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Update - Week 34,  2017 
 
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

Review of statin benefits in cirrhotic patients
In the past patients that presented with AS/ALT elevations, we’re not considered to be eligible for statins and statins were stopped if these plasma levels increased. Over the last few years the benefits of statins in patients with NASH/NAFLD has gained more attention. Partly because these patients have an increased risk of CVD and statins were often stopped, exposing patients to an increased risk CVD complications. But also, direct benefits of statins on chronic liver disease parameters were observed. In this review, the authors present a current update of the observed improvements CVD risk as well as liver cirrhosis related parameters. The increase in transaminases, frequently observed in statin users, are considered not clinically significant. Increases in bilirubin, a superior marker of hepatotoxicity, is rare <1% of patients. Routine monitoring of transaminases in patients using statins is no longer required. In patients with compensated liver cirrhosis, statins use was associated with improved outcomes for hepatic decompensation and even mortality. Statins provided also benefits for patients with portal hypertension, reducing volume expansion and increasing microvascular dilatation. Observational and RCT data support the benefits of statin in primary hepatocellular carcinoma, reducing the incidence in patients at risk as well as increasing survival time in patients diagnosed with HCC. Pharmacokinetic studies in patients with Child– Turcotte–Pugh (CTP) Class A and B did show increased Cmax concentrations of atorvastatin of 4-fold in class A to 16-fold in CTP class B. These were observed with other statins as well but to a lesser extent. No studies have been conducted in patients with CTP class C and satins use in discouraged in these advanced stages of cirrhosis. The authors conclude that the benefits of statins warrant their use in patient with compensated cirrhosis.  
Wright AP, Adusumalli S, Corey KE. Statin therapy in patients with cirrhosis. Frontline gastroenterology 2015; 6:255-261. http://www.ncbi.nlm.nih.gov/pubmed/?term=28839820
 
Is a Friedewald calculated LDL-C < 70 mg/dl reliable or not?
Measuring LDL-C by using the Friedewald formula has been criticized not being accurate enough. With new treatments that recently have become available, like the PCSK9ab, lower ranges of LDL-C are reached and question the accuracy of the Friedewald calculation particular in these low ranges. In this analysis use of the Friedewald formula is compared to a new LDL-C estimation tool. Participants from 3 sources were used for this analysis: participants in NHANES 2011-2012 (N=334); patients from Johns Hopkins Hospital (N=1150) and patients from the Mayo Clinic’s (n=2381). Individuals that reached an LDL-C guideline target <70 mg/dl, based on the Friedewald formula, did not reach this target in 15% of the cases from the NHANES study participants, 20% of the patients from Johns Hopkins and 20% of the individuals from the Mayo clinics. Of the patients not reaching the target, approximately 25% had an LDL-C of > 80 mg/dl. Patients with higher LDL-C using the personalized LDL-C calculation were also found to have significant higher median levels of non-HDL-C and Apo B in all the three cohorts. Patients using statins were not different form non-statin users. The authors concluded that 1/5 of patients with expected LDL-C <70 mg/dl were found to have higher plasma concentrations using a more accurate method for calculation LDL-C concentrations. If confirmed in future studies, this finding has important repercussions in terms of misclassification of high risk patients and under utilizations of lipid lowering treatments.
Whelton SP, Meeusen JW, Donato LJ et al. Evaluating the atherogenic burden of individuals with a Friedewald-estimated low-density lipoprotein cholesterol <70 mg/dL compared with a novel low-density lipoprotein estimation method. J Clin Lipidol 2017; 11:1065-1072. http://www.ncbi.nlm.nih.gov/pubmed/?term=28826567
 
Can statin therapy affect platelet reactivity in ACS -PCI patients?
Pharmacodynamics studies have shown that statins exhibit a dose dependent effect on platelet activation by inhibiting ADP-and thrombin-induced platelet reactivity. The observed effects are adjunctive to that exerted by a standard dual antiplatelet treatment regimen of aspirin and Clopidogrel in patients with stable CAD. The effects of statin on platelet reactivity in ACS patients is less known. In this sub study of the GEne polymorphisms, Platelet REactivity, and Syntax Score (GEPRESS) trial, the effects of statin use in combination with Clopidogrel in ACS patients scheduled for PCI were evaluated. On-treatment P2Y12 platelet reactivity was measured using the vasodilator stimulated phosphoprotein (VASP) analysis. High platelet reactivity (HPR) was defined as a platelet reactivity index ≥50%. Statins were used by 835/962 (87%) of the patients in the GENPRESS trial. HPR was evaluated after 1 and 12 months. Patients using statins had a significantly lower HPR at 1 month compared to no statin users (39.6% vs 52% P=0.009). after adjustment for differences in baseline characteristics statin use at discharges was associated with a significantly lower HPR rate (OR: 0.58 (0.39-0.89; P=0.015). No statistical significant difference was observed in MACE, stent thrombosis and bleeding complications.
Toso A, De Servi S, Leoncini M et al. Effects of statin therapy on platelet reactivity after percutaneous coronary revascularization in patients with acute coronary syndrome. Journal of thrombosis and thrombolysis 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28840456
 
