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Update - Week 04, 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

Not LDL- but sdLDL-c predicts CV risk in liver transplant recipients
Liver transplant patients (LTR) were studied to examine the CVD risk of classic lipoprotein concentrations e.g. total cholesterol LDL-c, HDL-c and triglycerides vs particle characteristics of VLDL, HDL and LDL using NMR spectroscopy and qualitative assay kits. The primary endpoint was a composite of angina, myocardial infarction, need for revascularization or cardiac death. The LTR were recruited from a single institution between 2012 and 2014. Out of the 170 patients screened, 130 met the entry criteria. Overall 20 patients reported a CVD complication after a median follow up of 45 months (35-48). None of the traditional lipid fractions was significantly different between the patients that suffered an event and the ones that did not. Baseline LDL-c >100 mg/dl was not associated with increased risk. Baseline sdLDL-c was discovered to be predictive. In patients an sdLDL-c > 25 mg/dl, 17 CVD events were observed vs 3 events in patients with an sdLDL-c <25 mg/dl; HR:6.375 (2.65-15.34, P<0.001). This remained statistically significant after corrections for liver disease, ethnicity, gender, hypertension, obesity and statin use. The suggested mechanism for the increase in plasma sdLDL-c was the abnormal VLDL particle synthesis resulting from chronic immunosuppressive therapies, insulin resistance and fatty liver diseases after LT. Large, TG rich VLDL particle circulate longer in plasma and are metabolized to very small LDL particles,  these are considered extremely atherogenic. This increased CVD risk in LTR’s cannot be discerned by simply measuring LDL-c. The authors suggest that sdLDL-c may provide LTR’s with a more accurate biomarker to determine CVD risk. If aggressive LDL-lowering therapeutic approaches could lower this risk needs to be studied in larger and properly designed studies.
Siddiqui MB, Arshad T, Patel S et al. Small Dense Low-Density Lipoprotein Cholesterol Predicts Cardiovascular Events In Liver Transplant Recipients. Hepatology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30672598
 
Meta-analysis confirms that statins reduce vascular wall inflammation
This meta-analysis analyzed studies that examined the anti-inflammatory effects of statins by 18F-FDG PET/CT imaging. This imaging technique is used to determine inflammatory changes in the vascular wall. The authors included 7 eligible studies with 10 treatment arms and evaluated 287 subjects. Target-to-background ratio (TBR), was used as the predefined endpoint. This is an indicator of blood-corrected 18F-FDG uptake and reflects the anti-inflammatory properties of statins. Overall and differentiated effects of high and low/moderate intensity statins showed significant improvements of vascular wall inflammation, Weighted Mean Difference (WMD): -0.104, p = 0.002, WMD: -0.132, p = 0.019 and WMD 0.069, p = 0.037, respectively. Correction for statin dose/duration, plasma cholesterol and C-reactive protein level changes, and baseline TBR did not affect the TBR treatment response to statins. The authors concluded that statin use was effective in reducing vascular wall inflammation as measured by 18F-FDG PET/CT. It was not possible to determine if these effects were caused by LDL-c lowering or if direct anti-inflammatory properties of statins are responsible for the observed benefits. This will need to be studied in larger well-designed randomized trials. Noteworthy is that a recent study, examining if PCSK9ab could reduce vascular wall inflammation, failed.to show anti-inflammatory effects.
Pirro M, Simental-Mendia LE, Bianconi V et al. Effect of Statin Therapy on Arterial Wall Inflammation Based on 18F-FDG PET/CT: A Systematic Review and Meta-Analysis of Interventional Studies. Journal of clinical medicine 2019; 8. http://www.ncbi.nlm.nih.gov/pubmed/?term=30669380
 
The clinical relevance of statins in immune-mediated disease
The uses of statins in patients with hepatic disease are for many doctors uncharted territories. In clinical trials, patients were instructed to stop their statin if transaminases started to rise. In recent years the impact of transaminase increases was only very seldom associated with liver damage, and the observed benefits of statins in NAFLD/NASH patients resulted in a more pro-active approach to prescribe this class of drugs. In this retrospective registry analysis American veterans diagnosed with liver cirrhosis. Between 2008 and 2016, 72 944 cirrhotic patients were selected; 21 921 used statins and 51 023 were statin naïve, of which 8 794 started with statins. Using a propensity score model statin-naive patients that started with a statin were matched with patients that did not. Exposure time to statins and updated lipid measurements were used to examine effects on survival and liver decompensation. In statin naïve patients every 10 mg/dl increase in total cholesterol was associated with a 3.6% reduction in mortality. Although this seems paradoxical, the explanation offered is that a decompensated liver function is compromised for VLDL synthesis as well. Statin users showed improved survival with an HR of 0.920 (0.0897-0.943) for each year statins were used. A similar HR 0.913 (0.890-0.937) was observed in patients that were statin naïve but started using statins. The authors concluded that in newly diagnosed cirrhosis patients longer survival and preserved hepatic function was associated with higher levels of plasma cholesterol. Despite this finding continued use of statins in patients with cirrhosis of Child-Turcotte-Pugh classes A and B, was associated with an independent improved survival of 8.0% - 8.7% for each year statins were used. The underuse of statins in patients with cirrhosis due to concerns for liver-related toxicity deprives them of potential CVD and hepatic benefits as well as improved survival.
Koch CA, Krabbe S, Hehmke B. Statins, metformin, proprotein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors and sex hormones: Immunomodulatory properties? Reviews in endocrine & metabolic disorders 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30673921
 
