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Update - Week 02,  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

Can HF patients benefit from statins?
The number of heart failure patients are increasing globally, and preventing complications is challenging in this population. Rosuvastatin has been tested in (advanced) heart failure patients (AURORA and GISI-HF studies) but in these RCT with hard clinical endpoints no benefits were observed. Despite this evidence there have been reports showing some benefits particular in HF patients with less advanced disease and with preserved ejection fraction (pEF). The authors present new findings from a retrospective analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. The trial included 3378 HFpEF patients that were followed for 3.3 years. Based on propensity score matching, statin users were compared to participants who were not using statins Patients on statins had a better overall survival HR 0.79, (0.63–0.99; P=0.04). Patients with ischemic heart disease (IHD) and using statins had a significantly lower risk of dying, HR 0.63 (0.44–0.91; P = 0.01) and CVD events HR 0.59 (0.37–0.94; P = 0.02). No significant differences were observed in HFpEF patients with IHD using statins vs those who did not, for total mortality or CVD events; HR 0.97, (0.72–1.31; P = 0.83) and HR 0.95 (0.66–1.36; P=0.77) respectively. The authors suggest that this intriguing finding can partly be explained by the pleiotropic effects of statins, improving vascular smooth muscle proliferation, platelet aggregation, endothelial function, blood flow, and reduction of vascular inflammation. They noted that HFrEF patients with IHD did not derive benefit from statins either.
Tsujimoto T, Kajio H. Favorable effects of statins in the treatment of heart failure with preserved ejection fraction in patients without ischemic heart disease. Int J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29307549
 
Statin tolerance review for lipidologists
Updated review on statin intolerance, addressing common issues, based on recent trials and observations. The definition of statin intolerance is pivotal when determining consequences and management strategies. A general description of statin intolerance (SI) is the inability to tolerate a suitable dose of a statin required for a given patient’s CV risk and this can be partial or complete. Complete SI is uncommon and, after a correct evaluation, can be found in no more than 2-3% of statin treated patients. The National Lipid Association (2014), International Lipid Expert Panel (2014), European Atherosclerosis Society (2015) and the Canadian Consensus Working Group (2016), published different definitions that are presented and discussed in this review. Symptoms and biomarkers of SI are reviewed, including recent genetic and lipodomic analyses. Non-statin drugs are suggested as alternatives in combination with low dose statins or mono-therapy. 1st generation non-statins small molecules e.g. bile acid sequestrants and ezetimibe and 2nd generation biologicals e.g. PCSK9 antibodies and PCSK siRNA’s) are reviewed and so are the trials that evaluated safety and efficacy. Nutraceuticals as an alternative to pharmacological interventions are appraised as well. For clinicians, routinely prescribing statins and managing patients with statin tolerance issues, this review can help how to initiate a comprehensive evaluation of SI patients as well as selecting an appropriate alternative treatment strategy.
Toth PP, Patti AM, Giglio RV et al. Management of Statin Intolerance in 2018: Still More Questions Than Answers. Am J Cardiovasc Drugs 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29318532
 
Meta-analysis shows promise for (atorva)statin, in preventing AF after CABG
The onset of atrial fibrillation (AF) after a cardiac surgical procedure is not uncommon (20% for non-cardiac surgery and 10%-65% for cardiac surgery) and is associated with serious short- and long-term consequences in term of complications as well as medication add-on’s. To date no large randomized hard clinical endpoint trial has been performed; data from observational studies have shown conflicting results. To fill this knowledge gap, the authors executed a meta-analysis of all published RCT’s of starting statins, in statin-naïve patients with sinus rhythm, before cardiac surgeries. Of the 20 studies included, 17 were graded as high quality (Jadad score) and 4003 patients participated; 2009 (51.2%) received a statin.  Of these tirals, 13 evaluated atorvastatin, 2 rosuvastatin, 2 simvastatin, 1 pravastatin and 2 studies compared different dosages of atorvastatin. Starting a statin before surgery was associated with a reduced risk of AF, RR: 0.57 (0.45-0.73; P=0.0001) Subgroup analyses showed preferred outcomes for atorvastatin only in new-onset AF, RR: 0.53 (0.41-0.69; P=0.0001) as well as better results for CABG patients, RR: 0.52 (0.39-0.68). Optimal results were observed with moderate statin dosing, RR: 0.42 (0.28-0.64). Intriguingly Asian patients showed superior benefits when compared to European/American patients. Based on the presented results and taking into account the suggested limitations of the selected studies, study designs and this meta-analysis, well planned prospective follow-up studies are warranted.
Sai C, Li J, Yingbin X, Ruiyan M. Atorvastatin Prevents Postoperative Atrial Fibrillation for Patients undergoing Cardiac Surgery. Hellenic journal of cardiology: HJC = Hellenike kardiologike epitheorese 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29307691
 
High intensity statins save lives and prevent amputations!