Rosuvastatin 20 mg in homozygous FH patients significantly reduced LDL-C
Homozygous FH (hoFH) patients are characterized by extremely elevated plasma LDL-C levels and atherothrombotic complications are observed in teens or even pre-teens. To assess the effects of rosuvastatin in this challenging patient group, 14 hoFH patients (mean age 10.9 years) were evaluated in a 12-week crossover randomized placebo controlled clinical trial. Primary endpoint was efficacy of rosuvastatin 20 mg on LDL-C compared to placebo. Secondary endpoints were changes in in lipoproteins and apolipoproteins. Patients were allowed to continue using their pre-randomized ezetimibe and/or apheresis therapies. The treatment effects were evaluated every 6 weeks. Of the 13 patients that completed the study 7 patients were treated with LDL-apheresis and 8 with ezetimibe as well. Rosuvastatin was well tolerated and no serious adverse events were observed. Mean LDL-C in the placebo arm was 481 mg/dl (229 – 742 mg/dl).  Patients randomized to rosuvastatin achieved an LDL-C of 396 (130-700mg/dl). A difference of 85.4 mg/dl (22.3%) between the two treatment arms was observed (P=0.005). When comparing patients with 2 defective alleles with patients that had two absent alleles, the LDL-C difference amounted to 23.5% (P=0.0044) and 14% (P=0.038) lower LDL-C respectively. In this first-ever study evaluating statins in hoFH children, there was a clinically relevant and statistically significant reduction of LDL-C. The doses effect response depended on the underlying type of genetic mutations and in line with observations in adult hoFH patients. Based on the results of this study, rosuvastatin, alone or in combinations with Ezetimibe or apheresis, was approved by the U.S. FDA for the treatment of hoFH pediatric patients aged 7-17 years.
Stein EA, Dann EJ, Wiegman A et al. Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations. J Am Coll Cardiol 2017; 70:1162-1170. http://www.ncbi.nlm.nih.gov/pubmed/?term=28838366
 
Statins and cancer, a survival bias?
The authors of this analysis questioned the frequently observed longer survival of cancer patients using statins compared to non-statin users in a substantial number of observational studies. They performed an elaborate investigation in 17 323 cancer patients from the Surveillance Epidemiology and End Results (SEER)-Medicare database, comprising 17 cancer registries across 12 US states (2007-2009) with complete follow-up until 2011. They included confirmed cases of stages I to III colorectal, breast, prostate, and bladder cancer in individuals ≥66 years. Primary outcomes were cancer specific mortality and all-cause mortality. Patients evaluated started with statins within 6 months of their cancer diagnosis and were matched with patient that not initiated statins. A total of 1099 individuals died of cancer during follow-up. After adjusting for baseline and post baseline variables, the cancer specific mortality for statin user’s vs no statin use was 1.0 (0.88-1.15). The 3-year risk of cancer death was 10.2% in patients that did not initiate statins and 9.4 % in those that did. A risk difference of -0.8% (-3.7% to 2.7%). For all-cause mortality (n=3286) they calculated a HR: 1.07 (0.93-1.21). With 3-year death rates of 22.3% in patients not using statins and 23.0% in those that did, a 0.7% (-4.0 to 4.1) difference. The authors concluded that the previously reported improved survival rates of patients diagnosed with cancer and using statins were likely due to selection and immortal time bias. Correcting for these factors negated the suggested protective effects. Despite the limitations of this analysis; relatively short follow-up time, cancer diagnoses based on diagnostic codes and the possibility of residual confounding the authors were confident that these would not affect the main conclusions of their analysis.
Emilsson L, Garcia-Albeniz X, Logan RW et al. Examining Bias in Studies of Statin Treatment and Survival in Patients With Cancer. JAMA Oncol 2017. https://www.ncbi.nlm.nih.gov/pubmed/28822996

