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Update - Week 10, 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

Elevated baseline hs CRP and hs-CRP rise, after ACS, associated with CV recurrence and death
The Vascular Inflammation Suppression to Treat Acute Coronary Syndromes (VISTA-16) trial was a double-blind, randomized, multicenter trial of the secretory phospholipase A2 inhibitor varespladib, (2010 – 2012). Patients started varespladib <96 hrs. after ACS admission. All patients were treated with atorvastatin, mean dosage 40 mg. Varespladib was not successful in reducing the recurrence of cardiac complications and even increased CVD risk. In this post-hoc analysis, the impact of baseline hs-CRP on subsequent CV events was evaluated. Measurements of relevant biomarkers were executed at 1,2,4,8 and 16 weeks. Primary endpoints were MACE (composite of cardiovascular death, myocardial infarction, nonfatal stroke, or unstable angina with documented ischemia requiring hospitalization), cardiovascular death, and all-cause death. At 16 weeks median LDL-c reached 64.9 mg/dl (IQR 50.3-82.3 mg/dl) and hs CRP 2.4 mg/dl (IQR 1.1-5.2). Both initial and rise of hsCRP were associated with increased risk for MACE, CV death, and all-cause mortality. For MACE, a HR 1.36 (1.13-1.63; P = .001) and HR 1.15 (1.09-1.21; P < .001) was observed; for initial and rise in hs-CRP levels respectively. CVD death, HR 1.61 (1.07-2.41], P = .02) and HR 1.26 (1.19-1.34, P < .001) for initial and rise in hs-CRP levels respectively. All-cause mortality HR 1.58 (1.07-2.35, P = .02; and HR, 1.25 (1.18-1.32, P < .001) for initial and rise in hs-CRP levels respectively. The authors suggested that to reduce residual cardiovascular risk after ACS, initial and serial hsCRP measurements can be useful to guide anti-inflammatory therapies.
Mani P, Puri R, Schwartz GG et al. Association of Initial and Serial C-Reactive Protein Levels With Adverse Cardiovascular Events and Death After Acute Coronary Syndrome: A Secondary Analysis of the VISTA-16 Trial. JAMA cardiology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30840024
 
Statins as add-on therapy in cirrhotic patients
The expected harmful, toxic hepatic effects of statins have made an 1800 turn. Statins are now considered a valuable add-on treatment option for patients suffering from chronic hepatic disease such as NAFLD, NASH and even hepatic fibrosis/cirrhosis. In this updated review, targeting hepatologists, current therapeutic options for patients with advanced chronic liver disease are discussed. The standard libraries, PubMed, Medline and Cochrane were screened, up to December 2018, for articles on safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Next to Beta-blockers (reduce variceal re-bleeding), rifaximin (hepatic encephalopathy and bacterial peritonitis), diuretics (uncomplicated ascites) and alpha-adrenergic agonists (improve diuretic response in refractory ascites), statins have shown improved outcomes in cirrhotic patients. Additionally, statins retard fibrosis progression, hepatic decompensation, and even mortality. The authors do caution that the majority of evidence was based on observational studies. To substantiate these findings, as well as incorporate statins as a therapeutic strategy, in (inter)national guidelines, adequately powered, small scale RCTs need to be executed to validate that (statins can, in fact, modulate clinical endpoints in cirrhotic patients.
Kockerling D, Nathwani R, Forlano R et al. Current and future pharmacological therapies for managing cirrhosis and its complications. World J Gastroenterol 2019; 25:888-908. http://www.ncbi.nlm.nih.gov/pubmed/?term=30833797
 
Red Yeast Rise an alternative statin food additive?
