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Update - Week 08, 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

ACOS patients reduce CAD and stroke risk when using statins
asthma- and chronic obstructive pulmonary disease (COPD) overlaps syndrome or ACOS are not an uncommon occurrence. Patients diagnosed with ACOS are exposed to a higher CAD/stroke risk due to overlapping exacerbating risk factors e.g. inflammation and hypoxia. Using inhaled hydro-corticosteroid or oral steroid, a frequently prescribed medication, is aimed at reducing the inflammatory response and this could potentially have an effect on CVD risk as well. In this retrospective analysis, 7 254 Taiwanese ACOS patients were analyzed, 916 patients were using statins and 6 338 were not. Primary endpoints were the cumulative incidence of CAD and stroke (ischemic and hemorrhagic). Using a Cox proportional regression analysis, adjusted for sex, age, co-morbidities and steroid used HR estimate was derived for long term statins users (> 600 days), short term statin users (<600 days) versus no-statin users. Reassuring was the observation that statin use did not show a detrimental effect on the incidence of hemorrhagic strokes. Overall statin uses were associated with a markedly decreased risk for CAD, HR 0.50 (0.41-0.62) and stroke, HR 0.83 (0.63-1.09). The adjusted HR (aHR) for ischemic stroke and hemorrhagic stroke were 0.30 (0.09–0.99) and 0.90 (0.68–1.20), respectively in the short term statin users and 0.23 (0.13–0.41) and 0.42 (0.19–0.89) respectively in the long term statin users. Based on this analysis the use of statins was associated with a reduced risk of CAD, irrespective of the duration of statin use, while the risk of developing an ischemic stroke was only attenuated in the long-term statin users. Risk of hemorrhagic stroke was similar in both statin users and no statin users, alleviating concerns regarding the statin-associated increased bleeding risk.
Yeh JJ, Lin CL, Hsu CY et al. Associations between statins and coronary artery disease and stroke risks in patients with asthma-chronic obstructive pulmonary disease overlap syndrome: A time-dependent regression study. Atherosclerosis 2019; 283:61-68. http://www.ncbi.nlm.nih.gov/pubmed/?term=30782562
Are statins able to reduce Prinz-metal related anginal complaints?
Prinz-metal anginal complaints, more frequently observed in women as compared to men, could be the result of microvascular dysfunction. It not only produces indistinguishable anginal complaints but is associated with increased CVD risk as well. Statins could ease microvascular function, as one of their purported pleiotropic effects is improving endothelial nitric oxide synthetase (eNOS) activity. In this double-blind randomized controlled single center trial, 66 Norwegian women, referred for coronary angiography but without obstructive CAD, were allocated to rosuvastatin 20 mg or placebo for a duration of 6 months. At baseline and at the end of the study participating microvascular function was assessed by a thermodilution-derived test to measure their “index of microvascular resistance” (IMR) as well as measurements of relevant biochemical biomarkers e.g. hs CRP.  IMR scores at baseline and after 6 months, in the placebo group and treated patients, were 14.6 (SD 5.7) and 14.4 (SD 6.5) vs 16.5 (SD 7.5) and 14.2 (SD 5.8), respectively. Important to mention is that only 17% of the women had IMR levels that reached the 20.8 mmHg-s cut of levels commonly used to diagnose microvascular dysfunction. Baseline IMR was 1.9 mmHg-s higher in the rosuvastatin group and the change of 2.3 mmHg-s in the rosuvastatin treatment arm was not statistically significantly different from the 0.2 mmHg-s in the placebo group.  No significant differences in plasma concentrations of natriuretic peptides, troponins, and markers of endothelial activation (i.e., vWF, sVCAM-1, and ADMA) were noted. Lipid levels improved as expected in patients using rosuvastatin. At baseline the hs-CRP plasma levels were comparable, but after six months patients allocated to rosuvastatin achieved significantly lower plasma concentrations compared to the placebo group, 0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L (p = 0.002). The authors concluded that 6 months of rosuvastatin treatment of women presenting with anginal complaints not caused by obstructive CAD did not improve microvascular dysfunction, as assessed by IMR. However only 17% of the women included in this study presented with microvascular dysfunction (IMR>20.8 mmHg-s). Future studies should examine the effects of statins in women that have proven microvascular dysfunction.