Relevant publications
  1. Emilsson L, Garcia-Albeniz X, Logan RW et al. Examining Bias in Studies of Statin Treatment and Survival in Patients With Cancer. JAMA Oncol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28822996
  2. Priti K, Agrawal A, Ranwa BL. High versus low dose statin therapy in Indian patients with acute ST-segment elevation myocardial infarction undergoing thrombolysis. Indian Heart J 2017; 69:453-457. http://www.ncbi.nlm.nih.gov/pubmed/?term=28822510
  3. Li G, Mayer CL, Morelli D et al. Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults. Neurology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28821686
  4. Lin FJ, Tseng WK, Yin WH et al. Residual Risk Factors to Predict Major Adverse Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients with and without Diabetes Mellitus. Scientific reports 2017; 7:9179. http://www.ncbi.nlm.nih.gov/pubmed/?term=28835613
  5. Khoury Abdulla R, Kheder E, Yeow R et al. The impact of statin therapy on survival for inhospital cardiac arrest. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28824004
  6. Haukka J, Niskanen L, Auvinen A. Risk of cause-specific death in individuals with cancer - modifying role diabetes, statins, and metformin. International journal of cancer. Journal international du cancer 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28840596
  7. Hashikata T, Tojo T, Muramatsu Y et al. Lower Level of Low Density Lipoprotein Cholesterol is Associated with a Higher Increase in the Fractional Flow Reserve in Patients with Fixed-dose Rosuvastatin. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28824048
  8. Gunasekaran P, Jeevanantham V, Sharma S et al. Implications of the 2013 ACC/AHA cholesterol guidelines on contemporary clinical practice for patients with atherosclerotic coronary and peripheral arterial disease. Indian Heart J 2017; 69:464-468. http://www.ncbi.nlm.nih.gov/pubmed/?term=28822512
  9. Garg N, Muduli SK, Kapoor A et al. Comparison of different cardiovascular risk score calculators for cardiovascular risk prediction and guideline recommended statin uses. Indian Heart J 2017; 69:458-463. http://www.ncbi.nlm.nih.gov/pubmed/?term=28822511
  10. Awad K, Serban MC, Penson P et al. Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis. J Clin Lipidol 2017; 11:972-985.e979. http://www.ncbi.nlm.nih.gov/pubmed/?term=28826569
  11. Anyanwagu U, Mamza J, Donnelly R, Idris I. Effects of background statin therapy on glycemic response and cardiovascular events following initiation of insulin therapy in type 2 diabetes: a large UK cohort study. Cardiovascular diabetology 2017; 16:107. http://www.ncbi.nlm.nih.gov/pubmed/?term=28830436
  12. Zhao S, Peng D. Efficacy and safety of rosuvastatin versus atorvastatin in high-risk Chinese patients with hypercholesterolemia: a randomised, double blind, active-controlled study. Current medical research and opinion 2017:1-18. http://www.ncbi.nlm.nih.gov/pubmed/?term=28836458
  13. Yagi S, Fukuda D, Aihara KI et al. n-3 Polyunsaturated Fatty Acids: Promising Nutrients for Preventing Cardiovascular Disease. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28835582
  14. von Schuckmann LA, Smith D, Hughes MCB et al. Associations of statins and diabetes with diagnosis of ulcerated cutaneous melanoma. The Journal of investigative dermatology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28842323
  15. Steely AM, Callas PW, Hohl PK et al. Underutilization of antiplatelet and statin therapy after postoperative myocardial infarction following vascular surgery. Journal of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28830706
  16. Salna MP, Singer HM, Dana AN. Pravastatin-Induced Eczematous Eruption Mimicking Psoriasis. Case reports in dermatological medicine 2017; 2017:3418204. http://www.ncbi.nlm.nih.gov/pubmed/?term=28831316
  17. Rosenson RS. Trial designs for statin muscle intolerance. Curr Opin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28832369
  18. Prado Y, Zambrano T, Salazar LA. Transporter genes ABCG2 rs2231142 and ABCB1 rs1128503 polymorphisms and atorvastatin response in Chilean subjects. Journal of clinical pharmacy and therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28833323
  19. Mosepele M, Letsatsi V, Mokgatlhe L et al. Cholesterol Screening and Statin Prescription is Low Among HIV-Infected Patients on Protease-Inhibitor Regimens in Botswana. The open AIDS journal 2017; 11:45-51. http://www.ncbi.nlm.nih.gov/pubmed/?term=28839514
  20. Mikkelsen MK, Thomsen FB, Berg KD et al. Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy. Scandinavian journal of urology 2017:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28831860
  21. Matsui S, Kajikawa M, Hida E et al. Optimal Target Level of Low-density Lipoprotein Cholesterol for Vascular Function in Statin Naive Individuals. Scientific reports 2017; 7:8422. http://www.ncbi.nlm.nih.gov/pubmed/?term=28827781
  22. Mathisen SR, Abdelnoor M. Beneficial effect of statins on total mortality in AAA repair. Vascular medicine (London, England) 2017:1358863x17724221. http://www.ncbi.nlm.nih.gov/pubmed/?term=28835175
  23. Mammen AL. Which nonautoimmune myopathies are most frequently misdiagnosed as myositis? Curr Opin Rheumatol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28832350
  24. Liao KF, Huang PT, Lin CC et al. Fluvastatin use and risk of acute pancreatitis: a population-based case-control study in Taiwan. BioMedicine 2017; 7:17. http://www.ncbi.nlm.nih.gov/pubmed/?term=28840831
  25. Gidding SS. Managing Patients With Homozygous Familial Hypercholesterolemia. J Am Coll Cardiol 2017; 70:1171-1172. http://www.ncbi.nlm.nih.gov/pubmed/?term=28838367
  26. Fairman KA, Davis LE, Sclar DA. Real-world use of PCSK-9 inhibitors by early adopters: cardiovascular risk factors, statin co-treatment, and short-term adherence in routine clinical practice. Therapeutics and clinical risk management 2017; 13:957-965. http://www.ncbi.nlm.nih.gov/pubmed/?term=28831261
  27. El-Refai SM, Black EP, Adams VR et al. Statin use and venous thromboembolism in cancer: A large, active comparator, propensity score matched cohort study. Thrombosis research 2017; 158:49-58. http://www.ncbi.nlm.nih.gov/pubmed/?term=28822240
  28. El-Mohandes EM, Moustafa AM, Khalaf HA, Hassan YF. The role of mast cells and macrophages in amiodarone induced pulmonary fibrosis and the possible attenuating role of atorvastatin. Biotechnic & histochemistry : official publication of the Biological Stain Commission 2017:1-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=28836856
  29. Cheng KK, Swallow DM, Grosset KA, Grosset DG. Statin usage, vascular diagnosis and vascular risk factors in Parkinson's disease. Scottish medical journal 2017:36933017727432. http://www.ncbi.nlm.nih.gov/pubmed/?term=28836927

