the statins were used. Endpoints Composite endpoint of cardiovascular death or hospitalization for myocardial infarction, unstable angina, ischemic stroke, heart failure, or revascularization. Hazard ratios were estimated by comparing the adherent patient to patients that did not continue their statin regimen. Evaluated were 29 797 newly treated patients; there were 16 701, 12 422, and 674 patients with documented CVD, type 2 diabetes without CVD or CKD, and CKD without CVD, respectively. Patients with CVD were more likely to be Adherent if they used high-intensity statins; 84.1%in year 1 and 72.3%in year 6. In patients receiving low-intensity therapy, 57.4% were adherent in year 1 and 48.4% in year 6. Combining the parameters of adherence and statin intensity showed a graded relationship with % LDL-c decrease and CVD outcomes. For each 10% upturn of the combined grade was associated with a 10% lower CVD risk, HR: 0.90 (0.86-0.94). The best outcomes were seen in patients that used high-intensity statin and were adherent for 1 year or longer, HR: 0.60 (0.54-0.68) compared to patients that were not treated for 1 year or longer. The results were congruent in diabetics, HR: 0.67 (0.57-0.79) and CKD patients, HR: 0.39 (0.25-0.61). Noteworthy was that patients treated with high-intensity statins vs low-intensity statins had similar adherence rates. These results prioritize the use of high-intensity statins in patients at risk for CVD complications, even in a primary prevention setting! Strategies to ensure adherence as well as promoting high-intensity statins prescriptions need to be prioritized if we want to succeed in optimally reducing CVD risk.
Khunti K, Danese MD, Kutikova L et al. Association of a Combined Measure of Adherence and Treatment Intensity With Cardiovascular Outcomes in Patients With Atherosclerosis or Other Cardiovascular Risk Factors Treated With Statins and/or Ezetimibe. JAMA network open 2018; 1:e185554. http://www.ncbi.nlm.nih.gov/pubmed/?term=30646277
Relevant publications
  1. Miname MH, Bittencourt MS, Nasir K, Santos RD. Subclinical coronary atherosclerosis and cardiovascular risk stratification in heterozygous familial hypercholesterolemia patients undergoing statin treatment. Curr Opin Lipidol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30649025
  2. Zhou Y, Yao X, Liu G et al. Level and variation on quality of care in China: a cross-sectional study for the acute myocardial infarction patients in tertiary hospitals in Beijing. BMC Health Serv Res 2019; 19:43. http://www.ncbi.nlm.nih.gov/pubmed/?term=30658628
  3. Zhang Y, Liang M, Sun C et al. Statin Use and Risk of Pancreatic Cancer: An Updated Meta-analysis of 26 Studies. Pancreas 2019; 48:142-150. http://www.ncbi.nlm.nih.gov/pubmed/?term=30640225
  4. Patel MS, Kurtzman GW, Kannan S et al. Effect of an Automated Patient Dashboard Using Active Choice and Peer Comparison Performance Feedback to Physicians on Statin Prescribing: The PRESCRIBE Cluster Randomized Clinical Trial. JAMA network open 2018; 1:e180818. http://www.ncbi.nlm.nih.gov/pubmed/?term=30646039
  5. Omori M, Okuma Y, Hakozaki T, Hosomi Y. Statins improve survival in patients previously treated with nivolumab for advanced non-small cell lung cancer: An observational study. Molecular and clinical oncology 2019; 10:137-143. http://www.ncbi.nlm.nih.gov/pubmed/?term=30655989
  6. Mefford MT, Rosenson RS, Deng L et al. Trends in Statin Use Among US Adults With Chronic Kidney Disease, 1999-2014. J Am Heart Assoc 2019; 8:e010640. http://www.ncbi.nlm.nih.gov/pubmed/?term=30651020
  7. Ma G, Bi S. Effect of rosuvastatin on vascular endothelial functions and inflammatory factors of patients with type 2 diabetes mellitus and coronary heart disease. Experimental and therapeutic medicine 2019; 17:332-336. http://www.ncbi.nlm.nih.gov/pubmed/?term=30651799
  8. Lamy A, Lonn E, Tong W et al. The cost implication of primary prevention in the HOPE 3 trial. European heart journal. Quality of care & clinical outcomes 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30657891
