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Update - Week 09, 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

Statin-related Myopathies a narrated review
The journal that published this article is primarily targeting neurologist caring for patients in whom statins are indicated. The attractive, simple and structured outline of this narrative review, including the 6 boxed key points, would make the presented information on statin related myopathies equally suited for cardiologists and internists as well. The articles discuss the different statin myopathies including the immune mediated type as well as simple strategies how to manage patients presenting with muscle aches. It highlights which commonly prescribed concomitant drugs are prone to trigger myositis and/or rhabdomyolysis as well as how to manage an acute rhabdomyolysis. Challenging presentations such as persistent myalgia after statin withdrawal as well as the use of statins in patients with pre-existing neuromuscular disorders are discussed as well. The 3 key points the authors close their review with are that statin induced myalgia’s is quite common but, in most cases, respond very well to reducing the dosage of the statin or changing it.  The most frequently reported cause of rhabdomyolysis is statin use but more importantly, we should watch out for drug-drug or drug-food (grapefruit!) interactions that precipitate increased statin plasma concentration and subsequent serious muscle damaging effects. Last point is the immune mediated necrotizing myopathy that will require immunosuppressant treatment for a prolonged period even if statins are stopped.
Hilton-Jones D. Statin-related myopathies. Practical neurology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29496886
 
A serious muscle problem with (and without!) statins?
Statin related muscle problems are not uncommon. The majority of patients experiencing mild to moderate symptoms, but serious underlying conditions need to be excluded when symptoms are severe. Statin associated autoimmune myopathy is rare and less than 50 patients have been described in case reports. The distinguishing characteristics, when compared to statin intolerance or statin induce toxic myopathy, are the persistent CK elevations and muscle complaints long after statins are stopped. In this updated review the authors summarize current strategies to diagnose and manage anti-HMGCR myopathy. Not only patients that use or used statins are diagnosed with anti-HMGCR antibodies, but even in (pediatric) patients, without a history of statin use, symptoms + anti-bodies have been discovered. To confirm the diagnosis clinical features, CK levels, EMG, muscle biopsy, muscle imaging and judicious determining of HMGCR antibodies are needed. Risk factor such as statin use, and specific class II HLA alleles are implicated in the pathogenesis. Therapeutic strategies are challenging, using different immunosuppressant regimens for a prolonged period showed promising results but discoveries for new disease specific therapeutic strategies are needed.
Mohassel P, Mammen AL. Anti-HMGCR Myopathy. Journal of neuromuscular diseases 2018; 5:11-20. http://www.ncbi.nlm.nih.gov/pubmed/?term=29480216
 
Low dose statin and new onset diabetes fact or fallacy?

New onset diabetes is an established and not uncommon side effect of statin use. In this retrospective Japanese registry of 2 554 patients that started to use high or low potency statins between November 2006 and December 2016, the incidence of NODM was the primary outcome of the study. The six statins used were: atorvastatin (5 or 10 mg/d), pitavastatin (2 mg/d), rosuvastatin (2.5 mg/d), fluvastatin (20 mg/d), pravastatin (5 or 10 mg/d) and simvastatin (5 mg/d). Statins were labeled high potency: atorvastatin, pitavastatin and rosuvastatin; and low potency: fluvastatin, pravastatin and simvastatin. The incidence of NODM in the complete group (N=2554) was 7.4% (n=190). When comparing high potency to low-potency: HR 1.868 (1.336-2.611, P<0.001). Additional statistical significant predictors for NODM were fasting glucose: HR 1.008 (1.006-1.012, P<0.001); Calcium channel blockers: HR 1.508 (1.087-2.092, p=0.014); high potency statins: HR 1.51 (1.026-2.222, p=0.37); Male sex: HR 1.616 (1.158-2.257, p=0.005); Steroid use: HR 2.369 (1.679-3.361, <0.001) and Immunosuppressant’s: HR 2.637 (1.553-4.477, p<0.001). Despite the inherent limitations of the study design, an increased risk for NODM in patients using a low potency statin was noted. However, the combination of statins with steroids or immunosuppressant far outweighed the risk for NODM as compared statin dose and/or potency and this an important finding for clinicians caring for patients that are treated with statins.
Kato S, Miura M. Risk of new-onset diabetes mellitus during treatment with low-dose statins in Japan: A retrospective cohort study. Journal of clinical pharmacy and therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29484697
 