Miscellaneous publications
  1. Xu X, Gao W, Cheng S et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. Journal of neuroinflammation 2017; 14:167. http://www.ncbi.nlm.nih.gov/pubmed/?term=28835272
  2. Wat E, Ng CF, Koon CM et al. The adjuvant value of Herba Cistanches when used in combination with statin in murine models. Scientific reports 2017; 7:9391. http://www.ncbi.nlm.nih.gov/pubmed/?term=28839280
  3. Kou X, Yang Y, Jiang X et al. Vorinostat and Simvastatin have synergistic effects on triple-negative breast cancer cells via abrogating Rab7 prenylation. Eur J Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28826913
  4. Kornelius E, Li HH, Peng CH et al. Mevastatin promotes neuronal survival against Abeta-induced neurotoxicity through AMPK activation. Metabolic brain disease 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28840430
  5. Jiang QF, Huang MY, Wu KY et al. Intervention Effects of Atorvastatin Combined with Panax notoginseng Saponins on Rats with Atherosclerosis Complicated with Hepatic Injury. Pharmacognosy magazine 2017; 13:430-438. http://www.ncbi.nlm.nih.gov/pubmed/?term=28839368
  6. Hori E, Kikuchi C, Nagami C et al. Role of Glyceraldehyde-derived AGEs and Mitochondria in Superoxide Production in Femoral Artery of OLETF Rat and Effects of Pravastatin. Biological & pharmaceutical bulletin 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28835584
  7. Cheung DW, Koon CM, Wong PH et al. Evaluating Efficacy and Safety of Combination Medication of Atorvastatin and a Herbal Formula Containing Salvia miltiorrhiza and Pueraria lobata on Hyperlipidemia. Phytotherapy research : PTR 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28840970
  8. Chen MJ, Cheng AC, Lee MF, Hsu YC. Simvastatin induces G1 arrest by up-regulating GSK3beta and down-regulating CDK4/cyclin D1 and CDK2/cyclin E1 in human primary colorectal cancer cells. Journal of cellular physiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28833099
  9. Barthelmes J, Sudano I. Praxis 2017; 106:933-940. http://www.ncbi.nlm.nih.gov/pubmed/?term=28830329

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