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Update - Week 37,  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

Calcium scoring to determine statin intensity in Korean patients
Non-invasive imaging is gaining ground not only as a prognostic marker to be used in stratifying patients risk but as a motivational to enhance medication adherence as well! In this Korean retrospective analysis of 3914 asymptomatic patients were a calcium score was calculated were subdivided in 3 groups: use of high intensity statin (n=1284; 32.8%), moderate intensity statin (N=602; 40.9%) and low intensity statin (n=931; 23.8%). A 10-year CVD risk was calculated using the ACC/AHA pooled risk equation. There was a clear correlation between the use of hihgh intensity statins and a high ASCVD risk or Calcium score. The 10-year risk was 12.6 ± 5.3% vs. 2.9 ± 1.9%, p < 0.001. The CACS 98 ± 270 vs. 3 ± 2, p < 0.001. A high Calcium score (>300) in the patients using high intensity statins more frequently found in in older participants, OR:1.299 (1.137–1.483), p < 0.001; Males, OR: 44.252 (1.959–999.784), p = 0.001 and increased fasting glucose, OR: 1.046 (1.007–1.087), p = 0.021. The authors suggested to use Calcium scoring for CVD risk stratification that would allow to individualized type and dosage of statin therapy, information on clinical outcome of the participants was not available.
Lee DH, Youn HJ, Jung HO et al. Coronary artery calcium score plays an important role for cardiovascular risk stratification in the statin benefit groups of asymptomatic individuals. Lipids Health Dis 2017; 16:172. http://www.ncbi.nlm.nih.gov/pubmed/?term=28899385
 
High intensity statins taken consistently protect Korean stroke patients
Observational study examining the long-term benefits of statin intensity and adherence in 8001 Korean acute ischemic stroke patients. Using collected clinical information in a nationwide health insurance claim database between 2002 and 2012. Statin dosage and intensity were determined 1 year after the index stroke. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. After a mean follow-up of 4.69±2.72 years primary endpoint was recorded for 2284 patients. Patients not using statins were the designated comparator group. Patients with good adherence had an adjusted HR of 0.74 (064-084); intermediate adherence RH: 0.93 (0.79-1.03) and patients with poor adherence HR: 1.07 (0.95-1.20). The patients with good adherence (N=1712) and using high intensity statins were found to have a reduced adverse event rate; HR:0.48 (0.24-0.96) compared to patients on low intensity statins. No increased risk of hemorrhagic stroke was observed in either good adherent or the high intensity statin users, as was suggested in the SPARCLE trial. The authors concluded that based on their analysis high intensity statin therapy combined with good adherence reduced the risk of subsequent events significantly without an increase in hemorrhagic stroke occurrence.
Kim J, Lee HS, Nam CM, Heo JH. Effects of Statin Intensity and Adherence on the Long-Term Prognosis After Acute Ischemic Stroke. Stroke 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28916672
 
Statin induced NODM more benign if compliance is good
The role of statins in new onset diabetes (NODM) has been firmly established. Pro diabetogenic factors in patients play an important part in determining who will be affected and who not as well. The question the researchers sought to answer is what clinical consequences patients suffer if statins trigger NODM. For this they compared patients that developed NODM after initiating statins to patients where other factors were responsible for provoking NODM. They conducted a retrospective analysis in a data set of 651 552 beneficiaries of the Lombardy Health Service. Statin treatment was initiated in 84 828 patients between 2003 and 2005. In this phase of the analysis patients were followed until 2009 to monitor NODM development. Patients were matched (1:3) to patients not developing NODM. The second phase of the study followed patients until 2012, after starting with anti-diabetic medication. In the study 65,833 person years of follow-up accumulated (5.1 years per patient). During this period 376 and 760 diabetic and non-diabetic patients respectively experienced an event. Patients with diabetes had a 39% (23–57%) higher risk of macrovascular complications. Statin adherence, as reflected by Proportions of days covered by medications (PDC), closely coincided with a higher risk of developing NODM. However, in the second phase of the study better adherence, detected in the first part of the study, resulted in lower risk of macrovascular complications. The observed HR’s were 1.70 (1.18–2.44), 1.41 (1.17–1.70), 1.30 (1.07–1.57) and 1.10 (0.40–2.80) respectively for patients with very low (<10% PDC); low (11%-50% PDC), intermediate (51-89% PPDC) and high (>90% PDC) adherence. The authors concluded that in patients with very high statin adherence the CVD risk was the same as in non-diabetic patients. The non-adherent patient experienced an almost doubling of their risk for macro-vascular complications as compared to their non-diabetic counterparts. The onset of the feared macro-vascular complications in patients with statin induced NODM seem to have a more benign nature if patients diligently use their statins.
Corrao G, Monzio Compagnoni M, Rea F et al. Clinical significance of diabetes likely induced by statins: Evidence from a large population-based cohort. Diabetes Res Clin Pract 2017; 133:60-68. http://www.ncbi.nlm.nih.gov/pubmed/?term=28892732
 
