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Update - Week 41,  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

Basilar artery stenosis in Korean patient using statins show improved outcomes
Basilar artery stenosis (BAS) is associated with an increased risk of ischemic stroke recurrence. In this Korean retrospective study 153 patients with acute ischemia related to BAS, diagnosed by MRI at admission that was repeated after 1 year. Statins were used by 114 (74.5%) of the patients. Symptomatic progression of BAS occurred in 7% of the statins user’s vs 28.2% of patients that were not on statins. Regression of BAS was observed more frequently in statin users as well 22.8% vs 15.4% (P=0.002) respectively. Stroke recurrence 14.9% vs 35.9% (P=0.05) and composite vascular endpoints: recurrent ischemic stroke, transient ischemic attack, coronary disease, and vascular death. 17.5% and 46.2%; OR: 0.29 (0.13-0.64) showed better outcomes in statins users compared to patient that were not using statins. The observational data of this retrospective study suggest that statin therapy prevents the progression of symptomatic BAS and decreases recurrent stroke risk. Randomized trials need to confirm these results.
Yum KS, Chang JY, Jeong WJ et al. Effect of statin on progression of symptomatic basilar artery stenosis and subsequent ischemic stroke. PLoS One 2017; 12:e0183798. http://www.ncbi.nlm.nih.gov/pubmed/?term=29020008
 
SWEDEHEART registry: improved outcomes in STEMI patients (1995-2014)
The Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry collected data on all cases admitted to a coronary care unit or other specialized facility in all 72 Swedish hospitals with a suspected or definite acute coronary syndrome are continuously included in this international recognized Swedish National registry.  From 1995-2014 data on 105 674 patients was collected. Evidence based treatments progressively improved. Reperfusion rates 66.2% à. 81.7%; Primary PTCA 4.5% à 78.0%; DAPT 0 à89.6%; statins 14.1% à 93.6%; beta-blocker 78.2% à 91%; ACE/ARB 40.8% à 85.2%. One year mortality improved from 22.1% à 14.1%. In the General population, the standard incidence ratio decreased 5.54 à 3.74 (P<0.001). Death from CVD, MI, stroke, and heart failure decreased: 20.1% à 11.1%, 11.5% à 5.8%; 2.9% à 2.1% and 7.1% à 6.2% respectively. The 1-year risk for index MI was 50% lower, the risk for re-admission for stroke and heart failure by respectively 30% and 20% Between 1994 – 2004 the greatest impact on treatment changes were realized with subsequent plateauing around 2008. Additional lowering of events by expanding current treatment modalities is questionable and underlines the need for new treatment modalities, especially for STEMI patients who remain at a 3.7 higher mortality risk compared to the general population of approximately 19% in the first-year post event. 
Szummer K, Wallentin L, Lindhagen L et al. Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29020314
 
Do the elderly need statins?
Statins prescription in elderly patients is Updated review on statin use in elderly patients (>65 years) with emphasis on the 75+ age group. Especially important in this age group is a balance between benefits and harms. Increased co-morbidities and medication use could offset this balance and needs to be evaluated on an individual basis. In this review 4 primary prevention studies showed improved outcomes in elderly participants, Jupiter and HOPE-3 were able to show this for 70+ but in the very elderly >85 years, evidence is not available. Similar adverse events were observed in the elderly, new onset diabetes, myopathy and drug interactions. Cognitive decline, studied in properly designed trials that used validated cognitive evolution, showed no difference in statin treated patients and participants using placebo. No safety signal for liver and kidney damage could be discerned in the RCT’s as well. Based on the lack of high-quality studies, recent US guidelines (AAC-AHA and USPSTF) do not support the general use of statin for primary prevention, but physician judgement and shared decision-making are pivotal in this age group. The authors suggested that adding imaging such as a calcium score and/or carotid plaque imaging could improve the specificity of statin prescribing.