The impact of statin on CVD outcomes in PAD has been well established, resulting in the inclusion of PAD as a strong indicator for the use of high-dose, high-intensity statins in practically all recent lipid lowering guidelines. This retrospective analysis of a large US veteran’s registry (2003-2014), including 155 647 PAD patients, examined the PAD outcomes of amputation and mortality. Statin use, including high or low-moderate intensity statins, were compared to antiplatelet (AP) therapy without statin. A Cox proportional hazards model as well as a propensity score (PS) matched analysis and a sensitivity plus subgroup analysis were performed to limit confounding. Overall 28% of PAD patients were not prescribed any statin. High intensity statin use was observed in only 6.4% of patients with PAD; this percentage increased to 18.4% in those with coronary or carotid co-morbidities. Risk of amputations and death declined significantly in the high intensity statin users vs AP only, HR: 0.67 (0.61-0.74) and HR: 0.74 (0.70-0.77), respectively. Low-to moderate statins significantly reduced risk as well, HR amputation 0.81 (0.75-0.86) and HR death 0.83 (0.81-0.86) but to a lesser extent (P<0.001). The results remained robust even after PS matched controls and sensitivity subgroup analyses. The authors concluded that high-intensity statins are under-used in PAD patients and, based on their observations, could significantly reduce deaths and limb loss when started routinely on top of antiplatelet medication.  
Arya S, Khakharia A, Binney ZO et al. Statins Have a Dose-Dependent Effect on Amputation and Survival in Peripheral Artery Disease Patients. Circulation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29330214
 
Can statins affect outcome in chronic pancreatitis patients?
One of the feared complications of chronic pancreatitis (CP) is pancreatic cancer (PC). The effects of statins to promote or protect from PC have been confusing and inconclusive. Data from 5 National Danish health registries were combined to determine the benefits or harms of statins in this specific patient group. In these combined registries 16 108 patients were diagnosed with CP including 3692 (23%) CP patients hat used statins. in the final analysis 1696 statin using patients were compared to 3111 patients not on statins. Using propensity scoring, 339 statin users were matched with 339 patients without statins. A total of 2073 (43%) patients died during follow-up. Deaths occurred in 53 (48–58) per 1000 P-Y for statin users (median survival 11.3 years). Mortality in no statin users reached 59 (56–62) per 1000 P-Y. (median survival 11.3 years). Adjusted for covariates, resulted in a HR 0.77 (0.68–0.87). In the PS matched patients mortality numbers in statin vs no statin users were 46 (39–55)
and 66 (56–78) respectively. A HR 0.64 (0.49–0.83). No association was observed for mortality and statin dosage but only 24% used > 1.4 WHO defined DD/day. Progression of CP was observed less frequently in statin users, HR of 0.21 (0.17–0.26). Progression to cancer occurred in 117 (2.4%) patients. Statin-treated patients were less likely to develop this complication, HR 0.21 (0.06–0.70). Overall statins use was associated with reduced all-cause mortality, reduced progression of CP, and reduced risk of pancreatic cancer. Despite the limitations of a retrospective analysis and residual bias, the authors concluded that the presented data supports the hypothesis that statins can affect the course of chronic pancreatitis. Additional prospective follow=up studies are needed to confirm these observations.
Bang UC, Watanabe T, Bendtsen F. The relationship between the use of statins and mortality, severity, and pancreatic cancer in Danish patients with chronic pancreatitis. European journal of gastroenterology & hepatology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29309396
 
