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Update - Week 21, 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

Targeting LDL-c or Inflammation – what is the evidence
Both LDL-c and inflammation are key players in the development as well as ensuing complications atherosclerosis. In this narrative review the authors present an overview of historic and recent evidence of addressing these risk factors. Using data collected in major statin trials as well as the CANTOS trial with canakinumab, targeting inflammation only, and PCSK9ab studies. The effects of reducing both LDL-c as well mitigating inflammation have shown to reduce CV events and patients with the lowest levels of LDL- and/or Inflammatory markers had the greatest benefit. The authors review the trials with statins, statins + ezetimibe, PCSK9 and canakinumab to illustrate the observed protective effects. The added benefit of combining statins with ezetimibe or PCSK9 has proven to be a successful strategy because of the added LDL-c lowering effects only. The anti-inflammatory effects of statins are dose dependent and seem to have extra impact in patients during the acute phase of CV complications. The ARMYDA trial using in a two-tablet approach prior to a PCI illustrate this elegantly. The clinical relevance of Canakinumab is debated, partly because of the modest risk reducing effects, the high costs and the observed side effects. The cornerstone of CV risk management was and remains appropriate statin treatment. The solid evidence base of efficacy, safety and at a very affordable price, is an unique feature of this drug class and will be hard to beat by alternative, new therapeutic approaches, for the standard CV risk patient.
Reklou A, Doumas M, Imprialos K et al. Reduction of Vascular Inflammation, LDL-C, or Both for the Protection from Cardiovascular Events? The open cardiovascular medicine journal 2018; 12:29-40. http://www.ncbi.nlm.nih.gov/pubmed/?term=29785212
Can statins reduce plaque features and infarct size in patients at risk for ischemic stroke?
The atherosclerotic plaque changes observed after using statins have been studied extensively in patients with coronary atherosclerosis. The authors of this study show the effects of statins on carotid plaques. They examined carotid endarterectomy (CEA) specimens obtained after surgical removal in 79 consecutive Japanese patients (May 2015 – February 2017). Majority of patients presented with a carotid stenosis > 70%; 66 of these patients were not treated with statins and 13 did get a statin. The authors evaluated the prevalence of plaque ruptures, lumen thrombi, inflammatory cells, intra-plaque hemorrhages and intraplaque micro vessels. All evaluated plaque indicators were observed significantly less in patients treated with statins. Patients (N=66) that presented with infarct sizes > 1.0 cm3 (based on MRI evaluation), statin users had significantly smaller infarct volume; 4.2 ± 2.5 cm3 vs   8.2 ± 7.1 cm3, P = 0.031. Intriguingly the LDL-c concentrations were not significantly different, 105 ± 37 mg/dl vs 121 ± 32 mg/dl, p=0.118. The authors concluded that statins have a plaque stabilizing effect in patients at for risk ischemic stroke, because of carotid atherosclerosis , as well as reducing infarct volume, resulting in lesser damage to cerebral tissues.
Konishi T, Funayama N, Yamamoto T et al. Stabilization of symptomatic carotid atherosclerotic plaques by statins: a clinico-pathological analysis. Heart Vessels 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29789903
Simple strategies to improve statin adherence
This qualitative systematic review examined studies that evaluated patients attitudes and believes regarding statin use. Using multiple data sources, including PhD dissertations from inception – October 2016. Text and patient’s quotes were extracted and categorized. Included were 32 studies with 888 participants (aged 22-93 years) from 8 countries. The authors identified 7 recurring themes that provided insights on what motivated patients to use, continue taking statins or stop. Participants were more likely to continue with their medication if they expected that statins could CVD as well as integrating using statins in their daily life.  Barriers for statin adherence included: avoiding the ‘sick’ identity and prolonged dependence on medications, uncertainties about the pharmacological mechanisms, risks to health, side effects, costs, and skepticism about clinicians’ motives for prescribing statins. Helpful strategies to improve long term persistence of statin use were shared decision making, discussing the risks as well as the reasons why statins were prescribed. Patient priorities as well as pointers how to minimize lifestyle intrusions and manage side effects can improve patient trust, satisfaction and statin adherence.
Ju A, Hanson CS, Banks E et al. Patient beliefs and attitudes to taking statins: systematic review of qualitative studies. Br J Gen Pract 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29784867
Is “Time To Benefit” (TTB), a new parameter for lipid lowering interventions?