Solberg OG, Stavem K, Ragnarsson A et al. Index of microvascular resistance to assess the effect of rosuvastatin on microvascular function in women with chest pain and no obstructive coronary artery disease: A double-blind randomized study. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30790446
“Lower is better” for stroke risk as well
Strategies that focus on LDL-c lowering for the prevention for stroke are part of all major guidelines and lipid-lowering recommendations. With the introduction of the new PCSK9ab and the very low LDL-c plasma levels in the recent large clinical outcome studies, the question if very low LDL-c, as observed in these trials would provide additional benefits or harm? Additionally, the impact of lowering LDL-c to very low levels on hemorrhagic strokes risk has not been fully explored. In this update meta-regression analysis of 23 trials (N=222 149) re-affirmed the benefits of LDL-c lowering, using statins or non-statins, in preventing strokes. Relevant to add is that no harmful effects on hemorrhagic strokes were noted. For each 1 mmol/l decrease in LDL-c, the risk of stroke was reduced by 23.5% (slope 0.235; 95% CI 0.007–0.464, P=0.044). This was a consistent benefit down to an LDL-c of 0.78 mmol/l. A heterogeneity test for subgroup difference showed no difference between the groups (P=0.23, I2=31%). The lower incidence of strokes was reported in both primary and secondary prevention of stroke. The results of the meta-regression analysis reconfirm the consistent benefit of lowering LDL-c even when achieving extremely low LDL-c levels. Importantly non-statins seem to provide a similar benefit on stroke risk, but what is puzzling is the observation that in the meta-analysis of statin trials MI’s were reduced by 21% vs stroke with 13/ per mmol/l LDL-c reduction. In the non-statin trials such as FOURIER and ODYSSEY OUTCOMES the effects were reversed, a 21% risk reduction of stroke and a 15% relative risk reduction on MI. A play of chance or are there different mechanisms at play? The authors recommend to lower LDL-c using statins or non-statins to reduce Stroke risk and that, similar as observed in the CAD endpoint trials, no LDL-c threshold has been observed. Risk of Hemorrhagic strokes related to (very) low LDL-c levels seems absent or if minimal.
Shin J, Chung JW, Jang HS et al. Achieved low-density lipoprotein cholesterol level and stroke risk: A meta-analysis of 23 randomised trials. Eur J Prev Cardiol 2019:2047487319830503. http://www.ncbi.nlm.nih.gov/pubmed/?term=30782002
Managing CV risk, the next challenge for China
The China PEACE Million Persons Project is a government-funded public health program. Initiated between September 2014 to June 2017, it aimed to survey a total of 141 county-level geographic regions (88 rural counties, 53 urban districts) in all 31 provinces of China. In these regions individual patient data was collected to evaluate population structure, risk factor exposure and disease patterns in local residents aged 35 -75 years. In individuals estimated to have a high CVD risk, the use of statins and aspirin was evaluated. High CVD risk was detected in 9.5% (9.5%-9.6%) of the 1 680 126 participants. High risk was more frequently observed in Han Chinese, individuals that had a medical insurance, used alcohol or were obese. Use of statins and/or aspirin was noted in only a very small percentage of these high-risk individuals; only 0.6% (0.5%-0.6%) were prescribed statins and 2.4% (2.3% - 2.5%) reported using aspirin. Anti-hypertensive drugs were used by 31.8% of the high-risk individuals that had hypertension. The results of this nationwide screening program in China shows the increased prevalence of treatable CVD risk factors in urban as well as rural regions. The lack of awareness of CVD risk and appropriate management is illustrated by the very low percentage of high CVD risk patients that are using appropriated medication such as statins, aspirin and anti-hypertensive medication. The authors commented on the opportunities as well as challenges to address to reduce risk in the Chinese population with over 1.4 billion Chinese.
