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Update - Week 08, 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

Apixaban and rosuvastatin a safe combination in NAFLD patients?
The potential interaction of two commonly used drugs and a common disposition, warrants a more in-depth analysis into the potential harms if patients score this hatrick. The authors examined the pharmacokinetics of the combining apixaban (2.5 mg) and rosuvastatin (5 mg) in patients diagnosed with NAFLD (N=22; 11 with and 11 without fibrosis) and healthy controls (N=12). MR imaging and MR elastography were used to quantify hepatic steatosis and fibrosis. Based on cell culture studies, no effects on apixaban hepatic cellular transport (basolateral to apical and vice versa) in the presence of rosuvastatin were noted. Verapamil did attenuate the basolateral to apical transport. The transport or rosuvastatin, in the presence of apixaban, in both directions was not affected either, but verapamil did impair the basolateral to apical transport, similar to what was observed with apixaban. Pharmacokinetic parameters of apixaban were not significantly different in NAFLD patients vs the controls, neither were presence of fibrosis, age, CYP3A5 nor BCRP genotypes. Apixaban AUC0-12 was strongly correlated with total body weight with univariate (P<0.001) and multivariable linear regression analysis. For rosuvastatin similar findings were observed with no effects of NAFLD (with or without fibrosis), age or genotype. For bodyweight there was a small but significant correlation between rosuvastatin (P=0.035) and a trend (P=0.06) with multivariable linear regression analysis. The authors conclude that the pharmacokinetics of apixaban and rosuvastatin are not affected by NAFLD.
Tirona RG, Kassam Z, Strapp R et al. Apixaban and Rosuvastatin Pharmacokinetics in Nonalcoholic Fatty Liver Disease. Drug metabolism and disposition: the biological fate of chemicals 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29472495
 
Statins in RA patients – Review
Risk for cardiovascular complications is increased in patients with chronic auto immune inflammatory conditions like inflammatory bowel disease and rheumatoid arthritis. This review provides a comprehensive update on the role of statins in reducing CVD risk as well as the potential mitigation of RA disease progression. The authors reviewed all PubMed and EMBASE published articles from January 2000 – July 2017, as well as recently completed or ongoing trials in ClinicalTrials.gov. In their review they discuss the effects of statins on CVD risk factors, biomarkers as well as imaging. Improvements of lipids and lipoproteins as well as markers of oxidation seem to be quite consistent. Trials included patents with RA in a primary and secondary prevention setting are sparse and most of the data is from sub-analysis of the large clinical endpoint trials such as IDEAL and TNT as well as observational registries. some trials reporting benefit and some fail to prove superior outcome in patients using statins or when comparing high dose – high intensity vs low dose – low intensity statins. The number of patients in the subgroup analyses of large clinical outcome trials is small and the limited follow-up time in trials designed to study the effects of statins in RA patients are partly to blame for the inconsistent findings. The studies evaluating the RA disease modifying effects of statins have been conducted in patients on a number of disease suppressing drugs. Benefits of mitigated disease progression and lower concentrations of inflammatory markers have been noted in patients with statin add-on therapy. However, these effects have not been consistent or adequately quantified. Re-assuring is the lack of adverse effects in patients treated with hepatotoxic medications. There are still large gaps in our knowledge and understanding of the benefits of statin ins RA, their excellent safety profile plus the improvement in lipid and non-lipid risk markers makes this drug class very attractive to use in RA patients. Better study design and improved quality of the collected data remains pivotal to translate these observations and opinions into evidence based guidelines. This pertains to their role in CVD risk reduction as well as their potential benefit in arresting RA disease progression.
Soulaidopoulos S, Nikiphorou E, Dimitroulas T, Kitas GD. The Role of Statins in Disease Modification and Cardiovascular Risk in Rheumatoid Arthritis. Frontiers in medicine 2018; 5:24. http://www.ncbi.nlm.nih.gov/pubmed/?term=29473041
 