Are high intensity statin superior if LDL-c targets are reached ?
The National Korean Acute Myocardial Infarction Registry (KAMIR) was used to study the effects of statin intensity on clinical outcomes in 12 183 Korean AMI patients. After a 1 year follow up patients were compared by use of statin intensity. The authors evaluated patients using no statin with patients on low-moderate-intensity statin or high-intensity statin. Primary outcome was major adverse cardiac events (MACE). Compared with the no statin group patients using low-moderate and high intensity had significant lower LDL-c levels as well as reduced MACE incidences. LDL-c after one year were 94.3 mg/dl, 76.2 mg/dl and 71.6 mg/dl in patients using no statins, low-intermediate potency and high potency statins respectively. No significant MACE differences were noted in the low-intermediate potency users and the high intensity users HR: 0.506 (0.413-0.619, p<0.001) vs HR 0.464 (0.352-0.611, P<0.001) respectively. Comparing patient using high intensity with the ones that used low-intermediate intensity statins resulted in a HR of 0.917 (0.760-1.107, p=0.368). Re-analysis based on multivariable adjustment, propensity score matching, and inverse probability weighted analysis produced similar results. The authors concluded that based on this analysis, post AMI patients, that achieved similar and adequate LDL-c targets, had comparable CVD outcomes irrespective of the statin intensity used.
Hwang D, Kim HK, Lee JM et al. Effects of Statin Intensity on Clinical Outcome in Acute Myocardial Infarction Patients. Circulation journal : official journal of the Japanese Circulation Society 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29491327

After an ACS aim for LDL-c or LDL-c + hs CRP targets?
LDL-cholesterol and HsCRP (reflecting inflammation) two important risk markers that can be improved by using high intensity statins. In this single center prospective randomized study, 400 Chinese ACS patients received atorvastatin 40 mg for one month and continued with atorvastatin 20 mg. The study was conducted between July 2013 and June 2015. Patients were grouped by LDL-c level < 2.07 mmol/l or LDL-c<2.07 + hsCRP <3 mg/dl targets and evaluated at 6, 12 and 18 months. Patients not on target for LDL-c or hsCRP, atorvastatin dose was increased to 40 mg for 4-6 weeks. Patient that reached the targets continued with 10 mg atorvastatin. Baseline characteristics were not different between the two groups as were the on trial LDL-c plasma concentrations. However, hsCRP measurements differed at 12 and 18 months. As a result, revascularizations and MACE were significantly lower in patients that achieved the dual LDL-c and hs CRP targets. Recorded revascularizations reached 8.7% versus 3.6% (P=0.04) and MACE 16.8% versus 9.7% (P=0.04) after 18 months follow-up. The authors concluded that aiming for a dual target of LDL-c and hs CRP could further reduce the incidence of MACE and residual cardiovascular risk.
Fang M, Qian Q, Zhao Z et al. High-Sensitivity C-Reactive Protein Combined with Low-Density Lipoprotein Cholesterol as the Targets of Statin Therapy in Patients with Acute Coronary Syndrome. Int Heart J 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29479010
 