LuJ, Lu Y, Yang H et al. Characteristics of High Cardiovascular Risk in 1.7 Million Chinese Adults. Annals of internal medicine 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776800
Are statin beneficial in the primary prevention of elderly patients
Due to conflicting results in clinical trials and observational data, clear recommendations on statin use for primary prevention in the very elderly are missing in most guidelines. Large randomized controlled trials examining the harms and benefits of statins in patients > 75 years s are unlikely to be conducted over the next few years. Treatment remains hotly debated clinical challenge and alternative information sources are needed to aid clinicians in their therapeutic decision-making process. In this Korean nationwide, nested case control study, Individuals who developed CVD, including myocardial infarction (MI), stroke, or death from all causes, were matched to controls by using duration of follow-up, age, and sex at the index date. Statin use in both groups was retrospectively collected from the index date to five years before. Recorded CV events were used to calculate Odds ratio’s (OR) for statin related outcomes. In this retrospective analysis, 11 017 cases were matched with 55 085 controls. The risk for the composite endpoint was significantly attenuated in the participants that used statins, adjusted OR (aOR) 0.77 (0.71-0.88). This was observed as well for the endpoints stroke and all-cause mortality, aOR: 0.74 (o.61-0.89) and  aOR 0.73 (0.66-0.81) respectively. Former statin use did not show a clear relationship with CVD or all-cause mortality. Longer duration of statin therapy showed decreasing trends of benefit on the composite endpoint, as well as individual endpoints of stroke and all cause death. The authors commented that treatment should be individualized based on comorbidities, polypharmacy, potential side effects, life expectancy and in line with current international guidelines. This observational study can be seen as an alternative to RCT’s supporting the appropriateness of statins for primary prevention in very elderly (Asian) subjects.
Ji Eun Jun, In-Jin Cho, Kyungdo Han et al Statins for primary prevention in adults aged 75 years and older: Anationwide population-based case-control studynationwide population-based case-control study. Atherosclerosis 2019; 283:28-34. http://www.ncbi.nlm.nih.gov/pubmed/?term=30772771
Relevant publications
  1. Upreti S, Fayyaz B, Bongu RP. Anti-HMG-CoA reductase myopathy, an undesirable evolution of statin induced myopathy: a case report. Journal of community hospital internal medicine perspectives 2019; 9:33-35. http://www.ncbi.nlm.nih.gov/pubmed/?term=30788073
  2. Gill EA, Blaha MJ, Guyton JR. JCL roundtable: Coronary artery calcium scoring and other vascular imaging for risk assessment. J Clin Lipidol 2019; 13:4-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=30773212  
  3. Thomson SR, Chogtu B, Shetty R, Devasia T. Analysis of glycemic status in diabetes-naive patients on statins: A hospital-based cross-sectional study. Indian journal of pharmacology 2018; 50:320-325. http://www.ncbi.nlm.nih.gov/pubmed/?term=30783324
  4. Shek AB, Kurbanov RD, Alieva RB et al. Personalized rosuvastatin therapy in problem patients with partial statin intolerance. Archives of medical sciences. Atherosclerotic diseases 2018; 3:e83-e89. http://www.ncbi.nlm.nih.gov/pubmed/?term=30775595
  5. Sharp AJ, Patel N, Reeves BC et al. Pharmacological interventions for the prevention of contrast-induced acute kidney injury in high-risk adult patients undergoing coronary angiography: a systematic review and meta-analysis of randomised controlled trials. Open heart 2019; 6:e000864. http://www.ncbi.nlm.nih.gov/pubmed/?term=30774964
  6. Puttarajappa CM, Tevar AD, Hariharan S et al. Screening Coronary Angiography in Patients with Long-Standing Diabetes Mellitus undergoing Kidney Transplant Evaluation. Clinical transplantation 2019:e13501. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776157
  7. Markossian TW, Kramer HJ, Burge NJ et al. Statin use among Veterans with dialysis-dependent chronic kidney disease. Hemodialysis international. International Symposium on Home Hemodialysis 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30779455