Due to the media attention on statin skeptics and cholesterol critics, patients, and doctors are exploring alternatives to lower cholesterol. The notion that a “natural” dietary supplement of red yeast rice (RYR) is less prone to side effects is gaining popularity and interest in this product. First generation statins such as pravastatin, simvastatin and lovastatin were yeast products; RYR contains compactin and monacolin M, L, J, X and K (type K is identical to lovastatin). Studies that evaluated efficacy showed and LDL-c lowering potency equivalent to low-intensity low dose statins such as simvastatin 10 mg, lovastatin 20 mg, and pravastatin 40 mg. Average dosages RYR used were 1200 -4800 mg, containing 2.4 – 4.8 mg Monacolin K. Safety concerns of RYR surfaced after several case reports claiming toxicity. Recently published RYR meta-analyses focused on efficacy and not safety. This updated review and meta-analysis evaluated reported safety parameters from randomized controlled clinical trials. Primary outcomes were musculoskeletal disorders (MuD). Secondary outcomes were non-musculoskeletal adverse events (Non-MuD) and serious adverse events (SAE). In Total 53 RCT’s including 8535 participants, were included in this meta-analysis. MuD risk was not observed in patients allocated to RYR, OR 0.94 (0.53-1.65), Non-Mud and SAE were less frequently noted, OR=0.59 (0.50-0.69) and OR=0.54 (0.46-0.64), respectively. Dose increases did not result in a rise of reported side effect. The authors warned that manufacturing procedures are of great importance, all products used in the trials were citrinin free. Citrinin is a mycotoxin, derived from Monascus fermentation with substantial toxicity. Prolonged exposure results in nephrotoxicity, carcinogenic and reproductive as well as embryotoxicity. Quality control of these natural dietary supplements is essential to guarantee safety beyond the pharmacological effects. Overall, safety signals in patients using RYR were not observed in this meta-analysis. The significantly reduced risk of non-MuD and SAE’s could make this an attractive alternative for patients unable or unwilling to use standard statin formulations.
Fogacci F, Banach M, Mikhailidis DP et al. Safety of Red Yeast Rice Supplementation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pharmacol Res 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30844537
 
Statin use and NODM – observations in the ROTTERDAM study
The Rotterdam study was used to study the effects of statins on new-onset diabetes type 2 (NODM). Included were only patients free of DM2 at baseline. Those that used statins at the start of the study had increased values of several glycemic parameters. New statin-users were followed for a period of up to 15 years, and a Cox regression analysis was used to estimate the risk of new-onset diabetes (NODM). Statins users, compared to non-users, had higher fasting insulin concentrations and were more frequently diagnosed with insulin resistance; β = 0.07 (0.02-0.13) and β= 0.09 (0.03-0.14) respectively. Patients that used, or had used statin were more likely to develop NODM; HR 1.38 (1.09-1.74). Patients with impaired glucometabolic parameters and/or overweight/obese individuals were far more likely to develop NODM. Intermediate (31-365 days), and long term (>365 days) statin users had a significantly higher risk of NODM as well. Hyperglycemia and overweight/obesity were the predominant characteristics of patients that developed NODM. These observations underline the necessity of concomitant dietary and exercise interventions in patients that start statins and are prone to develop NODM, based on their weight and dysglycemia. These are the patients in whom statins use will have the greatest CVD-risk reducing benefits as well.
Ahmadizar F, OchoaRosales C, Glisic M et al. Associations of statin use with glycaemic traits and incident type 2 diabetes. Br J Clin Pharmacol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30838685
 
Statin use and perioperative mortality; 30 days post AFBA surgery
Atherosclerosis of the larger peripheral arteries (PAD) reflects a very high risk for CV events. Statins continue to be underused in PAD patients, despite the observed benefits, as shown in this retrospective analysis of patients that were followed in the American College of Surgeons National Surgical Quality Improvement Program (2011-2016). Selected Patients had an elective aortobifemoral bypass (ABFB) procedure for aortoiliac occlusive disease. They were followed for 30 days to evaluate if statins could improve survival. Univariable and multivariable regression analysis was used as well as propensity score matching between statin users and non-users. Overall 4445 patients had an ABFB procedure and of those, 3032 (68.2%) used statins. Statin users were older (67 vs 63 years p<0.05), more likely to be diabetic (31% vs 16%, p<0.05), hypertensive (84% vs 63%, p<0.05) and suffer from COPD (20% vs 17%, p<0.05). Statin use was associated with a better survival; the 30-day mortality was 3.4% vs 4.7% (p=0.03). Renal complications were observed less frequently as well, 2.5% vs 3.7%. Adjustments for patients demographics, co-morbidities, smoking, clinical presentation and type elective surgery, resulted in a RR of 32%, for 30-day mortality in statin users. OR 0.68 (0.47-0.96; p=0.03). After propensity score matching, almost identical benefits were observed OR 0.63 (0.41-0.95; p=0.03. This study reaffirms the importance of statins in PAD patients, and that 1/3 of patients with severe PAD, scheduled for an elective AFBA procedure are not treated according to guideline standards.