Cirrhotic patients live longer when statins are used
The uses of statins in patients with hepatic disease are for many doctors uncharted territories. In clinical trials, patients were instructed to stop their statin if transaminases started to rise. In recent years the impact of transaminase increases was only very seldom associated with liver damage, and the observed benefits of statins in NAFLD/NASH patients resulted in a more pro-active approach to prescribe this class of drugs. In this retrospective registry analysis American veterans diagnosed with liver cirrhosis. Between 2008 and 2016, 72 944 cirrhotic patients were selected; 21 921 used statins and 51 023 were statin naïve, of which 8 794 started with statins. Using a propensity score model statin-naive patients that started with a statin were matched with patients that did not. Exposure time to statins and updated lipid measurements were used to examine effects on survival and liver decompensation. In statin naïve patients every 10 mg/dl increase in total cholesterol was associated with a 3.6% reduction in mortality. Although this seems paradoxical, the explanation offered is that a decompensated liver function is compromised for VLDL synthesis as well. Statin users showed improved survival with an HR of 0.920 (0.0897-0.943) for each year statins were used. A similar HR 0.913 (0.890-0.937) was observed in patients that were statin naïve but started using statins. The authors concluded that in newly diagnosed cirrhosis patients longer survival and preserved hepatic function was associated with higher levels of plasma cholesterol. Despite this finding continued use of statins in patients with cirrhosis of Child-Turcotte-Pugh classes A and B, was associated with an independent improved survival of 8.0% - 8.7% for each year statins were used. The underuse of statins in patients with cirrhosis due to concerns for liver-related toxicity deprives them of potential CVD and hepatic benefits as well as improved survival.
Kaplan DE, Serper M, Mehta R et al. Effects of Hypercholesterolemia and Statin Exposure on Survival in a Large National Cohort of Patients With Cirrhosis. Gastroenterology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30660733
 