  8. Kunlamas Y, Areepium N, Ariyachaipanich A, Bunditanukul K. Real-World Effectiveness of High- Versus Moderate-Intensity Statin Therapy in Thai Patients With Acute Coronary Syndrome and Who Had Undergone Primary Percutaneous Coronary Intervention. Journal of pharmacy practice 2019:897190019825915. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776951
  9. Jose Gagliardino J, Arechavaleta R, Goldberg Eliaschewitz F et al. Dyslipidemia: The untreated metabolic dysfunction in people with type 2 diabetes in Latin America. ARETAEUS study outcomes. Journal of clinical & translational endocrinology 2019; 15:76-80. http://www.ncbi.nlm.nih.gov/pubmed/?term=30788219
  10. Hori E, Kikuchi C, Imaeda K et al. [Effect of Statins on Glycemic Status and Plasma Adiponectin Concentrations in Patients with Type 2 Diabetes Mellitus and Hypercholesterolemia]. Yakugaku Zasshi 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30773524
  11. Haque T, Bhaheetharan S, Khan BV. Is there a role for pleiotropic effects of atorvastatin and fenofibrate in the metabolic syndrome and prediabetes? Expert review of endocrinology & metabolism 2010; 5:835-837. http://www.ncbi.nlm.nih.gov/pubmed/?term=30780833
  12. Fernandez-Ruiz I. Statin efficacy in primary CVD prevention might diminish with patient age. Nat Rev Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30783252
  13. de Dios Garcia-Diaz J, Corral-Bueno IM, Mesa-Latorre JM et al. Proprotein Convertase Subtilisin/Kexin Type 9 Antibody and Statin-Associated Autoimmune Myopathy. Annals of internal medicine 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776798
  14. Ballantyne CM, Manku MS, Bays HE et al. Icosapent Ethyl Effects on Fatty Acid Profiles in Statin-Treated Patients With High Triglycerides: The Randomized, Placebo-controlled ANCHOR Study. Cardiology and therapy 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30788718
  15. Xia DK, Hu ZG, Tian YF, Zeng FJ. Statin use and prognosis of lung cancer: a systematic review and meta-analysis of observational studies and randomized controlled trials. Drug design, development and therapy 2019; 13:405-422. http://www.ncbi.nlm.nih.gov/pubmed/?term=30774306
  16. Wolska-Krawczyk M, Drunck M, Behnke S, Reith W. Risk Factors for Restenosis After Stenting or Angioplasty of Vertebral Artery Origin : Results of Short-term and Long-term Follow-up. Clinical neuroradiology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30783694
  17. Turgeon RD, Althouse AD. Inappropriate inclusion of multiple studies in a meta-analysis of randomized controlled trials of atorvastatin loading prior to percutaneous coronary intervention for acute coronary syndrome. Eur Heart J 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30783662
  18. Rodriguez-Jimenez C, Gomez-Coronado D, Frias Vargas M et al. A new variant (c.1A>G) in LDLRAP1 causing autosomal recessive hypercholesterolemia: Characterization of the defect and response to PCSK9 inhibition. Atherosclerosis 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30777337
  19. Riis AH, Erichsen R, Ostenfeld EB et al. Validating registry data on statins prescriptions by blood measurements. Pharmacoepidemiol Drug Saf 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30779395
  20. Luscher TF, Davies A. Inclusion of multiple inappropriate studies in a meta-analysis of randomized controlled trials of atorvastatin loading prior to percutaneous coronary intervention for acute coronary syndrome: editor's response. Eur Heart J 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30783647
  21. Limwattananon C, Waleekhachonloet O. Access to and price trends of antidiabetic, antihypertensive, and antilipidemic drugs in outpatient settings of the Universal Coverage Scheme in Thailand. PLoS One 2019; 14:e0211759. http://www.ncbi.nlm.nih.gov/pubmed/?term=30785916
  22. Li K, Si-Tu J, Qiu J et al. Statin and metformin therapy in prostate cancer patients with hyperlipidemia who underwent radiotherapy: a population-based cohort study. Cancer management and research 2019; 11:1189-1197. http://www.ncbi.nlm.nih.gov/pubmed/?term=30787638