Abdelkarim AH, Dakour-Aridi H, Gurakar M et al. Association between statin use and perioperative mortality after aorto-bi-femoral bypass in patients with aortoiliac occlusive disease. Journal of vascular surgery 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30837182
Relevant publications
  1. Wu SY, Fang SC, Shih HJ et al. Mortality associated with statins in men with advanced prostate cancer treated with androgen deprivation therapy. European journal of cancer (Oxford, England : 1990) 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30827745
  2. Van Rompay MI, Solomon KR, Nickel JC et al. Prostate cancer incidence and mortality among men using statins and non-statin lipid-lowering medications. European journal of cancer (Oxford, England : 1990) 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30850323
  3. Suppressa P, Carbonara C, Lugani F et al. Congenital analbuminemia in a patient affected by hypercholesterolemia: A case report. World journal of clinical cases 2019; 7:466-472. http://www.ncbi.nlm.nih.gov/pubmed/?term=30842957
  4. Sundvall H, Fastbom J, Wallerstedt SM, Vitols S. Use of statins in the elderly according to age and indication-a cross-sectional population-based register study. Eur J Clin Pharmacol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30826850
  5. Reiner Z. Can Lp(a) Lowering Against Background Statin Therapy Really Reduce Cardiovascular Risk? Curr Atheroscler Rep 2019; 21:14. http://www.ncbi.nlm.nih.gov/pubmed/?term=30847681
  6. Lan NS, Fegan PG, Yeap BB et al. Icosapent ethyl for dyslipidaemia in patients with diabetes and coronary artery disease: act now to reduce it. Diabetes Obes Metab 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30834678
  7. Femlak M, Gluba-Brzozka A, Franczyk B, Rysz J. Diabetes-induced Alterations in HDL Subfractions Distribution. Current pharmaceutical design 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30827232
  8. Coakley JC. Lipids in Children and Links to Adult Vascular Disease. The Clinical biochemist. Reviews 2018; 39:65-76. http://www.ncbi.nlm.nih.gov/pubmed/?term=30828113
  9. Chen Y, Yuan Z, Lu J et al. Randomised study of Evolocumab in Patients With Type 2 Diabetes and Dyslipidaemia on Background Statin: Pre-Specified Analysis of the China Population From the BERSON Clinical Trial. Diabetes Obes Metab 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30851062
  10. Arnold N, Koenig W. [Atherosclerosis as an Inflammatory Disease - Pathophysiology, Clinical Relevance and Therapeutic Implications]. Deutsche medizinische Wochenschrift (1946) 2019; 144:315-321. http://www.ncbi.nlm.nih.gov/pubmed/?term=30836402
  11. Yakimenko capital O C, Maznichenko I. EVALUATION OF TREATMENT EFFICACY IN PATIENTS WITH NON-ALCOHOLIC-STEATOHEPATITIS AND HETEROZYGOTIC FAMILIAL HYPERCHOLESTEROLEMIA. Georgian medical news 2019:67-72. http://www.ncbi.nlm.nih.gov/pubmed/?term=30829592
  12. Son KB, Bae S. Patterns of statin utilisation for new users and market dynamics in South Korea: a 13-year retrospective cohort study. BMJ Open 2019; 9:e026603. http://www.ncbi.nlm.nih.gov/pubmed/?term=30842117
  13. Shrestha A, Mulmi A, Munankarmi R. Statins and Abnormal Liver Enzymes. South Dakota medicine : the journal of the South Dakota State Medical Association 2019; 72:12-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=30849222
  14. Nicholls SJ. The New Face of Hyperlipidemia and the Role of PCSK9 Inhibitors. Current cardiology reports 2019; 21:18. http://www.ncbi.nlm.nih.gov/pubmed/?term=30828741