Relevant publications
  1. Tan JT, Barry AR. Coenzyme Q10 for statin-associated myalgia. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 2018; 75:15. http://www.ncbi.nlm.nih.gov/pubmed/?term=29317393
  2. Szymanski FM, Platek AE, Rys A et al. Utilization of the lipid-lowering therapies in outpatient settings in Poland - epidemiological survey Economedica Dyslipidemia 2015. Kardiol Pol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29313565
  3. Borissov B, Urbich M, Georgieva B et al. Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years. Journal of market access & health policy 2017; 5:1412753. http://www.ncbi.nlm.nih.gov/pubmed/?term=29321830
  4. Ruscica M, Macchi C, Pavanello C et al. Appropriateness of statin prescription in the elderly. Eur J Intern Med 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29310996
  5. Ruisinger JF, Moriarty PM, Backes JM. Coenzyme Q10 for statin-associated myalgia. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 2018; 75:14-15. http://www.ncbi.nlm.nih.gov/pubmed/?term=29317392
  6. Raman VK, Geladari E, Papademetriou V. Is statin therapy safe and effective in patients with chronic Kidney disease? Current pharmaceutical design 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29318962
  7. Qiu C, Zhou Q, Li X et al. High circulating proprotein convertase subtilisin/Kexin type 9 concentration associates with cardiovascular risk: A meta-analysis of cohort studies. Medicine (Baltimore) 2017; 96:e8848. http://www.ncbi.nlm.nih.gov/pubmed/?term=29310364
  8. Bogsrud MP, Langslet G, Wium C et al. Treatment goal attainment in children with familial hypercholesterolemia: A cohort study of 302 children in Norway. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29310990
  9. Poredos P, Poredos P. Peripheral arterial occlusive disease and perioperative risk. International angiology : a journal of the International Union of Angiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29327897
  10. Kang J, Kim YC, Park JJ et al. Increased epicardial adipose tissue thickness is a predictor of new-onset diabetes mellitus in patients with coronary artery disease treated with high-intensity statins. Cardiovascular diabetology 2018; 17:10. http://www.ncbi.nlm.nih.gov/pubmed/?term=29325562
  11. Acar D, Gulpembe M, Yildiz CG et al. The reno-protective effects of atorvastatin in crush syndrome and rhabdomyolysis:is there a dilemma? Turk J Med Sci 2017; 47:1920-1924. http://www.ncbi.nlm.nih.gov/pubmed/?term=29306258
  12. Sun S, Wang R, Fan J et al. Effects of Danshen tablets on pharmacokinetics of atorvastatin calcium in rats and its potential mechanism. Pharmaceutical biology 2018; 56:104-108. http://www.ncbi.nlm.nih.gov/pubmed/?term=29322864
  13. Schreiber K, Sciascia S, de Groot PG et al. Antiphospholipid syndrome. Nature reviews. Disease primers 2018; 4:17103. http://www.ncbi.nlm.nih.gov/pubmed/?term=29321641
  14. Rafeeq MM, Habib HS, Murad HAS et al. Effect of genetic polymorphisms in SREBF-SCAP pathway on therapeutic response to rosuvastatin in Saudi metabolic syndrome patients. Pharmacogenomics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29318930
  15. Masjuan J, Gallego J, Aguilera JM et al. Use of cardiovascular polypills for the secondary prevention of cerebrovascular disease. Neurologia 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29325730
Miscellaneous publications
  1. Zakrajsek J, Bevc-Cernilec K, Bohanec S, Urleb U. Optimization of UPLC Method for Simultaneous Determination of Rosuvastatin and Rosuvastatin Degradation Products. Acta chimica Slovenica 2017; 64:968-979. http://www.ncbi.nlm.nih.gov/pubmed/?term=29318320
  2. Singh I, Samuvel DJ, Choi S et al. Combination therapy of lovastatin and AMPK activator improves mitochondrial and peroxisomal functions and clinical disease in EAE model. Immunology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29331024
  3. Rebalka IA, Cao AW, Raleigh MJ et al. Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice. Front Physiol 2017; 8:1088. http://www.ncbi.nlm.nih.gov/pubmed/?term=29311999
  4. Liu WH, Xu XH, Luo Q et al. Inhibition of the RhoA/Rho-associated, coiled-coil-containing protein kinase-1 pathway is involved in the therapeutic effects of simvastatin on pulmonary arterial hypertension. Clinical and experimental hypertension (New York, N.Y. : 1993) 2018:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29319354
  5. Khan TJ, Ahmed YM, Zamzami MA et al. Effect of atorvastatin on the gut microbiota of high fat diet-induced hypercholesterolemic rats. Scientific reports 2018; 8:662. http://www.ncbi.nlm.nih.gov/pubmed/?term=29330433
  6. Kamal AHM, Chakrabarty JK, Udden SMN et al. Inflammatory Proteomic Network Analysis of Statin-treated and Lipopolysaccharide-activated Macrophages. Scientific reports 2018; 8:164. http://www.ncbi.nlm.nih.gov/pubmed/?term=29317699
  7. Jones HM, Fang Z, Sun W et al. Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro. American journal of cancer research 2017; 7:2478-2490. http://www.ncbi.nlm.nih.gov/pubmed/?term=29312801
  8. Jha A, Ryu MH, Ojo OO et al. Prophylactic benefits of systemically delivered simvastatin treatment in a house dust mite challenged murine model of allergic asthma. Br J Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29318574
  9. Chen CH, Cheng CY, Chen YC et al. Corrigendum to ' Rosuvastatin inhibits pressure-induced fibrotic responses via the expression regulation of prostacyclin and prostaglandin E 2 in rat renal tubular cells.': [European Journal of Pharmacology 700 (2013) 65-73]. Eur J Pharmacol 2018; 819:290. http://www.ncbi.nlm.nih.gov/pubmed/?term=29325908
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This activity is supported by an educational grant from Pfizer.