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Update - Issue 3-4, 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

Issue 3

Severe muscle damage due to HMG-CoA antibodies triggered by atorvastatin?
How can we recognize, diagnose and manage a rare but serious myopathy frequently associated with Atorvastatin use? The so-called Atorvastatin induced necrotizing autoimmune myositis (atorAIM) was diagnosed in 12 Canadian patients by experts of the Centre Hospitalier de l’Université de Montréal (CHUM) and Hôpital du Sacré-Coeur in Montreal, Quebec, Canada. over a 10 year period (2005 -2014). Diagnosis was established if patients had autoimmune antibodies against HMG-CoA and fulfilled 7 additional diagnostic criteria. AtorAIM Patients were prospectively followed and evaluated to determine outcome and effects of treatment. Surprisingly only patients using or having used Atorvastatin presented with this diagnosis. If this is a product specific issue or because Atorvastatin was the most prescribed statin is unclear. Patients using other statins and reporting similar complaints have been reported. The 3 stages of atorAIM: Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram[EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). Most patients (10/12) were in stage 3.  All patients presenting with stage 1 (6/12) progressed to stage 3, even after discontinuation of atorvastatin, with a mean delay of 37 months. Treatment consisted of corticosteroids, intravenous immunoglobulins and methotrexate.  A valuable review for lipid specialist caring for statin intolerant patients. 
Troyanov Y, Landon-Cardinal O, Fritzler MJ et al. Atorvastatin-induced necrotizing autoimmune myositis: An emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotype. Medicine (Baltimore) 2017; 96:e5694. http://www.ncbi.nlm.nih.gov/pubmed/?term=28099331
Full recovery of HMG-CoA autoimmune myopathy is uncommon especially in younger patients.
Patients diagnosed with HMG-CoA associated myositis were followed for ≥ 2 years. In this cohort of 50 participant’s, older patients fared better compared to younger patients. Only 22 patients regained full muscle strengths, 12 of those continued to have elevated CK levels (> 500 IU/l) and no more than 3 patients were able stop immunosuppressive therapy. Persistent and sometimes progressive muscle weakness were more frequently observed in younger patients. Their muscle strength measurements were worse at all time points and refractory disease was often observed. In patients with refractory disease whole exome sequencing did not show any pathogenic mutations in the known dystrophy genes.
Tiniakou E, Pinal-Fernandez I, Lloyd TE et al. More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Rheumatology (Oxford) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28096458
Should we prescribe statins to patients at risk for venous thromboembolism (VTE)?
This meta-analysis and systematic review of 13 observational studies (3 148 259 participants) and 23 randomized controlled trials (118 464 participants) seems to corroborate the protective effects. Statins use was associated with less VTE; RR 0.75 (95% CI 0.65-0.87; p<0.0001) in observational cohorts. In RCT’s this amounted to a RR of 0.85 (95% CI 0.73-0.99; p=0.038). Rosuvastatin was associated with lowest risk: RR 0.55 (95% CI 0.42-0.75; p=0.015, when compared to other statins. Pulmonary embolisms were not affected by statins. The authors suggest that the statins could play a role in the prevention of VTE’s but emphasized that further evidence is needed.
Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. The Lancet. Haematology 2017; 4:e83-e93. http://www.ncbi.nlm.nih.gov/pubmed/?term=28089655
What can we expect from ezetimibe + plant sterols on top of statin to reduce LDL-C?
Patients not at target despite maximal (tolerated) statin were able to achieve an additional 27% LDL-C reduction by using a combination of ezetimibe 10 mg combined with 2 gram of plant sterols. In this small prospective open label study 41 patients with stable CAD and LDL-C >70mg/dl were randomized into 4 groups for a 6-week treatment regimen. Patients continued with their prescribed statins or received add on treatment consisting of ezetimibe, plant sterols or ezetimibe + plant sterols. LDL-C increased in the control group (+8.9% p.0.05) and dropped in the Ezetimibe, plant sterol and ezetimibe + plant sterol groups with respectively -19.1% (p=0.06); -16.6% (p=0.01) and -27.3% (p<0.01). Mean LDL-C levels in control group remained elevated: 106.1 ± 34.9 mg/dl and were lower in the ezetimibe, plant sterol and ezetimibe + plant sterol groups with respectively 85.5 ± 35.6 mg/dl, 79.6.1 ± 29.7 mg/dl and 70.5 ± 19.9 mg/dl. The questions that could not be answered is what the clinical benefit of this add on regimen on cardiovascular events would be, but in line with the observed benefits in the IMPROVE-IT study this is not unlikely.
Gomes GB, Zazula AD, Shigueoka LS et al. A Randomized Open-Label Trial to Assess the Effect of Plant Sterols Associated with Ezetimibe in Low-Density Lipoprotein Levels in Patients with Coronary Artery Disease on Statin Therapy. Journal of medicinal food 2017; 20:30-36. http://www.ncbi.nlm.nih.gov/pubmed/?term=28098515
Less non fatal MI’s and strokes  but no mortality benefit of ezetimibe ad on treatment
Systematic review of ezetimibe add-on treatment showed modest benefits of long term non-fatal event (AMI and stroke) reductions but not mortality abatements. Of the 8 trials included the IMPROVE-IT was responsible for 93% of the patients. The pooled results of the 7 smaller trials did not show benefits from ezetimibe the authors could not find statistically significant differences between subgroups for all outcomes. The results were observed in populations with high risk of cardiovascular events – secondary prevention patients.  Analysis of MPROVE-IT showed that the addition of Ezetimibe reduced 17 non-fatal MI’s, 6 non-fatal strokes/1000 patient treated for 6 year. All-cause mortality and cardiovascular death did not improve. And there was no change in myopathy incidence. The authors suggested that a formal cost-benefit analysis would be instructive. They also pointed out that in IM-PROVE-IT only 27% of the patients not using ezetimibe and 6% of the participants on ezetimibe used high dose simvastatin. the impact of ezetimibe in patients using maximum dose of high intensity statins can only be speculated.
Fei Y, Guyatt GH, Alexander PE et al. Addition of Ezetimibe to statins for patients at high cardiovascular risk: Systematic review of patient-important outcomes. J Eval Clin Pract 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28090731

