up-to-date with a click!
Update - Week 17, 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

Comparing statins with ezetimibe + Fenofibrate in Japanese diabetic patients
In diabetic patients, the most common lipid abnormalities are an elevated TG, increased small dense LDL + decreased HDL. In this open label randomized prospective follow-up study 50 diabetic patients, treated with statins were randomized to continuing statins or a combination of Fenofibrate + Ezetimibe, for 12 weeks. Flow mediated dilatation (FMD) and lipoproteins using high performance liquid chromatography, were evaluated. The combination of Fenofibrate + ezetimibe resulted in significant lower VLDL, total TG, chylomicron-TG, VLDL-TG, HDL-TG, malondialdehyde LDL (reflecting oxidized LDL) and raised HDL-C. The diameter of LDL increased as well, while the diameter HDL decreased. Vascular function improved, reflected by increased FMD. These vascular changes were directly related to the hike of the smaller HDL fraction. Concentrations of Lp(a) were not different in the two treatment arms, but two-hour post-prandial lipoprotein measurements improved as well.  In this small 12 weeks study of Japanese diabetics the combinations of Fenofibrate + ezetimibe was superior to statin monotherapy when evaluating LDL and HDL sub-fractions as well as FMD. Of note, in the statin arm only low dosages of all currently available statins were used, except lovastatin (e.g. Atorvastatin 5 and 10 mg / Rosuvastatin 2.5 and 5 mg).
Shinnakasu A, Yamamoto K, Kurano M et al. The Combination Therapy of Fenofibrate and Ezetimibe Improved Lipid Profile and Vascular Function Compared with Statins in Patients with Type 2 Diabetes. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28450679
Tips, Tricks and Trap’s when managing SAMS patients
Statin associated muscle complaints have surfaced as a commonly reported problem in patients that use or start to use statins. In this review, the authors guide clinicians by providing a structured approach that is based on published data as well as their expert opinion. The topics discussed are: Recognizing and diagnosing SAMS, based on earlier published definitions. Psychological issues and how to address these. Interpretation of CK elevations. Strategies to re-challenge patients and motivate patients to do so and what statin – statin dosage to use for re-challenge. There is an overview of nutraceuticals e.g red yeast rice and phytosterols plus complimentary therapies such as vitamin D and Co-enzyme Q10. The authors suggest that in different patient populations, the approach for managing SAMS should not be different. Other LDL-C therapeutic approaches, such as  Ezetimibe, PCSK9ab and fibrates are reviewed as well. A SAMS algorithm, based on the recent EHJ publications by Stroes et al., is provided; as is a frequently asked question list + answers in an appendix.
Laufs U, Filipiak KJ, Gouni-Berthold I, Catapano AL. Practical aspects in the management of statin-associated muscle symptoms (SAMS). Atherosclerosis. Supplements 2017; 26:45-55. http://www.ncbi.nlm.nih.gov/pubmed/?term=28434484
Is a poly pill strategy superior to single drug combination?
This was a sub-analysis of the Use of a Multidrug Pill in Reducing cardiovascular Events (UMPIRE) study, a randomized clinical trial comparing a polypill-based treatment strategy with usual care in high risk individuals. Participants (N=2002) were recruited in India, Netherlands, UK and Ireland. Follow-up was planned for 12 to 24 months. The poly-pill consisted of the following combined drugs: aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg or hydrochlorothiazide 12.5 mg. This strategy improved the use of indicated medication by 33%; RR 1.33 (95% CI: 1.26 to 1.41). Observed LDL-C differences of 0.37, 0.22, 0.14 and 0.07 mmol/L for respectively no statin, less potent, equi-potent and more potent statin at baseline. For BP control the poly-pill users showed 5.4, 6.2, 3.3 and 1.8 mmHg lower systolic BP among patients taking 0, 1, 2 or 3 BP-lowering agents. Who, at baseline, used a more potent statin in the control group, no significant differences in the LDL-C were noted, but also in these patients there was better blood pressure control and aspirin compliance. Similar non-significant BP changes were observed for the control patients who used 3 anti-hypertensive agents at baseline. Overall, better compliance and risk factor control was achieved in the poly-pill users. Best results were observed in patient who were up-titrated from partial or less potent treatment.