 
Relevant publications
  1. Kosinski C, Tran C, Kuntzer T et al. [Statin-associated muscle symptoms : Current management in 2018]. Revue medicale suisse 2018; 14:462-469. http://www.ncbi.nlm.nih.gov/pubmed/?term=29489126
  2. Henry RR, Muller-Wieland D, Taub PR et al. Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome and without diabetes: Pooled data from 10 phase 3 trials. Diabetes Obes Metab 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29493859
  3. Cicero AFG. [Red yeast rice, monacolin K, and pleiotropic effects.]. Recenti progressi in medicina 2018; 109:154e-157e. http://www.ncbi.nlm.nih.gov/pubmed/?term=29493648
  4. Arca M, Ansell D, Averna M et al. Statin utilization and lipid goal attainment in high or very-high cardiovascular risk patients: Insights from Italian general practice. Atherosclerosis 2018; 271:120-127. http://www.ncbi.nlm.nih.gov/pubmed/?term=29499359
  5. Zhang HW, Li S, Guo YL et al. [Prevalence and clinical characteristics of familial hypercholesterolemia among Chinese patients undergoing coronary angiography due to angina-like chest pain]. Zhonghua xin xue guan bing za zhi 2018; 46:104-108. http://www.ncbi.nlm.nih.gov/pubmed/?term=29495232
  6. Weber ML. [Can Pravastatin influence Pregnancies at High-risk for Preeclampsia?]. Zeitschrift fur Geburtshilfe und Neonatologie 2018; 222:31-33. http://www.ncbi.nlm.nih.gov/pubmed/?term=29499584
  7. Sun D, Li S, Zhu CG et al. [Prevalence and clinical features of familial hypercholesterolemia in Chinese patients with myocardial infarction]. Zhonghua xin xue guan bing za zhi 2018; 46:109-113. http://www.ncbi.nlm.nih.gov/pubmed/?term=29495233
  8. Stivaros S, Garg S, Tziraki M et al. Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA). Molecular autism 2018; 9:12. http://www.ncbi.nlm.nih.gov/pubmed/?term=29484149
  9. Perrone C, Rauch A, Furrer H et al. Fewer pills do not mean fewer drug-drug interactions: severe rhabdomyolysis on Elvitegravir/Cobicistat and statin treatment. Aids 2018; 32:676-678. http://www.ncbi.nlm.nih.gov/pubmed/?term=29494427
  10. Peng C, Ding Y, Yi X et al. Polymorphisms in CYP450 Genes and the Therapeutic Effect of Atorvastatin on Ischemic Stroke: A Retrospective Cohort Study in Chinese Population. Clinical therapeutics 2018; 40:469-477.e462. http://www.ncbi.nlm.nih.gov/pubmed/?term=29500141
  11. Oliveira CV, Zorzi VN, Fighera MR et al. Subtle improvement of seizure susceptibility by atorvastatin treatment during epileptogenesis. Pharmacological reports : PR 2017; 70:364-371. http://www.ncbi.nlm.nih.gov/pubmed/?term=29477945
  12. Liu J, Wang W, Liu J et al. [Impact of different intervention models on adherence to secondary prevention therapies in patients with acute coronary syndrome]. Zhonghua xin xue guan bing za zhi 2018; 46:124-130. http://www.ncbi.nlm.nih.gov/pubmed/?term=29495236
  13. Ingrand I, Solinas M, Ingrand P et al. Lack of effects of simvastatin on smoking cessation in humans: A double-blind, randomized, placebo-controlled clinical study. Scientific reports 2018; 8:3836. http://www.ncbi.nlm.nih.gov/pubmed/?term=29497063
  14. Gregg LP, Hedayati SS. Management of Traditional Cardiovascular Risk Factors in CKD: What Are the Data? American journal of kidney diseases : the official journal of the National Kidney Foundation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29478869
  15. Gencer B, Nanchen D, Collet TH et al. [Current update on PCKS9 inhibitors]. Revue medicale suisse 2018; 14:482-486. http://www.ncbi.nlm.nih.gov/pubmed/?term=29489129
  16. Dias IHK, Milic I, Lip GYH et al. Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia. Redox biology 2018; 16:139-145. http://www.ncbi.nlm.nih.gov/pubmed/?term=29501047
  17. Chen Y, Chen L, Zhang H et al. Interaction of Sulfonylureas with Liver Uptake Transporters OATP1B1 and OATP1B3. Basic & clinical pharmacology & toxicology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29498478
  18. Blaha V, Blaha M, Lanska M et al. [The role of PCSK9-inhibitors and of lipoprotein apheresis in the treatment of homozygous and severe heterozygous familial hypercholesterolemia: A rivalry, or are things quite different?]. Vnitr Lek 2018; 64:43-50. http://www.ncbi.nlm.nih.gov/pubmed/?term=29498875
Miscellaneous publications
  1. Yue Y, Yan S, Li H et al. The role of oral fluvastatin on postoperative peritoneal adhesion formation in an experimental rat model. Acta chirurgica Belgica 2018:1-8. http://www.ncbi.nlm.nih.gov/pubmed/?term=29482467
  2. Xu R, Shi G, Xu L et al. Simvastatin improves oral implant osseointegration via enhanced autophagy and osteogenesis of BMSCs and inhibited osteoclast activity. Journal of tissue engineering and regenerative medicine 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29498229
  3. Najjari M, Vaezi G, Hojati V et al. Involvement of IL-1beta and IL-6 in antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in rats. Immunopharmacology and immunotoxicology 2018:1-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29486618
  4. Martinez TA, Zeybek ND, Muftuoglu S. Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on Mcf-7 Breast Cancer Cells. Balkan medical journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29485098
  5. Karlsson EA, Schultz-Cherry S, Rosch JW. Protective Capacity of Statins during Pneumonia Is Dependent on Etiological Agent and Obesity. Frontiers in cellular and infection microbiology 2018; 8:41. http://www.ncbi.nlm.nih.gov/pubmed/?term=29497602
  6. Dianat O, Mashhadiabbas F, Ahangari Z et al. Histologic comparison of direct pulp capping of rat molars with MTA and different concentrations of simvastatin gel. Journal of oral science 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29479026
  7. Asad F, Khan M, Rizvi F. Atorvastatin as an adjuvant with betamethasone valerate reduces disease severity and cardiovascular risks in Psoriasis. Pak J Med Sci 2017; 33:1507-1511. http://www.ncbi.nlm.nih.gov/pubmed/?term=29492087
  8. Rezk MR, Badr KA. Quantification of amlodipine and atorvastatin in human plasma by UPLC-MS/MS method and its application to a bioequivalence study. Biomedical chromatography : BMC 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29498757
  9. Karasulu HY, Gundogdu E, Turk UO et al. Enhancing Solubility and Bioavailability of Rosuvastatin into Self Emulsifying Drug Delivery System. Current drug delivery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29484996
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This activity is supported by an educational grant from Pfizer.