Issue 4

Ramifications if all eligible US adults would use statins for primary prevention?

Data from NHANES III study was used to calculate the benefits of statins if not 8.8 million, but all 33 million eligible US adults would use them. If, based on the ACC/AHA 2013 guidelines, all diabetic and non-diabetic patients would use statins >2500 and >5400 deaths would be prevented annually. Side effects such as myopathy, based on randomized clinical trial data, would be diagnosed in approx. 480 patients or roughly 11 800 cases if population-based studies were used to predict the incidence.  For statin, eligible patients without diabetes the myopathy incidence would be 660 (based on RCT’s) and 15 500 (based on pop. studies). New onset diabetes would occur in approximately 10 500 patients. Total costs would amount to US$ 6.5 billion dollars annually if all eligible patients would use statins. Authors concluded that up to 12.6% of annual ASCVD deaths could be prevented but at the costs of myopathies and new onset diabetes. 
Yang Q, Zhong Y, Gillespie C et al. Assessing potential population impact of statin treatment for primary prevention of atherosclerotic cardiovascular diseases in the USA: population-based modelling study. BMJ Open 2017; 7:e011684. http://www.ncbi.nlm.nih.gov/pubmed/?term=28119384
Benefits of statins observed in patients at risk for open angle glaucoma (OAG)
Based on a retrospective analysis of a large managed care health claim registry including > 500 000 US individuals. After correction for possible confounders and baseline LDL-C, the risk of developing OAG was reduced by 1% for every month statins were used. Patients that filled statin prescriptions for >2years had a 21% reduced risk of developing glaucoma versus no-statin users. This protective effect was not independent of the statin dosage used. Atorvastatin was the most frequently used statin (34.6%) and chosen as a comparator to all other used statins.  Neither type of statin nor dosage showed superior or inferior protection. Baseline LDL-C, comparing the highest with the lowest quartile, did not influence the observed risk either. The authors concluded that, within the limits of observational nature of this study, statins independent of type or dosage can prevent or halt the progression of OAG. This however still needs to be confirmed in a properly designed randomized controlled clinical trial.
Talwar N, Musch DC, Stein JD. Association of Daily Dosage and Type of Statin Agent With Risk of Open-Angle Glaucoma. JAMA ophthalmology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28114645
Fixed dose or targets?
Review examining the expected benefits of statin monotherapy as a fixed dose and combing statins with add-on treatment e.g. Ezetimibe and/or PCSK9ab therapy to reach an LDL-C target. Reviewing the broad evidence base of LDL-C lowering from genetic and population data as well as the large number of intervention studies to illustrate what we can expect in terms of CVD risk reduction as well as safety. Important variables to consider when treatment strategies are contemplated and/or discussed with patients, are the LDL-C starting levels as well as the baseline CVD risk. Favoring targets makes monitoring on treatment LDL-C levels essential. The authors emphasize that a target approach that in patients with lower initial LDL-C levels using a low dose statin would seem sufficient but would not provide the risk reducing effects as shown in the trials that overall used high dose, high intensity statins  
Soran H, Dent R, Durrington P. Evidence-based goals in LDL-C reduction. Clinical research in cardiology : official journal of the German Cardiac Society 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28124099
Rhabodmyolysis in patient using fusidic acid and Atorvastatin
Rhabdomyolysis, a complication that is infrequently observed in patients using Atorvastatin, occurred after this 75-year-old male started to combine his Atorvastatin 80 mg with Fusidic acid 500 mg twice a day + moxifloxacin 400 mg daily. Six days after adding the antibiotic prophylaxis to his regimen, he presented at the ER with the classical symptoms of Rhabdomyolysis. Patient was treated with intravenous fluid and discharged after 5 weeks with normal muscle enzymes. He continued Atorvastatin and moxifloxacin but the Fusidic acid was successfully switched to Co-Amoxiclav 500/125 mg daily. This case illustrates that proper instructions to this patient allowed for early recognition and treatment of this rare but life-threatening complication. Although fusidic acid is not well known for drug interactions with statins, cases have surfaced since 2008, when the first report was published.
Nandy A, Gaini S. Severe Rhabdomyolysis as Complication of Interaction between Atorvastatin and Fusidic Acid in a Patient in Lifelong Antibiotic Prophylaxis: A Dangerous Combination. Case reports in medicine 2016; 2016:4705492. http://www.ncbi.nlm.nih.gov/pubmed/?term=28115938
Comparing a single high-dose vs low-dose or no Atorvastatin pre PTCA
Pre-procedural Atorvastatin was evaluated in 138 Chinese STEMI patients. Patients were randomized into 3 equal sized groups of 46 patients: receiving a single dose of 40 mg, 20 mg or no Atorvastatin on the day prior to the procedure and examining the effects on “No-Reflow” (failure to restore circulation in despite patency of the coronary arteries). High dose atorvastatin (40 mg) showed better outcome despite no difference in echocardiographic parameters. There was a dose dependent improvement of pro-BNP, CK-MB and CRP levels. After 1 year, clinical events such as re-stenosis, death, non-fatal MI, and non-fatal cardiac shock were reported less frequently; circulation improvements of the treated blood vessel more frequently by patients that received the 40-mg dosage. However, no information on statin use post PCI procedure were provided. Despite the relatively small size of the study the presented results re-confirm the early dose dependent benefits of Atorvastatin in these high-risk Chinese STEMI patients.
Liu W, Zou Z, Jiang H et al. Clinical effect of preoperative high-dose atorvastatin against no-reflow after PCI. Experimental and therapeutic medicine 2017; 13:97-102. http://www.ncbi.nlm.nih.gov/pubmed/?term=28123475