The authors of this article weighed an additional parameter to compare different cholesterol lowering strategies; the time to benefit (TTB), or how did it take before treatment curves started to diverge. They evaluated 24 successful cholesterol lowering endpoint trials, 17 statins and 7 using alternative lipid lowering interventions such as gemfibrozil, cholestyramine, ezetimibe, PCSKab and anacetrapib (a CETP inhibitor). The range of TTB was 1-30 months (mean 13.1 months). TTB with statins was shorter, 10.3 months compared to non-statins, 20.0 months. When comparing the different statins, atorvastatin had the shortest TTB of 4.75 months compared to 11.4 months for the other statins. The observed TTB differences are most likely related to the type of interventions and the special, perhaps non-cholesterol lowering, properties of these different pharmacological interventions. The authors also suggested other factors to take into account, such as the sample size and event rates in different type of patients (primary prevention – secondary prevention – ACS). Baseline LDL-c and changes of LDL-c were not correlated with TTB. They concluded statins in general, and atorvastatin in particular, showed the shortest TTB. However, when evaluation novel lipid lowering strategies, patience’s should be exercised, as benefits may not occur before 2 years.
Barter PJ, Waters DD. Variations in time to benefit among clinical trials of cholesterol-lowering drugs. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29779997
Practical recommendations on managing NODM in patients using statins
New onset diabetes mellitus (NODM) is a recognized side effect of statins that causes considerable concern in the shared decision process of starting this class of drugs. The authors of this review discussed the mechanisms that can explain the pro diabetogenic effects, as well as sharing recommendations on what strategies to employ to avoid or minimize this risk. The annual risk of NODM is approximately 0.1%/year in contrast with the 0.42% annual reduction of major coronary events. An overview of all published primary and secondary prevention trials with the benefits on CVD as well as the observed increased incidence of NODM are presented. Only the WOSCOPS primary prevention trial, using pravastatin 40 mg showed a decrease of NODM. The predisposing risk factors for diabetes play a very important role, and one might argue that this is an added responsibility of the patients and not only statin related consequence. Despite the efforts to find the underlying cause of the pro-diabetogenic effects, there remains considerable uncertainty what pathways are affected by the different statins. Insulin secretion as well as insulin resistance are seen as major factors but for more precise explanations additional studies will need to provide the answers. In their recommendations the authors suggest that pitavastatin appears to have a more neutral effect on glucose metabolism and could be an alternative choice in patients at risk for developing diabetes. A more active approach in monitoring and managing lifestyle related factors to avoid NODM are suggested as well.   
Agarwala A, Kulkarni S, Maddox T. The Association of Statin Therapy with Incident Diabetes: Evidence, Mechanisms, and Recommendations. Current cardiology reports 2018; 20:50. http://www.ncbi.nlm.nih.gov/pubmed/?term=29779165
Relevant publications
  1. Colombo M, Looker HC, Farran B et al. Apolipoprotein CIII and N-terminal prohormone b-type natriuretic peptide as independent predictors for cardiovascular disease in type 2 diabetes. Atherosclerosis 2018; 274:182-190. http://www.ncbi.nlm.nih.gov/pubmed/?term=29793175
  2. Yamashita S, Masuda D, Arai H, Matsuzawa Y. Cultural Barriers in the Treatment of Dyslipidemia: A Survey of Japanese Physician Attitudes. J Atheroscler Thromb 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29780067
  3. Thakkar J, Redfern J, Khan E et al. Healthcare resource utilisation by patients with coronary heart disease receiving a lifestyle-focused text message support program: an analysis from the TEXT ME study. Australian journal of primary health 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29789100
  4. Nguyen KA, Li L, Lu D et al. A comprehensive review and meta-analysis of risk factors for statin-induced myopathy. Eur J Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29785580
  5. Harewood-Marshall AS, Craig LS, Martelly TP et al. Managing acute ischaemic stroke in a small island developing state: meeting the guidelines in Barbados. BMC public health 2018; 18:648. http://www.ncbi.nlm.nih.gov/pubmed/?term=29788951
  6. Dalugama C, Pathirage M, Kularatne SAM. Delayed presentation of severe rhabdomyolysis leading to acute kidney injury following atorvastatin-gemfibrozil combination therapy: a case report. Journal of medical case reports 2018; 12:143. http://www.ncbi.nlm.nih.gov/pubmed/?term=29784023
  7. Carvalho AAS, da Silva VG, Zanoteli E, Feder D. Myopathy due to HMGCR antibodies in adult mimicking muscular dystrophy associated with cancer and statin exposure - narrative review of the literature - case report. Therapeutics and clinical risk management 2018; 14:903-907. http://www.ncbi.nlm.nih.gov/pubmed/?term=29785116