Leya M, Stone NJ. Statin Prescribing in the Elderly: Special Considerations. Curr Atheroscler Rep 2017; 19:47. http://www.ncbi.nlm.nih.gov/pubmed/?term=29019063
 
Directions on co-prescribing statins and anti-microbial agents
High intensity – high dose statin use in 50+ patients is pervasive, consequently the occasional antibiotic co-prescription in statin users is not an uncommon phenomenon. In this review, an appropriate use of antimicrobials is presented and discussed. Macrolide anti-biotics and antifungals are metabolized by the same CYP450-3A4 enzyme as lovastatin, simvastatin and atorvastatin, consequently this could boost statin plasma levels and increase the risk of statin related adverse events. Rifampicin can have a limiting effect on statin efficacy provoked by lower plasma concentrations. Label warnings have been added by the FDA since 2012 giving directions about statin dose adjustments when combined with anti-microbial’s. Prescribing physicians need to have up to date knowledge about drug-drug interactions and adjust medication selection and/or dosing. Using electronic health records alarms and innovative solutions to trigger early alerts for potential drug-drug interactions and prevent the sometimes life threatening adverse effects.
Hylton Gravatt LA, Flurie RW, Lajthia E, Dixon DL. Clinical Guidance for Managing Statin and Antimicrobial Drug-Drug Interactions. Curr Atheroscler Rep 2017; 19:46. http://www.ncbi.nlm.nih.gov/pubmed/?term=28990114
 
Only 1:5 ACS patients achieve guideline LDL-c. targets in DYSIS II
The dyslipidemia International Study II (DYSIS II) included 10 661 patients with ACS (N=3 867) or stable CHD (N=6794) from 18 countries were included. The aim of the study was to evaluate LDL-c. levels plus statin type and statin dosage used as well as cardiovascular outcomes by the included patients. Patients data was collected at baseline and after 180 days follow-up. LDL-c. levels at 180 days follow up were 88 mg/dl and 108 mg/dl for stable CHD and ACS patients respectively. A guideline goal of < 70 mg/dl was observed in 29.4 % (stable CHD) and 18.9% (ACS) patients. The mean atorvastatin equivalent dosage used was a modest 25 ±18 mg. Percentage of ACS patients on LLT increased from 65.3% to 95.6%. Patients with DM2, CKD or using a higher statin dosage were more likely to achieve a <70mg/dl LDL-c. target. Females, obese or current smokers were less likely reach the guideline dictated LDL-c. target. The findings of the DYSIS II underscore the world wide treatment gap observed in very high risk patients in terms of achieving LDL-c. target < 70mg/dl. Prescribing high dose atorvastatin in combination with non-statin lipid lowering agents e.g. ezetimibe or PCSK9ab needs to improve in order to reach LDL-c. guideline dictated targets of 70 mg/dl. Even more challenging will be to achieve the putative new LDL-c. < 55 mg/dl target in extremely elevated CVD risk patients. Country specific data will be made available in the near future.
Gitt AK, Lautsch D, Ferrieres J et al. Cholesterol target value attainment and lipid-lowering therapy in patients with stable or acute coronary heart disease: Results from the Dyslipidemia International Study II. Atherosclerosis 2017; 266:158-166. http://www.ncbi.nlm.nih.gov/pubmed/?term=29028484
 
Is low cholesterol responsible for higher mortality in 80+ patients
The consequences of low total cholesterol in the very elderly (>80 years) is confusing because of the observed increased mortality in patients with decreased cholesterol. The authors used the UK Clinical Practice Research Datalink, to analyze primary care electronic health records of 88 758 participants (80 – 105 years), mean age 86 years. Statins were used by 41 164 participants at baseline. Individuals with a TC between 4.5-5.4 were compared with those that had a TC < 3.0 mmol/l. The latter group was prone to higher mortality. In the statin users, HR: 1.53 (1.43-1.64; p<0.001) similar as patients not treated; HR 1.41: (1.29-1.54; p<0.001). In the last 2 years of life a rapid TC decline was noted. Patients with a TC <3.0 mmol/l who died were compared with the survivors. Statin users had an OR: 1.88 (1.68-2.11; p<0.001) and the untreated patients an OR: 3.33 (284-3.91; p<0.001). the authors concluded that the fatal TC decline in the last years of life were associated with a higher mortality but this was likely to be an expression of reverse causation. Plausible explanations for this  are  deteriorating organ functioning, diminishing nutritional status, as well as inflammatory processes. Similarities exist between the observed blood pressure decline in the last two years of life that is associated with increased mortality as well.