No increased cancer risk in meta-analysis of statin RCT’s
Low cholesterol and cancer remains a topic that stirs interest particularly in a group that have coined the name “cholesterol sceptics”. This updated meta-analysis re-confirms that lowering cholesterol by means of HMG-CoA reductase inhibitors is not associated with an increased incidence of cancer. The authors of this study included only randomized, double‑blind, placebo‑controlled trials (RDBPCTs) in their meta-analysis. After searching Pub Med, EMBASE and Cochrane library databases they found 676 articles that included 21 RDBPCTs. Of the 65 197 participants, 32 618 used statins and 32 578 were in the placebo group. No increased cancer risk was determent, RR 0.97 (0.92-1.02; i2 =0.0%). By means of subgroup analyses of statin type, country, follow‑up period, methodological quality, underlying diseases/population, and type of cancer, the authors were unable to prove any protective effects of statins on cancer development either. In previous met-analyses that used data from observational cohorts and case control studies, a reduced incidence of cancer was reported. No effects, either harmful or beneficial, were observed in this meta-analysis of RDBPCTs with statins.
Kim MK, Myung SK, Tran BT, Park B. Statins and risk of cancer: A meta-analysis of randomized, double-blind, placebo-controlled trials. Indian journal of cancer 2017; 54:470-477. http://www.ncbi.nlm.nih.gov/pubmed/?term=29469081
 
Effects of statins in patients with ALT increases  >3ULN
Transaminase increases is frequently observed in patients starting with statins and is a frequently reported reason why doctors stop statins in patients that present with these lab-abnormalities. Despite the intention to protect their patients from harm, the opposite might be the factual reality because LDL-cholesterol and CVD risk remains high while the intrinsic harms of transaminase increases are controversial. The authors of this report include only patients with ALT increases of >3 x ULN. The patients were assigned to three groups based on co-medications that could increase liver function as well (HEPA). One group already used HEPA drugs before statins were initiated, one group started with (HEPA) after statins and the third group that did no use HEPA agents before of after statin initiation. ALT levels were determined <3 months after statin were started and monitored. The observational period started in January 2009 and was terminated December 2012. During this period 61 patients from a single hospital in Seoul – South Korea, were include in the study. There were improved ALT measurements in all three groups: HepCon, HepNew and HepNo, with decreases of 45 ± 8%, 64 ± 10%, and 42 ± 8%, respectively. In two subjects a deterioration of ALT levels was observed but they remained stable over time. The data presented in this study is explorative and cannot be seen as evidence to alter recommendations of statin use in patients with increased transaminase levels. However, the consequences of statin discontinuations in patients with increased CVD risk + elevated transaminase are serious. Patients with diabetes or metabolic syndrome are also at risk for developing NAFLD/NASH and higher plasma transaminases are a signature of these liver problems. Future studies are urgently needed to properly examine the effects of continuing statins in these patients 
Kim H, Lee H, Kim TM et al. Change in ALT levels after administration of HMG-CoA reductase inhibitors to subjects with pretreatment levels three times the upper normal limit in clinical practice. Cardiovasc Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29464863
 
Statin use in Diabetics has increased but treatment gaps remain a challenge
The 2013 ACC/AHA guidelines on lipid management recommend the use of high intensity statins in diabetic patients. Data collected in the National Health and Nutrition Examination Survey NHANES) from 1999 to 2014 were used for this analysis. Statin use increased from 26.2% to 49.5% over the 16 years that the study covered. Mean LDL-c decreased from 118.5 mg/dl to 103.3 mg/dl (Ptrend < 0.001). Comparing males and whites to females and blacks, statins were used less frequently; -10% and -16% respectively and LDL-c levels were significantly higher as well. The use of high intensity statins (atorvastatin and rosuvastatin) did not increase significantly; from 14.0% to 17.9%, Ptrend = 0.55. The users of high intensity statin had a significantly lower LDL-c (-8.0 mg/dl) when compared to patients that used other statins. The authors acknowledged the steady increase in statin use in diabetics aged 45 - 70 years from 1999 – 2014. Discrepancies based on age gender and race are of great concern and deserve to be further evaluated in order to address these issues.
Gu A, Kamat S, Argulian E. Trends and Disparities in Statin Use and Low-Density Lipoprotein Cholesterol Levels among US Patients with Diabetes, 1999-2014. Diabetes Res Clin Pract 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29476887
 