Lafeber M, Spiering W, Visseren FL et al. Impact of switching from different treatment regimens to a fixed-dose combination pill (polypill) in patients with cardiovascular disease or similarly high risk. Eur J Prev Cardiol 2017:2047487317695616. http://www.ncbi.nlm.nih.gov/pubmed/?term=28436727
Latest Lipid guideline update from American Association of Clinical Endocrinologists
In this recently released update guideline of AACE, LDL-C targets remain and a new risk category: extreme risk with lower treatment goals: LDL-C < 55 mg/dL are introduced. Extreme risk are patients with progressive ASCVD and an LDL-C of <70 mg/dL.. Patients with stable CHD and diabetes, CKD stages 3/4, or heterozygous FH. Or patients with premature ASCVD. This is the first international guideline incorporating the evidence of the IMPROVE-IT study were the addition of ezetimibe reduced CVD risk by reaching an LDL-C target of < 55 mg/dl. The Executive Summary contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 are Grade D (10.3%) are Grade D, and based on the collected evidence of the 695 references. Non HLD-C and Apo B are again part of this updated guideline and are superior targets in diabetic and/or hypertriglyceridemia patients.  This guideline aims to provide clinicians a n overview of the screening recommendations; assessment of risk, and treatment recommendations for various lipid disorders secondly there is special attention for diabetics, as well as dyslipidemic women and children/adolescents. Last a review of cost effectiveness data, to support clinical decision dilemma’s
Jellinger PS, Handelsman Y, Rosenblit PD et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2017; 23:1-87. http://www.ncbi.nlm.nih.gov/pubmed/?term=28437620

Do Statins and exercise mix?
The role of lifestyle improvement in combination with statins has been studied in a small number of trials.  `the focus of this systematic review and meta-analysis is the effects of exercise in statin users, for this only trials with statin monotherapy were selected. Seven trials were used to evaluate efficacy of these interventions and 13 trials provided data on safety when combining exercise with statins. No improvements of LDL-C, HDL-C or CVD endpoints were observed, although for the latter, the included trials were too small, too short and with not enough participants to draw any final conclusions. In patients that combined exercise with statins, improvement of insulin sensitivity, inflammation and exercise capacity were noted. Intense training, as well as acute eccentric and strenuous exercise, could enhance muscle complaints  from statin use! No harmful muscle effects were observed after moderate chronic physical activities. Patient that followed a regular exercise routine prior to statin initiation even reported less muscle related symptoms. Despite the limited number, the heterogeneity and lack of quality of the included studies, in this first meta-analysis of its kind, moderate intensity regular exercise seem to have benefits in patients that need to use statins.  
Gui YJ, Liao CX, Liu Q et al. Efficacy and safety of statins and exercise combination therapy compared to statin monotherapy in patients with dyslipidaemia: A systematic review and meta-analysis. Eur J Prev Cardiol 2017:2047487317691874. http://www.ncbi.nlm.nih.gov/pubmed/?term=28436720
EAS consensus statement on LDL and ASCVD
In this 12-page review (plus 2 pages of references), the authors, lead by dr. Brian Ference, crafted a critical appraisal of the genetic and clinical evidence that in fact LDL causes ASCVD. In the article eleven separate but related issues are discussed to make this a convincing case. First the pathophysiological process of atherosclerosis is presented and the role of Cholesterol, LDL, and LDL-C ; where noted that LDL particle number or Apo B may be a more accurate measurement than LDL-C. Evidence from inherited disorders of lipid metabolism and evidence from Mendelian randomization studies is put forward to make a very convincing argument for LDL and ASCVD risk. The evidence from randomized controlled trials using lipid lowering drugs most of which were statin trials re-enforce the causality of LDL in the development and in the management of ASCVD. The 8 Criteria for causality are ticked and confirm what was presented so far. New in this statement is the concept of the lifelong cumulative effect of exposure to LDL and ASCVD. Not only the level of LDL-C at a certain point in time but the lifelong exposure contributes to the observed risk. In the final discussion recommendations for treatment and the cumulative effects of other risk factors on top of LDL, e.g. smoking hypertension and diabetes, are discussed. The final conclusion of the authors: LDL is not merely a biomarker of increased risk but a causal factor in the pathophysiology of ASCVD!
Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28444290
What to do when patients report muscle pain? Re-challenge!
In this Canadian retrospective analysis of 118 patients referred to a tertiary center in London Ontario, for statin associated muscle symptoms (SAMS) were evaluated. Patients had a median follow up time of 17 months. The management strategies were: (1) re-challenge with a statin previously associated with muscle symptoms (same-statin re-challenge); (2) statin switch (switch to a different statin); (3) nondaily dosing of a statin; or (4) non-statin therapy (ezetimibe, niacin, bile acid sequestrants, and/or fibrates). Patients had a median follow up time of 17 months. For same-statin re-challenge, statin switch, and non-statin therapy success rates were 71%, 53%, and 57%, respectively (P= 0.11). Patients that continued with the same-statin had significantly greater LDL-C reductions and 50% achieved their LDL-C goal. For the non-statin users only 15% managed to achieve targets OR 6.8 (95% CI 1.5-40.7; P =0.04) In the statin switch group, tolerability was 31%, 42%, and 40% among those who attempted to switch to a third (n=81), fourth (n=43), or rarely fifth (n=10) statin, respectively. Fluvastatin was the most commonly tolerated statin (40%; P < 0.0001). Approximately 16% of all participants were intolerant to any lipid-lowering agent even when not using statins. The authors concluded that same-statin re-challenge is a feasible management strategy that is tolerable and efficacious in patients with a history of SAMS.