Relevant publications

Issue 3

  1. Yan L, Ye L, Wang K et al. Atorvastatin improves reflow after percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction by decreasing serum uric acid level. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 2016; 45:530-535. http://www.ncbi.nlm.nih.gov/pubmed/?term=28087914
  2. Kataoka Y, Andrews J, Puri R et al. Plaque burden, microstructures and compositions underachieving very low LDL-C levels. Current opinion in endocrinology, diabetes, and obesity 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28107247
  3. Wu PS. [Clinical considerations of statin therapy for hypertensive patients]. Zhonghua xin xue guan bing za zhi 2017; 45:3-4. http://www.ncbi.nlm.nih.gov/pubmed/?term=28100338
  4. Wadia SK, Belkin M, Chow KS et al. In-hospital statin underutilization among high-risk patients: delayed uptake of the 2013 cholesterol guidelines in a U.S. cohort. Hospital practice (1995) 2017; 45:16-20. http://www.ncbi.nlm.nih.gov/pubmed/?term=28092990
  5. Toth PP, Danese M, Villa G et al. Estimated burden of cardiovascular disease and value-based price range for evolocumab in a high-risk, secondary-prevention population in the US payer context. Journal of medical economics 2017:1-10. http://www.ncbi.nlm.nih.gov/pubmed/?term=28097904
  6. Taha DA, Zgair A, Lee JB et al. Hyperlipidaemia alone and in combination with acidosis can increase the incidence and severity of statin-induced myotoxicity. Eur J Pharm Sci 2017; 100:163-175. http://www.ncbi.nlm.nih.gov/pubmed/?term=28104473
  7. Smith A, Murphy L, Bennett K, Barron TI. Patterns of statin initiation and continuation in patients with breast or colorectal cancer, towards end-of-life. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28101676
  8. Sluyter JD, Hughes AD, Lowe A et al. Statin utilisation in a real-world setting: a retrospective analysis in relation to arterial and cardiovascular autonomic function. Pharmacol Res Perspect 2016; 4:e00276. http://www.ncbi.nlm.nih.gov/pubmed/?term=28097009
  9. Mazzanti G, Moro PA, Raschi E et al. Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system. Br J Clin Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28093797
  10. May MB, Glode A. Novel Uses for Lipid-Lowering Agents. Journal of the advanced practitioner in oncology 2016; 7:181-187. http://www.ncbi.nlm.nih.gov/pubmed/?term=28090367
  11. Lee JC, Zdrojewski T, Navar AM. Statin Eligibility Under American and European Cholesterol Guidelines-Reply. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28097333
  12. Kataoka Y, Andrews J, Puri R et al. Plaque burden, microstructures and compositions underachieving very low LDL-C levels. Current opinion in endocrinology, diabetes, and obesity 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28107247
  13. Gong J, Sun H, Yang Z et al. Effect of Simvastatin and Relationship between Bilirubin and Blood Lipid Level in Patients with Glucocorticoid-resistant Nephrotic Syndrome. The West Indian medical journal 2015. http://www.ncbi.nlm.nih.gov/pubmed/?term=28103332
  14. Falk E, Mortensen MB. Statin Eligibility Under American and European Cholesterol Guidelines. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28097366
Issue 4
  1. Zheng P, Wu QL, Li BB et al. Simvastatin ameliorates graft-vs-host disease by regulating angiopoietin-1 and angiopoietin-2 in a murine model. Leukemia research 2017; 55:49-54. http://www.ncbi.nlm.nih.gov/pubmed/?term=28122283