  8. Aljenedil S, Ruel I, Watters K, Genest J. Severe xanthomatosis in heterozygous familial hypercholesterolemia. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29778561
  9. Agirbasli D, Hyatt T, Agirbasli M. Familial hypercholesterolemia with extensive coronary artery disease and tuberous and tendinous xanthomas: A case report and mutation analysis. J Clin Lipidol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29784571
  10. VanWagner LB. Aspirin and Statin Use for Management of Atherosclerotic Cardiovascular Disease in Liver Transplant Candidates: Are We Missing the Mark? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29781097
  11. Oh TK, Kim K, Jheon S et al. Impact of Statin Use on Recurrence or Survival After Surgical Curative Resection of Non-Small Cell Lung Cancer. Cancer control : journal of the Moffitt Cancer Center 2018; 25:1073274818778000. http://www.ncbi.nlm.nih.gov/pubmed/?term=29781295
  12. Oh M, Ghim JL, Park SE et al. Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of fimasartan, amlodipine, and rosuvastatin using partial replicated design in healthy adult subjects. Drug design, development and therapy 2018; 12:1157-1164. http://www.ncbi.nlm.nih.gov/pubmed/?term=29780236
  13. Ofori-Asenso R, Ilomaki J, Zomer E et al. A 10-Year Trend in Statin Use Among Older Adults in Australia: an Analysis Using National Pharmacy Claims Data. Cardiovasc Drugs Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29790056
  14. Maksymets T, Karpyshyn N, Gutor T et al. Influence of risk factors on insulin resistance in patients with overweight and obesity. Wiadomosci lekarskie (Warsaw, Poland : 1960) 2018; 71:558-560. http://www.ncbi.nlm.nih.gov/pubmed/?term=29783224
  15. Maillart E. Treatment of progressive multiple sclerosis: Challenges and promising perspectives. Revue neurologique 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29779852
  16. Ginsberg HN, Farnier M, Robinson JG et al. Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies. Diabetes Ther 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29779195
  17. Delluc A, Lacut K, Pan-Petesch B et al. Statin exposure and thrombosis risk in patients with myeloproliferative neoplasms. Thrombosis research 2018; 167:57-59. http://www.ncbi.nlm.nih.gov/pubmed/?term=29787944
  18. Dawra VK, Cutler DL, Zhou S et al. Assessment of the Drug Interaction Potential of Ertugliflozin With Sitagliptin, Metformin, Glimepiride, or Simvastatin in Healthy Subjects. Clinical pharmacology in drug development 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29786959
  19. Dao N, Lee S, Hata M, Sarino L. Impact of Appointment-Based Medication Synchronization on Proportion of Days Covered for Chronic Medications. Pharmacy (Basel, Switzerland) 2018; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29786638
  20. Corsini A, Pacini D, Lovato L et al. Long-term Follow up of Patients with Acute Aortic Syndromes: Relevance of both Aortic and Non-aortic Events. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29779910
  21. Cartolano FC, Pappiani C, Freitas MCP et al. Is Lipid Accumulation Product Associated with an Atherogenic Lipoprotein Profile in Brazilian Subjects? Arquivos brasileiros de cardiologia 2018; 110:339-347. http://www.ncbi.nlm.nih.gov/pubmed/?term=29791572
  22. Auer J, Berent R. Alirocumab as add-on therapy to statins: current evidence and clinical potential. Ther Adv Cardiovasc Dis 2018:1753944718775352. http://www.ncbi.nlm.nih.gov/pubmed/?term=29792380
  23. Ageev FT, Blankova ZN, Samsonova NS. [The effect of changing of conventional antihypertensive therapy to a triple fixed combination therapy with rosuvastatin in high cardiovascular risk patients]. Kardiologiia 2018:46-54. http://www.ncbi.nlm.nih.gov/pubmed/?term=29782289
Miscellaneous publications
  1. Leite GAA, Figueiredo TM, Guerra MT et al. Ascorbic acid co-administered with rosuvastatin reduces reproductive impairment in the male offspring from male rats exposed to the statin at pre-puberty. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29778496
  2. Zhang K, Liu G, Tian F, Zhang L. [REGUL ATORY EFFECT OF SIMVASTATIN ON MIDDLE/L ATE STAGES OSTEOGENIC DIFFERENTIATION OF BONE MARROW MESENCHYMAL STEM CELLS VIA p38MAPK PATHWAY]. Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery 2016; 30:1038-1043. http://www.ncbi.nlm.nih.gov/pubmed/?term=29786238
  3. Matera MG, Calzetta L, Gritti G et al. Role of statins and mevalonate pathway on impaired HDAC2 activity induced by oxidative stress in human airway epithelial cells. Eur J Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29782855
  4. Bhadoriya A, Sanyal M, Shah PA, Shrivastav PS. Simultaneous quantitation of rosuvastatin and ezetimibe in human plasma by LC-MS/MS: Pharmacokinetic study of fixed-dose formulation and separate tablets. Biomedical chromatography : BMC 2018:e4291. http://www.ncbi.nlm.nih.gov/pubmed/?term=29782035
  5. Zhang JY, Bai QK, Zhang YD. Pretreatment with simvastatin upregulates expression of BK-2R and CD11b in the ischemic penumbra of rats. Journal of biomedical research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29784898
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