Brennan ET, Joy TR. Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge? Can J Cardiol 2017; 33:666-673. http://www.ncbi.nlm.nih.gov/pubmed/?term=28449837

Relevant publications
  1. Farnier M, Civeira F, Descamps O. How to implement clinical guidelines to optimise familial hypercholesterolaemia diagnosis and treatment. Atherosclerosis. Supplements 2017; 26:25-35. http://www.ncbi.nlm.nih.gov/pubmed/?term=28434482
  2. Liu B, Yi Z, Guan X et al. The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis. Breast Cancer Res Treat 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28432513
  3. Woo HI, Kim SR, Huh W et al. Association of genetic variations with pharmacokinetics and lipid-lowering response to atorvastatin in healthy Korean subjects. Drug design, development and therapy 2017; 11:1135-1146. http://www.ncbi.nlm.nih.gov/pubmed/?term=28435225
  4. Rodriguez F, Maron DJ, Heidenreich PA. Intensity of Statin Treatment and Mortality-Reply. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28445560
  5. Khera AV, Demler O, Adelman SJ et al. Cholesterol Efflux Capacity, HDL Particle Number, and Incident Cardiovascular Events. An Analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28450350
  6. DeCarlo C, Scher L, Shariff S et al. Statin use and other factors associated with mortality after major lower extremity amputation. Journal of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28431865
  7. Butters J, Brown A, Griffith L et al. Clinical Outcomes in Trials Evaluating Lipid-Lowering Drugs. Am J Cardiovasc Drugs 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28432573
  8. Bagdade J, Barter P, Quiroga C, Alaupovic P. Effects of Torcetrapib and Statin Treatment on ApoC-III and Apoprotein-Defined Lipoprotein Subclasses (from the ILLUMINATE Trial). Am J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28431663
  9. Zhao G, Wu L, Liu Y et al. Rosuvastatin reduces the recurrence rate following catheter ablation for atrial fibrillation in patients with heart failure. Biomedical reports 2017; 6:346-352. http://www.ncbi.nlm.nih.gov/pubmed/?term=28451398
  10. Zhang PY. PCSK9 as a therapeutic target for cardiovascular disease. Experimental and therapeutic medicine 2017; 13:810-814. http://www.ncbi.nlm.nih.gov/pubmed/?term=28450903
  11. Thompson A, Guthrie B, Payne K. Using the Payoff Time in Decision-Analytic Models: A Case Study for Using Statins in Primary Prevention. Med Decis Making 2017:272989x17700846. http://www.ncbi.nlm.nih.gov/pubmed/?term=28441087
  12. Silbernagel G, Scharnagl H, Kleber ME et al. Circulating proprotein convertase subtilisin-kexin type 9, all-cause mortality, and cardiovascular mortality: The Ludwigshafen Risk and Cardiovascular Health study. Eur J Prev Cardiol 2017:2047487317693938. http://www.ncbi.nlm.nih.gov/pubmed/?term=28436724
  13. Schnoeller TJ, Jentzmik F, Schrader AJ, Steinestel J. Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness. Oncotarget 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28445145
  14. Safouris A, Krogias C, Sharma VK et al. Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis. Arterioscler Thromb Vasc Biol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28450295
  15. Nunes JPL. Intensity of Statin Treatment and Mortality. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28445564
  16. Naugler C, Cook C, Morrin L et al. Statin Prescriptions for High-Risk Patients Are Increased by Laboratory-Initiated Framingham Risk Scores: A Quality-Improvement Initiative. Can J Cardiol 2017; 33:682-684. http://www.ncbi.nlm.nih.gov/pubmed/?term=28449839
  17. Mansour H, Ghaleb R. Atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery. Atherosclerosis. Supplements 2017; 25:e2. http://www.ncbi.nlm.nih.gov/pubmed/?term=28452305
  18. Liang X, Yang LX, Guo R et al. Atorvastatin attenuates plaque vulnerability by downregulation of EMMPRIN expression via COX-2/PGE2 pathway. Experimental and therapeutic medicine 2017; 13:835-844. http://www.ncbi.nlm.nih.gov/pubmed/?term=28450907
  19. Leibowitz M, Cohen-Stavi C, Basu S, Balicer RD. Targeting LDL Cholesterol: Beyond Absolute Goals Toward Personalized Risk. Current cardiology reports 2017; 19:52. http://www.ncbi.nlm.nih.gov/pubmed/?term=28432662