  9. Joentausta RM, Rannikko A, Murtola TJ. Prostate cancer survival among statin users after prostatectomy in a Finnish nationwide cohort. Prostate 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30652328
  10. Hynninen Y, Linna M, Vilkkumaa E. Value of genetic testing in the prevention of coronary heart disease events. PLoS One 2019; 14:e0210010. http://www.ncbi.nlm.nih.gov/pubmed/?term=30645616
  11. Hope HF, Binkley GM, Fenton S et al. Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease. PLoS One 2019; 14:e0201196. http://www.ncbi.nlm.nih.gov/pubmed/?term=30653535
  12. Hira RS, Kataruka A, Akeroyd JM et al. Association of Body Mass Index With Risk Factor Optimization and Guideline-Directed Medical Therapy in US Veterans With Cardiovascular Disease. Circ Cardiovasc Qual Outcomes 2019; 12:e004817. http://www.ncbi.nlm.nih.gov/pubmed/?term=30636483
  13. Gill SS. All, some or none? Statin prescribing for frail older adults. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2019; 191:E30-e31. http://www.ncbi.nlm.nih.gov/pubmed/?term=30642822
  14. Gidlow CJ, Ellis NJ, Cowap L et al. A qualitative study of cardiovascular disease risk communication in NHS Health Check using different risk calculators: protocol for the RIsk COmmunication in NHS Health Check (RICO) study. BMC family practice 2019; 20:11. http://www.ncbi.nlm.nih.gov/pubmed/?term=30642267
  15. El-Refai SM, Brown JD, Arnold SM et al. Epidemiologic Analysis Along the Mevalonate Pathway Reveals Improved Cancer Survival in Patients Who Receive Statins Alone and in Combination With Bisphosphonates. JCO clinical cancer informatics 2017; 1:1-12. http://www.ncbi.nlm.nih.gov/pubmed/?term=30657380
  16. Doumas M, Imprialos K, Dimakopoulou A et al. The role of statins in the management of nonalcoholic fatty liver disease. Current pharmaceutical design 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30652643
  17. Diamond DM, de Lorgeril M, Kendrick M et al. Formal comment on "Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease". PLoS One 2019; 14:e0205138. http://www.ncbi.nlm.nih.gov/pubmed/?term=30653537
  18. De Luca L, Luigi Temporelli P, Riccio C et al. Clinical Outcomes, Pharmacologic Treatment and Quality of Life of Patients with Stable Coronary Artery Diseases Managed by Cardiologists: 1-Year Results of the START Study. European heart journal. Quality of care & clinical outcomes 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30649303
  19. Chen Y, Li X, Zhang R et al. Effects of statin exposure and lung cancer survival: A meta-analysis of observational studies. Pharmacol Res 2019; 141:357-365. http://www.ncbi.nlm.nih.gov/pubmed/?term=30641276
  20. Campitelli MA, Maxwell CJ, Maclagan LC et al. One-year survival and admission to hospital for cardiovascular events among older residents of long-term care facilities who were prescribed intensive- and moderate-dose statins. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2019; 191:E32-e39. http://www.ncbi.nlm.nih.gov/pubmed/?term=30642823
  21. Almeida SO, Budoff M. Effect of statins on atherosclerotic plaque. Trends Cardiovasc Med 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30642643
  22. Zheng F, Liu M, Ye L et al. Statin use in patients undergoing carotid artery endarterectomy: still much to be uncovered. Acta neurochirurgica 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30648212
  23. van der Ploeg MA, Streit S, Achterberg WP et al. Patient Characteristics and General Practitioners' Advice to Stop Statins in Oldest-Old Patients: a Survey Study Across 30 Countries. Journal of general internal medicine 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30652277
  24. Najafipour M, Zareizadeh M, Khokhi MA, Najafipour F. Comparative study of the effect of atorvastatin and fenofibrate on high-density lipoprotein cholesterol levels in patients with type 2 diabetes. Journal of advanced pharmaceutical technology & research 2018; 9:135-138. http://www.ncbi.nlm.nih.gov/pubmed/?term=30637231
  25. Molina-Sotomayor E, Arreguin-Moreno R, Rodriguez-Rodriguez F et al. [Effects of exercise on the cognition of older women treated with lovastatin]. Biomedica : revista del Instituto Nacional de Salud 2018; 38:496-506. http://www.ncbi.nlm.nih.gov/pubmed/?term=30653863