  2. Shah P, Glueck CJ, Goldenberg N et al. Efficacy, safety, Low density lipoprotein cholesterol lowering, and calculated 10-year cardiovascular risk reduction of alirocumab and evolocumab in addition to maximal tolerated cholesterol lowering therapy: a post-commercialization study. Lipids Health Dis 2017; 16:19. http://www.ncbi.nlm.nih.gov/pubmed/?term=28115017
  3. Shagroni T, Park C, Rouah E, Whiteru O. Statin-associated autoimmune myopathy. Rheumatology (Oxford) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28115598
  4. Dimmitt SB, Martin JH. Lipid and other management to improve arterial disease and survival in end stage renal disease. Expert Opin Pharmacother 2017:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=28110562
  5. Zaid AN, Al Ramahi R, Cortesi R et al. Investigation of the Bioequivalence of Rosuvastatin 20 mg Tablets after a Single Oral Administration in Mediterranean Arabs Using a Validated LC-MS/MS Method. Scientia pharmaceutica 2016; 84:536-546. http://www.ncbi.nlm.nih.gov/pubmed/?term=28117319
  6. Watson KE, Sallam T. MY APPROACH to the Patient With Memory Loss Who Needs a Statin. Trends Cardiovasc Med 2017; 27:158-159. http://www.ncbi.nlm.nih.gov/pubmed/?term=28107839
  7. Thompson PD. MY APPROACH to Managing Statin-Associated Muscle Symptoms. Trends Cardiovasc Med 2017; 27:160-161. http://www.ncbi.nlm.nih.gov/pubmed/?term=28107840
  8. Rousan TA, Mathew ST, Thadani U. Drug Therapy for Stable Angina Pectoris. Drugs 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28120185
  9. Oliveira LP, Vieira CP, Marques PP, Pimentel ER. Do different tendons exhibit the same response following chronic exposure to statins? Canadian journal of physiology and pharmacology 2016:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=28112540
  10. Ng JC, Fung MM, Chan HH, Lai JS. Statin Use and Open-Angle Glaucoma: Evidence From Observational Studies. Investigative ophthalmology & visual science 2017; 58:155-157. http://www.ncbi.nlm.nih.gov/pubmed/?term=28114573
  11. McCann P, Hogg RE, Azuara-Blanco A. Author Response: Statin Use and Open-Angle Glaucoma: Evidence From Observational Studies. Investigative ophthalmology & visual science 2017; 58:158-161. http://www.ncbi.nlm.nih.gov/pubmed/?term=28114574
  12. May HT, Bair TL, Reiss-Brennan B et al. The association of antidepressant and statin use with death and incident cardiovascular disease varies by depression severity. Psychology, health & medicine 2017:1-13. http://www.ncbi.nlm.nih.gov/pubmed/?term=28111972
  13. Lee SH. Update on Familial Hypercholesterolemia: Diagnosis, Cardiovascular Risk, and Novel Therapeutics. Endocrinol Metab (Seoul) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28116871
  14. Feng X, Gao X, Jia Y et al. Atorvastatin Decreased Circulating RANTES Levels in Impaired Glucose Tolerance Patients with Hypercholesterolemia: An Interventional Study. Diabetes Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28120261
  15. Desai NR, Giugliano RP, Wasserman SM et al. Association Between Circulating Baseline Proprotein Convertase Subtilisin Kexin Type 9 Levels and Efficacy of Evolocumab. JAMA cardiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28122070
  16. Drug interaction: dabigatran (Pradaxa) and statins. The Medical letter on drugs and therapeutics 2017; 59:26. http://www.ncbi.nlm.nih.gov/pubmed/?term=28118653