 
Relevant publications
  1. Selva-O'Callaghan A, Alvarado-Cardenas M, Pinal-Fernandez I et al. Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert review of clinical immunology 2018:1-10. http://www.ncbi.nlm.nih.gov/pubmed/?term=29473763
  2. Hashiguchi M, Maruyama J, Shimizu M et al. Risk Factor for Diabetes Mellitus and High Blood Glucose With HMG-CoA Reductase Inhibitors Using a Postmarketing Surveillance Database in Japan. Clinical pharmacology in drug development 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29462515
  3. Hamada T, Khalaf N, Yuan C et al. Pre-diagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29474971
  4. de Paula TP, Santos PC, Duque do Nascimento Arifa R et al. Treatment with atorvastatin provides additional benefits to imipenem in a model of Gram-negative pneumonia induced by Klebsiella pneumoniae in mice. Antimicrobial agents and chemotherapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29463546
  5. de Jong HJI, Cohen Tervaert JW, Lalmohamed A et al. Pattern of risks of rheumatoid arthritis among patients using statins: A cohort study with the clinical practice research datalink. PLoS One 2018; 13:e0193297. http://www.ncbi.nlm.nih.gov/pubmed/?term=29474418
  6. Zhang P, Wang XH, Su XJ. Comment on the original paper entitled "The effect of Ezetimibe and Simvastatin Combination Therapy on percutaneous coronary intervention patients". Int J Cardiol 2018; 256:18. http://www.ncbi.nlm.nih.gov/pubmed/?term=29454400
  7. Wagner JB, Abdel-Rahman S, Van Haandel L et al. Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics. Journal of clinical pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29469964
  8. Taylor PC, Kremer JM, Emery P et al. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Ann Rheum Dis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29463520
  9. Sharma N, Cooper R, Kuh D, Shah I. Publisher Correction: Associations of statin use with motor performance and myalgia may be modified by 25-hydroxyvitamin D: findings from a British birth cohort. Scientific reports 2018; 8:3579. http://www.ncbi.nlm.nih.gov/pubmed/?term=29463876
  10. Olszewska-Banaszczyk M, Jackowska P, Gorzelak-Pabis P et al. Comparison of the effects of rosuvastatin monotherapy and atorvastatin-ezetimibe combined therapy on the structure of erythrocyte membranes in patients with coronary artery disease. Pharmacological reports : PR 2017; 70:258-262. http://www.ncbi.nlm.nih.gov/pubmed/?term=29475008
  11. McCullough PA, Ballantyne CM, Sanganalmath SK et al. Efficacy and Safety of Alirocumab in High-Risk Patients With Clinical Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from 5 Placebo-Controlled ODYSSEY Trials). Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29472008
  12. Masuda Y, Yamaguchi S, Suzuki C et al. Generation and Characterization of a Novel Small Biologic Alternative to PCSK9 Antibodies, DS-9001a, Albumin Binding Domain-Fused Anticalin Protein. J Pharmacol Exp Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29463608
  13. Chen Y, Liu L. Is the decrease of triglyceride level after acute myocardial infarction within a month by the effect of combination therapy of Ezetimibe and Simvastatin. Int J Cardiol 2018; 256:21. http://www.ncbi.nlm.nih.gov/pubmed/?term=29454404
Miscellaneous publications
  1. Taylor PC, Kremer JM, Emery P et al. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Ann Rheum Dis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29463520
  2. McCullough PA, Ballantyne CM, Sanganalmath SK et al. Efficacy and Safety of Alirocumab in High-Risk Patients With Clinical Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from 5 Placebo-Controlled ODYSSEY Trials). Am J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29472008
  3. Leite GAA, Sanabria M, Cavariani MM et al. Lower sperm quality and testicular and epididymal structural impairment in adult rats exposed to rosuvastatin during prepuberty. Journal of applied toxicology : JAT2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29460396
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This activity is supported by an educational grant from Pfizer.