  26. Khadir A, Kavalakatt S, Dehbi M et al. DUSP1 Is a Potential Marker of Chronic Inflammation in Arabs with Cardiovascular Diseases. Disease markers 2018; 2018:9529621. http://www.ncbi.nlm.nih.gov/pubmed/?term=30647800
  27. Anquetil C, Boyer O, Wesner N et al. Review: Myositis-specific autoantibodies, a cornerstone in immune-mediated necrotizing myopathy. Autoimmunity reviews 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30639649
  28. Ezetimibe + statin: insufficient benefit. Prescrire international 2016; 25:245-246. http://www.ncbi.nlm.nih.gov/pubmed/?term=30645833
Miscellaneous publications
  1. Zhao Z, Zhong L, He K et al. Cholesterol attenuated the progression of DEN-induced hepatocellular carcinoma via inhibiting SCAP mediated fatty acid de novo synthesis. Biochem Biophys Res Commun 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30638930
  2. Zhang ZZ, Zhang HZ, Zhang ZY. 3D printed poly(epsilon-caprolactone) scaffolds function with simvastatin-loaded poly(lactic-co-glycolic acid) microspheres to repair load-bearing segmental bone defects. Experimental and therapeutic medicine 2019; 17:79-90. http://www.ncbi.nlm.nih.gov/pubmed/?term=30651767
  3. Tanaka T, Matsushita T, Nishida K et al. Attenuation of osteoarthritis progression in mice following intra-articular administration of simvastatin-conjugated gelatin hydrogel. Journal of tissue engineering and regenerative medicine 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30644168
  4. Takahashi T, Uno Y, Yamazaki H, Kume T. Functional characterization for polymorphic organic anion transporting polypeptides (OATP/SLCO1B1, 1B3, 2B1) of monkeys recombinantly expressed with various OATP probes. Biopharmaceutics & drug disposition 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30652318
  5. Rodriguez-Perea AL, Rojas M, Velilla-Hernandez PA. High concentrations of atorvastatin reduce in vitro function of conventional T and regulatory T cells. Clinical and experimental immunology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30638266
  6. Encarnacao IC, Sordi MB, Aragones A et al. Release of simvastatin from scaffolds of poly(lactic-co-glycolic) acid and biphasic ceramic designed for bone tissue regeneration. Journal of biomedical materials research. Part B, Applied biomaterials 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30653823
  7. Beverly BEJ, Furr JR, Lambright CS et al. In utero exposure to simvastatin reduces postnatal survival and permanently alters reproductive tract development in the Crl:CD(SD) male rat. Toxicology and applied pharmacology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30639414
  8. An L, An S, Jia Z et al. Atorvastatin improves left ventricular remodeling and cardiac function in rats with congestive heart failure by inhibiting RhoA/Rho kinase-mediated endothelial nitric oxide synthase. Experimental and therapeutic medicine 2019; 17:960-966. http://www.ncbi.nlm.nih.gov/pubmed/?term=30651887
  9. Aktay G, Gursoy SO, Uyumlu U et al. Protective effect of atorvastatin on oxidative stress in streptozotocin-induced diabetic rats independently their lipid-lowering effects. Journal of biochemical and molecular toxicology 2019:e22295. http://www.ncbi.nlm.nih.gov/pubmed/?term=30657622
  10. Sommella E, Badolati N, Riccio G et al. A Boost in Mitochondrial Activity Underpins the Cholesterol-Lowering Effect of Annurca Apple Polyphenols on Hepatic Cells. Nutrients 2019; 11. http://www.ncbi.nlm.nih.gov/pubmed/?term=30646510
  11. Mouafi FE, Ibrahim GS, Abo Elsoud MM. Optimization of lovastatin production from Aspergillus fumigatus. Journal, genetic engineering & biotechnology 2016; 14:253-259. http://www.ncbi.nlm.nih.gov/pubmed/?term=30647623
  12. Auti P, Gabhe S, Mahadik K. Bioanalytical method development and its application to pharmacokinetics studies on Simvastatin in the presence of Piperine and two of its synthetic derivatives. Drug development and industrial pharmacy 2019:1-17. http://www.ncbi.nlm.nih.gov/pubmed/?term=30649976
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