Miscellaneous publications

Issue 3

  1. Tun T, Kang YS. Effects of simvastatin on CAT-1-mediated arginine transport and NO level under high glucose conditions in conditionally immortalized rat inner blood-retinal barrier cell lines (TR-iBRB). Microvascular research 2017; 111:60-66. http://www.ncbi.nlm.nih.gov/pubmed/?term=28089735
  2. Oikonomidis N, Kavantzas N, Korou LM et al. Pre-treatment with simvastatin prevents the induction of diet-induced atherosclerosis in a rabbit model. Biomedical reports 2016; 5:667-674. http://www.ncbi.nlm.nih.gov/pubmed/?term=28101339
  3. Long T, Tang T, Hao Y et al. Effect of simvastatin on osteogenesis of the lumbar vertebrae in ovariectomized rats. Experimental and therapeutic medicine 2016; 12:3951-3957. http://www.ncbi.nlm.nih.gov/pubmed/?term=28105128
  4. Lin W, Ji T, Einolf H et al. Evaluation of drug-drug interaction potential between sacubitril/valsartan (LCZ696) and statins using a physiologically-based pharmacokinetic model. Journal of pharmaceutical sciences 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28089685
  5. Chen Q, Shi X, Tan Q et al. Simvastatin Promotes Hematoma Absorption and Reduces Hydrocephalus Following Intraventricular Hemorrhage in Part by Upregulating CD36. Translational stroke research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28102508
  6. Beg S, Jain S, Kushwah V et al. Novel surface-engineered solid lipid nanoparticles of rosuvastatin calcium for low-density lipoprotein-receptor targeting: a Quality by Design-driven perspective. Nanomedicine (Lond) 2017; 12:333-356. http://www.ncbi.nlm.nih.gov/pubmed/?term=28093941
  7. Arpornmaeklong P, Pripatnanont P, Chookiatsiri C, Tangtrakulwanich B. Effects of Titanium Surface Microtopography and Simvastatin on Growth and Osteogenic Differentiation of Human Mesenchymal Stem Cells in Estrogen-Deprived Cell Culture. The International journal of oral & maxillofacial implants 2017; 32:e35-e46. http://www.ncbi.nlm.nih.gov/pubmed/?term=28095523
  8. Al-Kuraishy HM, Al-Gareeb AI. Effects of Rosuvastatin Alone or in Combination with Omega-3 Fatty Acid on Adiponectin Levels and Cardiometabolic Profile. Journal of basic and clinical pharmacy 2016; 8:8-14. http://www.ncbi.nlm.nih.gov/pubmed/?term=28104968
Issue 4
  1. Lee Y, Lee KH, Lee GK et al. Randomized Phase II Study of Afatinib Plus Simvastatin Versus Afatinib Alone in Previously Treated Patients with Advanced Non-Adenocarcinomatous Non-Small Cell Lung Cancer. Cancer research and treatment : official journal of Korean Cancer Association 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28111428
  2. Joshi PH, Miller PE, Martin SS et al. Greater remnant lipoprotein cholesterol reduction with pitavastatin compared to pravastatin in HIV-infected patients: The INTREPID trial. Aids 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28121706
  3. Jia YC, Xu J, Chen HH et al. The Effect of Atorvastatin on the Viability of Ischemic Skin Flaps in Diabetic Rats. Plastic and reconstructive surgery 2017; 139:425e-433e. http://www.ncbi.nlm.nih.gov/pubmed/?term=28121873

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