Charlton J, Ravindrarajah R, Hamad.a S et al. Trajectory of Total Cholesterol in The Last Years of Life Over Age 80 Years. Cohort Study of 99,758 Participants. J Gerontol A Biol Sci Med Sci 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29028914
Relevant publications
  1. Vuorio A, Watts GF, Kovanen PT. Depicting new pharmacological strategies for familial hypercholesterolaemia involving lipoprotein (a). Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29029165
  2. Taylor BA. Does Coenzyme Q10 Supplementation Mitigate Statin-Associated Muscle Symptoms? Pharmacological and Methodological Considerations. Am J Cardiovasc Drugs 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29027135
  3. Sathyapalan T, Coady AM, Kilpatrick E, Atkin S. The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome. Endocrine connections 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29018156
  4. M KS, Maroteau C, Veluchamy A et al. A common missense variant of LILRB5 is associated with statin intolerance and myalgia. Eur Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29020356
  5. Hamilton-Craig CR, Chow CK, Younger JF et al. Cardiac Society of Australia and New Zealand position statement executive summary: coronary artery calcium scoring. Med J Aust 2017; 207:357-361. http://www.ncbi.nlm.nih.gov/pubmed/?term=29020908
  6. Erlandson KM, Kitch D, Wester WC et al. The Impact of Statin and ACE-inhibitor/Angiotensin Receptor Blocker Therapy on Cognitive Function in Adults with HIV Infection. Clin Infect Dis 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29020174
  7. Byrne DD, Tate JP, Forde KA et al. Risk of Acute Liver Injury After Statin Initiation by Human Immunodeficiency Virus and Chronic Hepatitis C Virus Infection Status. Clin Infect Dis 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29020184
  8. Barkas F, Elisaf M. National hyperlipidemia management policies improve lipid target attainment in clinical practice. Current medical research and opinion 2017:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29019423
  9. Zhang L, Wang X, Wang M et al. Circulating Cholesterol Levels May Link to the Factors Influencing Parkinson's Risk. Frontiers in neurology 2017; 8:501. http://www.ncbi.nlm.nih.gov/pubmed/?term=29021777
  10. Vos E, Biron P, Rose CP. Letter by Vos et al Regarding Article, "Primary Prevention With Statin Therapy in the Elderly: New Meta-Analyses From the Contemporary JUPITER and HOPE-3 Randomized Trials". Circulation 2017; 136:1454-1455. http://www.ncbi.nlm.nih.gov/pubmed/?term=28993376
  11. Tall AR, Rader DJ. The Trials and Tribulations of CETP Inhibitors. Circulation research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29018035
  12. Singh SP, Sashidhara KV. Lipid lowering agents of natural origin: An account of some promising chemotypes. European journal of medicinal chemistry 2017; 140:331-348. http://www.ncbi.nlm.nih.gov/pubmed/?term=28987600
  13. Roth EM. A Safety Evaluation of Evolocumab. Expert opinion on drug safety 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28988500
  14. Kleipool EEF, Peters MJL, Muller M. Letter by Kleipool et al Regarding Article, "Primary Prevention With Statin Therapy in the Elderly: New Meta-Analyses From the Contemporary JUPITER and HOPE-3 Randomized Trials". Circulation 2017; 136:1456-1457. http://www.ncbi.nlm.nih.gov/pubmed/?term=28993377
  15. Kaiser P, Arnold AM, Benkeser D et al. Comparing methods to address bias in observational data: statin use and cardiovascular events in a US cohort. International journal of epidemiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29024975
  16. Haywood LJ, Davis BR, Piller LB et al. Influence of Prevalent and Incident Atrial Fibrillation on Post-Trial Major Events in ALLHAT. Journal of the National Medical Association 2017; 109:172-181. http://www.ncbi.nlm.nih.gov/pubmed/?term=28987246
  17. Greenlee H, Strizich G, Lovasi GS et al. Concordance with prevention guidelines and subsequent cancer, cardiovascular disease, and mortality: A longitudinal study of older adults. American journal of epidemiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29020206