  23. Lee SE, Sung JM, Andreini D et al. Differential association between the progression of coronary artery calcium score and coronary plaque volume progression according to statins: the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (PARADIGM) study. European heart journal cardiovascular Imaging 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30789215
  24. Khalilieh SG, Yee KL, Sanchez RI et al. Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions. Antimicrobial agents and chemotherapy 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30783000
  25. Bourgier C, Auperin A, Rivera S et al. Pravastatin Reverses Established Radiation-Induced Cutaneous and Subcutaneous Fibrosis in Patients with Head and Neck Cancer: Results of the Biology-Driven Phase Ii Clinical Trial Pravacur. International journal of radiation oncology, biology, physics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776452
  26. Correction to: Perceptions of Statin Discontinuation among Patients with Life-Limiting Illness; DOI: 10.1089/jpm.2016.0489. Journal of palliative medicine 2019; 22:351. http://www.ncbi.nlm.nih.gov/pubmed/?term=30794488
Basic Science publications
  1. Zhang J, Li Q, Wu Y et al. Cholesterol content in cell membrane maintains surface levels of ErbB2 and confers a therapeutic vulnerability in ErbB2-positive breast cancer. Cell communication and signaling : CCS 2019; 17:15. http://www.ncbi.nlm.nih.gov/pubmed/?term=30786890
  2. Wan X, Wang X, Li FL et al. [Protective effect of simvastatin on kidney of rats with diabetes mellitus and the possible mechanism]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 2018; 34:313-317. http://www.ncbi.nlm.nih.gov/pubmed/?term=30788938
  3. Terabe K, Takahashi N, Cobb M et al. Simvastatin promotes restoration of chondrocyte morphology and phenotype. Archives of biochemistry and biophysics 2019; 665:1-11. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776329
  4. Sun W, Pan R, Song J, Sun H. The effects of simvastatin preconditioning on the expression of caspase-3 after myocardial ischemia reperfusion injury in rats. Experimental and therapeutic medicine 2019; 17:2230-2234. http://www.ncbi.nlm.nih.gov/pubmed/?term=30783483
  5. Sanvee GM, Panajatovic MV, Bouitbir J, Krahenbuhl S. Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle. Biochem Pharmacol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30796916
  6. Marin-Medina A, Ruiz-Hidalgo G, Ble-Castillo JL et al. Combined Effect of Diosgenin Along with Ezetimibe or Atorvastatin on the Fate of Labelled Bile Acid and Cholesterol in Hypercholesterolemic Rats. International journal of environmental research and public health 2019; 16. http://www.ncbi.nlm.nih.gov/pubmed/?term=30791676
  7. Li FL, Wan X, Wang X et al. [Simvastatin prevented myocardium of diabetes rats from apoptosis through inhibition of oxidative stress]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 2018; 34:422-426 469. http://www.ncbi.nlm.nih.gov/pubmed/?term=30788922
  8. Lee KR, Midgette Y, Shah R. Fish Oil Derived Omega 3 Fatty Acids Suppress Adipose NLRP3 Inflammasome Signaling in Human Obesity. Journal of the Endocrine Society 2019; 3:504-515. http://www.ncbi.nlm.nih.gov/pubmed/?term=30788452
  9. Hosseinzadeh A, Bahrampour Juybari K, Kamarul T, Sharifi AM. Protective effects of atorvastatin on high glucose-induced oxidative stress and mitochondrial apoptotic signaling pathways in cultured chondrocytes. Journal of physiology and biochemistry 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30796627
  10. Hopkins RJ, Young RP. Mevalonate signaling, COPD and cancer: the statins and beyond. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30787037
  11. Li Z, Zhang J, Zhang Y, Zuo Z. Role of esterase mediated hydrolysis of simvastatin in human and rat blood and its impact on pharmacokinetic profiles of simvastatin and its active metabolite in rat. Journal of pharmaceutical and biomedical analysis 2019; 168:13-22. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776567
  12. Afrasiabi Garekani H, Aftabi SF, Fahimi Nia F et al. Synergistic Effect of Polyethylene Glycol and Superdisintegrant on Dissolution Rate Enhancement of Simvastatin in Pellet Formulation. Pharmaceutical development and technology 2019:1-23. http://www.ncbi.nlm.nih.gov/pubmed/?term=30776937
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