  15. Larsson BAM, Sundh D, Mellstrom D et al. Response to Letter: Association between cortical bone microstructure and statin use in older women. J Clin Endocrinol Metab 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30848828
  16. Gupta A, Stokes W, Eguchi M et al. Statin use associated with improved overall and cancer specific survival in patients with head and neck cancer. Oral oncology 2019; 90:54-66. http://www.ncbi.nlm.nih.gov/pubmed/?term=30846177
  17. Gencer B, Pagano S, Vuilleumier N et al. Clinical, behavioral and biomarker predictors of PCSK9 levels in HIV-infected patients naive of statin therapy: A cross-sectional analysis from the Swiss HIV cohort. Atherosclerosis 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30827714
  18. Ferrari F, Stein R, Motta MT, Moriguchi EH. PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice. Arquivos brasileiros de cardiologia 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30843929
  19. Al-Khazaali A, Situala S, Dhindsa S. Letter to the Editor: [Association Between Cortical Bone Microstructure and Statin Use in Older Women]. J Clin Endocrinol Metab 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30848797
  20. Adam TJ, Chi CL. Big Data Cohort Extraction for Personalized Statin Treatment and Machine Learning. Methods in molecular biology (Clifton, N.J.) 2019; 1939:255-272. http://www.ncbi.nlm.nih.gov/pubmed/?term=30848466
  21. Lipid-lowering drugs. The Medical letter on drugs and therapeutics 2019; 61:17-24. http://www.ncbi.nlm.nih.gov/pubmed/?term=30845106
  22. Comparison table: Some lipid-lowering drugs. The Medical letter on drugs and therapeutics 2019; 61:e24-e30. http://www.ncbi.nlm.nih.gov/pubmed/?term=30845107  
Basic Science publications
 
 
  1. Wei W, Peng J, Shen T. Rosuvastatin Alleviates Ischemia/Reperfusion Injury in Cardiomyocytes by Downregulating Hsa-miR-24-3p to Target Upregulated Uncoupling Protein 2. Cellular reprogramming 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30835496
  2. Tsubaki M, Takeda T, Obata N et al. Combination therapy with dacarbazine and statins improved the survival rate in mice with metastatic melanoma. Journal of cellular physiology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30834527
  3. Nezic L, Amidzic L, Skrbic R et al. Simvastatin Inhibits Endotoxin-Induced Apoptosis in Liver and Spleen Through Up-Regulation of Survivin/NF-kappaB/p65 Expression. Frontiers in pharmacology 2019; 10:54. http://www.ncbi.nlm.nih.gov/pubmed/?term=30828299
  4. Mallappa S, Neeli PK, Karnewar S, Kotamraju S. Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization. Molecular carcinogenesis 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30834613
  5. Lu L, Huang W, Hu W et al. Kruppel-like factor 2 mediated anti-proliferative and anti-metastasis effects of simvastatin in p53 mutant colon cancer. Biochem Biophys Res Commun 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30833076
  6. Biselli-Chicote PM, Lotierzo AT, Biselli JM et al. Atorvastatin increases oxidative stress and inhibits cell migration of oral squamous cell carcinoma in vitro. Oral oncology 2019; 90:109-114. http://www.ncbi.nlm.nih.gov/pubmed/?term=30846168
  7. Liao Y, Ouyang L, Ci L et al. Pravastatin regulates host foreign-body reaction to polyetheretherketone implants via miR-29ab1-mediated SLIT3 upregulation. Biomaterials 2019; 203:12-22. http://www.ncbi.nlm.nih.gov/pubmed/?term=30851489
  8. Hassan A, Saleem Y, Chaudhry MN et al. Optimization of process variables for increased production of lovastatin in Aspergillus terreus PU-PCSIR1 and its characterization. Pak J Pharm Sci 2019; 32:363-370. http://www.ncbi.nlm.nih.gov/pubmed/?term=30829216
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