  18. Girardi G. Pravastatin to treat and prevent preeclampsia. Preclinical and clinical studies. Journal of reproductive immunology 2017; 124:15-20. http://www.ncbi.nlm.nih.gov/pubmed/?term=29028516
  19. Ebtehaj S, Gruppen EG, Parvizi M et al. The anti-inflammatory function of HDL is impaired in type 2 diabetes: role of hyperglycemia, paraoxonase-1 and low grade inflammation. Cardiovascular diabetology 2017; 16:132. http://www.ncbi.nlm.nih.gov/pubmed/?term=29025405
  20. Dirajlal-Fargo S, El Kamari V, Sattar A et al. Effect of statin on arginine metabolites in treated HIV-infection. Atherosclerosis 2017; 266:74-80. http://www.ncbi.nlm.nih.gov/pubmed/?term=28992467
  21. Demirci D, Ersan Demirci D, Esin M et al. [Do Turkish reimbursement recommendations cover current European Lipid Guidelines? A retrospective analysis of patients presenting with first acute coronary syndrom]. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:623-629. http://www.ncbi.nlm.nih.gov/pubmed/?term=28990943
  22. Borges IBP, Silva MG, Misse RG, Shinjo SK. Lipid-lowering agent-triggered dermatomyositis and polymyositis: a case series and literature review. Rheumatology international 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29027009
  23. Booth JN, 3rd, Colantonio LD, Chen L et al. Statin Discontinuation, Reinitiation, and Persistence Patterns Among Medicare Beneficiaries After Myocardial Infarction: A Cohort Study. Circ Cardiovasc Qual Outcomes 2017; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=29021332
  24. Betto M, Fares J, Saliba N, Ballout H. Efficacy and safety of a generic rosuvastatin in a real-world setting: prospective, observational clinical study in Lebanese patients. Annals of Saudi medicine 2017; 37:366-374. http://www.ncbi.nlm.nih.gov/pubmed/?term=28988251
  25. Archibugi L, Piciucchi M, Stigliano S et al. Exclusive and Combined Use of Statins and Aspirin and the Risk of Pancreatic Cancer: a Case-Control Study. Scientific reports 2017; 7:13024. http://www.ncbi.nlm.nih.gov/pubmed/?term=29026148
Miscellaneous publications
  1. Wang Y, Yang W, Zhao X, Zhang R. Experimental Study of the Protective Effect of Simvastatin on Lung Injury in Rats with Sepsis. Inflammation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29022140
  2. Santos C, Dourado DM, Silva B et al. ATORVASTATIN CAN PREVENT HEPATIC REMOTE REPERFUSION INJURY. Arq Bras Cir Dig 2017; 30:197-200. http://www.ncbi.nlm.nih.gov/pubmed/?term=29019561
  3. Leung YH, Turgeon J, Michaud V. Study of Statin- and Loratadine-Induced Muscle Pain Mechanisms Using Human Skeletal Muscle Cells. Pharmaceutics 2017; 9. http://www.ncbi.nlm.nih.gov/pubmed/?term=28994701
  4. Huang B, Zhou ZY, Li S et al. Tanshinone I prevents atorvastatin-induced cerebral hemorrhage in zebrafish and stabilizes endothelial cell-cell adhesion by inhibiting VE-cadherin internalization and actin-myosin contractility. Pharmacol Res 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29017932
  5. Fujiwara D, Tsubaki M, Takeda T et al. Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 2017; 39:1010428317734947. http://www.ncbi.nlm.nih.gov/pubmed/?term=28990465
  6. Elmasry A, Aladeeb NM, Elkaref A, Aboulfotouh N. Simvastatin exerts antifibrotic effect and potentiates the antischistosomal effects of praziquantel in a murine model: Role of IL10. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2017; 96:215-221. http://www.ncbi.nlm.nih.gov/pubmed/?term=28987945
  7. Chang YL, Huang LC, Chen YC et al. The synergistic effects of valproic acid and fluvastatin on apoptosis induction in glioblastoma multiforme cell lines. The international journal of biochemistry & cell biology 2017; 92:155-163. http://www.ncbi.nlm.nih.gov/pubmed/?term=29017950
  8. Kong R, Zhu X, Meteleva ES et al. Enhanced solubility and bioavailability of simvastatin by mechanochemically obtained complexes. Int J Pharm 2017; 534:108-118. http://www.ncbi.nlm.nih.gov/pubmed/?term=28993167
  9. Hubert S, Chadwick A, Wacher V et al. Development of a Modified Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome with Constipation. Journal of pharmaceutical sciences 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28989013
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