  20. Knowles JW, Howard WB, Karayan L et al. Access to Non-Statin Lipid Lowering Therapies in Patients at High-Risk of Atherosclerotic Cardiovascular Disease. Circulation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28446516
  21. Donzelli A, Schivalocchi A. Intensity of Statin Treatment and Mortality. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28445577
  22. Bos S, Phillips M, Watts GF et al. Novel protein biomarkers associated with coronary artery disease in statin-treated patients with familial hypercholesterolemia. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28434814
  23. Averna M, Stroes E. How to assess and manage cardiovascular risk associated with lipid alterations beyond LDL. Atherosclerosis. Supplements 2017; 26:16-24. http://www.ncbi.nlm.nih.gov/pubmed/?term=28434480
  24. Ascaso JF, Ferrari R. Practical recommendations for the management of cardiovascular risk associated with atherogenic dyslipidemia, with special attention to residual risk. Spanish adaptation of a European Consensus of Experts. Clin Investig Arterioscler 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28433209
  25. Al Kindi M, Belanger AM, Sayegh K et al. Aortic Calcification Progression in Heterozygote Familial Hypercholesterolemia. Can J Cardiol 2017; 33:658-665. http://www.ncbi.nlm.nih.gov/pubmed/?term=28449836

Miscellaneous publications
  1. Yin M, Liu Q, Yu L et al. Downregulations of CD36 and Calpain-1, Inflammation, and Atherosclerosis by Simvastatin in Apolipoprotein E Knockout Mice. Journal of vascular research 2017; 54:123-130. http://www.ncbi.nlm.nih.gov/pubmed/?term=28448973
  2. Xu B, Wang Q, Sung C. Telomerase Inhibitory Effects of Red Pigment Rubropunctatin and Statin Monacolin L Isolated from Red Yeast Rice. Genes 2017; 8. http://www.ncbi.nlm.nih.gov/pubmed/?term=28445391
  3. Tian FM, Li SY, Yang K et al. Orally administered simvastatin partially preserves lumbar vertebral bone mass but not integrity of intervertebral discs in ovariectomized rats. Experimental and therapeutic medicine 2017; 13:877-884. http://www.ncbi.nlm.nih.gov/pubmed/?term=28450913
  4. Saito S, Nakanishi T, Shirasaki Y et al. Association of miR-145 with statin-induced skeletal muscle toxicity in human rhabdomyosarcoma RD cells. Journal of pharmaceutical sciences 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28438533
  5. Ribeiro NQ, Costa MC, Magalhaes TFF et al. Atorvastatin as a promising anticryptococcal agent. International journal of antimicrobial agents 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28450174
  6. Kebapcilar AG, Ilhan TT, Dursunoglu D et al. Efficacy comparison of oral rosuvastatin versus oral progesterone and bevacizumab on regression of surgically endometriotic implants in rats. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2017:1-5. http://www.ncbi.nlm.nih.gov/pubmed/?term=28452240
  7. Husain I, Akhtar M, Abdin MZ et al. Rosuvastatin ameliorates cognitive impairment in rats fed with high-salt and cholesterol diet via inhibiting acetylcholinesterase activity and amyloid beta peptide aggregation. Human & experimental toxicology 2017:960327117705431. http://www.ncbi.nlm.nih.gov/pubmed/?term=28441890
  8. Gonzalez-Herrera F, Cramer A, Pimentel P et al. Erratum for Gonzalez-Herrera et al., "Simvastatin Attenuates Endothelial Activation through 15-Epi-Lipoxin A4 Production in Murine Chronic Chagas Cardiomyopathy". Antimicrobial agents and chemotherapy 2017; 61. http://www.ncbi.nlm.nih.gov/pubmed/?term=28438799
  9. Feng Y, Lei B, Zhang F et al. Anti-inflammatory effects of simvastatin during the resolution phase of experimentally formed venous thrombi. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28442532
  10. Dai J, Liu T, Wang K et al. [Effects of Atorvastatin on Proliferation and Apoptosis of Leukemia Cell Line HL-60 and Its Mechanism of Signal Pathway]. Zhongguo shi yan xue ye xue za zhi 2017; 25:403-407. http://www.ncbi.nlm.nih.gov/pubmed/?term=28446283
  11. Al-Asmari AK, Ullah Z, Al Masoudi AS, Ahmad I. Simultaneous administration of fluoxetine and simvastatin ameliorates lipid profile, improves brain level of neurotransmitters, and increases bioavailability of simvastatin. Journal of experimental pharmacology 2017; 9:47-57. http://www.ncbi.nlm.nih.gov/pubmed/?term=28442937

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