The effects of on thrombus resolution in DVT patients
Should statins be part of the therapeutic strategies to resolve thrombus formation in patients with DVT? In this retrospective analysis using electronic health records (EHR)of patients diagnosed with lower extremity DVT (N=818), the authors aimed to address this dilemma. Patients were divided into 2 groups, those that used statins (N=279 - 39%) and those that did not (N=539 - 66%). Predictors of thrombus resolution or improvement, VTE recurrence, and mortality were compared between the two groups by multivariate analysis. Numerous significant differences between statin users and non-users were noted in the EHR’s; users were significantly older (P<0.001), had more CVD risk factors and ASVCD as well as more likely to use antiplatelets (P<.001). Hypercoagulable disorder (P=0.009) or prior DVT (P=0.33) was more frequently observed in the non-statin group. No differences in provoked DVT, the extent of DVT, or association with pulmonary embolism (PE), but patients on statins were more likely to have high-risk PE (P=0.046). There was no difference in patients receiving anticoagulation, type and duration of anticoagulation, inferior vena cava filter placement, or treatment with lytic therapy. There was no difference in mortality or recurrence of DVT, PE, or VTE between the groups. After multivariate corrections, higher mortality was observed in patients that were older, with proximal DVT, CAD, and cancer. Anticoagulation with Coumadin, direct oral anticoagulants and antiplatelet therapy were associated with lower mortality. Statin therapy, antiplatelet therapy, and younger age were associated with thrombus resolution or improvement. The authors concluded that in this observational retrospective analysis of a very diverse population with DVT statin use was associated with thrombus resolution or improved thrombus resolution. This is a hypothesis-generating outcome; causality remains to be determined by properly designed larger randomized controlled trials. For other parameters such as different clinical outcomes of VTE recurrence or mortality, no differences between statin users and non-users could be discerned.
Hsu C, Brahmandam A, Brownson KE et al. Statin therapy associated with improved thrombus resolution in patients with deep vein thrombosis. Journal of vascular surgery. Venous and lymphatic disorders 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30660579
Relevant publications
  1. Reklou A, Katsiki N, Karagiannis A, Athyros V. Effects of lipid lowering drugs on arterial stiffness. One more way to reduce cardiovascular risk? Current vascular pharmacology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30663570
  2. Pourhosseini H, Lashkari R, Aminorroaya A et al. Effects of high dose atorvastatin before elective percutaneous coronary intervention on highly sensitive troponin T and one year major cardiovascular events; a randomized clinical trial. International journal of cardiology. Heart & vasculature 2019; 22:96-101. http://www.ncbi.nlm.nih.gov/pubmed/?term=30671535
  3. Nixdorff U, Horstick G, Schlitt A. [Acute coronary syndrome : Prevention]. Herz 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30671595
  4. Lu Y, Chang R, Yao J et al. Effectiveness of long-term using statins in COPD - a network meta-analysis. Respiratory research 2019; 20:17. http://www.ncbi.nlm.nih.gov/pubmed/?term=30674312
  5. Hong SJ, Jeong HS, Cho JM et al. Efficacy and Safety of Triple Therapy With Telmisartan, Amlodipine, and Rosuvastatin in Patients With Dyslipidemia and Hypertension: The Jeil Telmisartan, Amlodipine, and Rosuvastatin Randomized Clinical Trial. Clinical therapeutics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30665829
  6. Lowenstern A, Navar AM, Li S et al. Association of Clinician Knowledge and Statin Beliefs With Statin Therapy Use and Lipid Levels (A Survey of US Practice in the PALM Registry). Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30660354
  7. Doshi P, Sieluk J, Hung A. The possible harms of statins: What do product labels, patient package inserts, and pharmacy leaflets tell us? Journal of the American Pharmacists Association : JAPhA 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30661956
  8. Bezin J, Moore N, Mansiaux Y et al. Real-life benefits of statins for cardiovascular prevention in elderly subjects: a population-based cohort study. Am J Med 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30660573
  9. Alonso R, Cuevas A, Cafferata A. Diagnosis and Management of Statin Intolerance. J Atheroscler Thromb 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30662020
  10. Song S, Liang L, Fonarow GC et al. Comparison of Clinical Care and In-Hospital Outcomes of Asian American and White Patients With Acute Ischemic Stroke. JAMA neurology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30667466
  11. Schettler VJJ, Muellendorff F, Schettler E et al. NMR-based lipoprotein analysis for patients with advanced hypercholesterolemia undergoing chronic lipoprotein apheresis or PCSK9-inhibitor therapy (NAPALI)-Study. Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30663261
  12. Larsen LE, Stoekenbroek RM, Kastelein JJP, Holleboom AG. Moving Targets. Arterioscler Thromb Vasc Biol 2019:Atvbaha118312028. http://www.ncbi.nlm.nih.gov/pubmed/?term=30676072
  13. Ironside N, Brenner D, Heyer E et al. In response to letter to the editor "Statin use in patients undergoing carotid artery endarterectomy: still much to be uncovered". Acta neurochirurgica 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30666454
  14. Devaraj S, Siegel D, Jialal I. Correction to: Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP? Curr Atheroscler Rep 2019; 21:3. http://www.ncbi.nlm.nih.gov/pubmed/?term=30662999
Miscellaneous publications
 
 
  1. Wang X, Chong S, Lin H et al. Discovery of atorvastatin as a tetramer stabilizer of nuclear receptor RXRalpha through structure-based virtual screening. Bioorganic chemistry 2019; 85:413-419. http://www.ncbi.nlm.nih.gov/pubmed/?term=30665035
  2. Ooi KG, Rao A, Goh JS et al. HMG-CoA reductase expression in human eyelid tissue and in a human meibomian gland epithelial cell line. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30666404
  3. Mo H, Jeter R, Bachmann A et al. The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins. Frontiers in pharmacology 2018; 9:1515. http://www.ncbi.nlm.nih.gov/pubmed/?term=30662405
  4. Li X, Dardik A, Guo R et al. Atorvastatin regulates pericardial patch healing via the microRNA140-ADAM10-ephrinB2 pathway. American journal of translational research 2018; 10:4054-4064. http://www.ncbi.nlm.nih.gov/pubmed/?term=30662650
  5. Jin H, He Y, Zhao P et al. Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery. Theranostics 2019; 9:265-278. http://www.ncbi.nlm.nih.gov/pubmed/?term=30662566
  6. Thassakorn P, Patchanee P, Pongkan W et al. Effect of atorvastatin on oxidative stress and inflammation markers in myxomatous mitral valve disease in dogs: A comparison of subclinical and clinical stages. Journal of veterinary pharmacology and therapeutics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30666669
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This activity is supported by an educational grant from Pfizer.