Should elderly (>70years) get statins for primary prevention

The Physicians Health Study has in the past served as an important source of relevant clinical data to determine the impact of risk factors or modification of CVD risk factors by (pharmacological) intervention. In this recent analysis, the Investigators evaluated the impact of statin use in elderly participants of this study. The cohort included 7 213 physicians >70 years, without CVD. The mean baseline age was 77 years (70-102); median follow-up 7 years. Using a multivariate 1:1 propensity score matching, 1 130 statin users were matched with non-statin users. The evaluated outcomes were total mortality, CVD events and stroke. Participants that used statins scored significantly better on all 3 endpoints with HR’s of 0.82 (0.69-0.98); 0.86 (0.70-1.06) and 0.70 (0.45-1.09) for total mortality CVD events and stroke respectively, but only total mortality achieved statistical significance. Elderly patients with elevated cholesterol and using statins were much better protected from CVD than non-users; HR 0.68 ( 0.50–0.94) vs 1.43 (0.99–2.07). The authors concluded that statin use in male elderly individuals was associated with a significant lower risk of mortality and a nonsignificant lower risk of CVD events.
Orkaby AR, Gaziano JM, Djousse L, Driver JA. Statins for Primary Prevention of Cardiovascular Events and Mortality in Older Men. J Am Geriatr Soc 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28892121
 
Non-fasting TG/HDL predicts MACE in post PCI statin treated patients

For this analysis 1 170 consecutive (primary) PCI patients from a single Japanese institute were included. All patients were on statins post index event. Patients were divided into three groups, based on non-fasting TG/HDL-c ratio’s, 3 months after the intervention. MACE were recorded in the subsequent period, spanning a maximum of 5 years. Patients in the highest TG/HDL-c ratio tertile had a significant higher event rate compared to the other two groups. Despite having a statin on board and an LDL-c <100 mg/dl. MACE were observed in 73/390 (18.7%); 114/390 (29.2%) and 156/390 (40.0%), respectively in the lowest, intermediate and highest tertile of the TG/HDL-c ratio. The cut-of values in the three tertile’s were 1.37 (0.50-2.00), 2.60 (2.02-3.34) and 5.60 (3.35-18.29). The authors concluded that non-fasting TG/HDL-c ratio was reliable predictors of MACE after PCI in statin treated patients. Based on the observed number of events they recommend to aim for a non-fasting TG/HDL radio <2.0.
Matsumoto I, Misaki A, Kurozumi M et al. Impact of nonfasting triglycerides/high-density lipoprotein cholesterol ratio on secondary prevention in patients treated with statins. J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28916255
 
Metformine as statin add-on to prevent NODM and SAMS?
In this provocative proposal, the authors suggest metformine as a statin add-on to prevent or treat the most frequently reported side effects, statin associated muscle symptoms (SAMS) and new onset diabetes (NODM). Statins inhibit HMG-CoA reductase and this reduces mevalonate, and GGPP, ultimately reducing the IGF-1/PI3K/AKT pathway activity. This in turn decreases mTOR S6 kinase activity. A decreased protein synthesis, plus In the presence of mitochondrial oxidative stress, resulting in apoptosis and muscle injury. Statin’s effect on FOXO enhances downstream mediators of muscle atrophy (atrogin-1). A decreases substrate oxidation, which in conjunction with the statin-induced decrease in GLUT4 expression produces insulin resistance. They point out that metformin decreases oxidative stress, and enhances AMPK inhibition of mTOR. This potentially could transform the statin induced muscle damage into muscle cell apoptosis followed by autophagy without triggering muscle pain. Although both apoptosis and autophagy would result in reduced muscle mass, the effect of metformin through AMPK acting on FOXO3 reduces atrogin-1 that would result in reduced muscle atrophy. Finally, metformin is able to reduce insulin resistance by enhanced GLUT4 and FOXO3 expression. They suggest testing their hypothesis by performing a meta-analysis, of statin randomised control trials, comparing patients taking metformine at baseline to patients not taking metformine when a statin is started. Thy also propose developing a skeletal muscle cell culture model to discover specific statin-associated muscle-symptom markers. By exposing these cells to metformine, the muscle cell damage markers should decrease and the damaged muscle cells rescued. The authors suggest that the combination of statin and metformin would allow for better compliance of the life-saving HMG-CoA reductase inhibitors  as well as preventing NODM by addressing insulin resistance earlier and preventing the transformation to diabetes mellitus type 2. 
Carris NW, Tipparaju SM, Magness DJ et al. Pleiotropic effects of metformin to rescue statin-induced muscle injury and insulin resistance: A proposed mechanism and potential clinical implications. Medical hypotheses 2017; 107:39-44. http://www.ncbi.nlm.nih.gov/pubmed/?term=28915960
Relevant publications
  1. Waters MJ, Limaye V. Clinico-serologic features of statin-induced necrotising autoimmune myopathy in a single-centre cohort. Clinical rheumatology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28905130
  2. Pagidipati NJ, Navar AM, Pencina MJ. Guideline Recommendations for Statin Therapy-Reply. Jama 2017; 318:964. http://www.ncbi.nlm.nih.gov/pubmed/?term=28898376
  3. Liu GL, Lei R, Duan SB et al. Atorvastatin alleviates iodinated contrast media-induced cytotoxicity in human proximal renal tubular epithelial cells. Experimental and therapeutic medicine 2017; 14:3309-3313. http://www.ncbi.nlm.nih.gov/pubmed/?term=28912882
  4. Lima-Martinez MM, Paoli M, Vazquez-Cardenas A et al. Frequency and clinical and molecular aspects of familial hypercholesterolemia in an endocrinology unit in Ciudad Bolivar, Venezuela. Endocrinologia, diabetes y nutricion 2017; 64:432-439. http://www.ncbi.nlm.nih.gov/pubmed/?term=28895539
  5. Khan NA, McAlister FA, Pilote L et al. Secondary prevention treatment after acute stroke in older South Asian, Chinese and other Canadians: a retrospective data analysis. CMAJ open 2017; 5:E702-e709. http://www.ncbi.nlm.nih.gov/pubmed/?term=28899946
  6. Grossman DC, Curry SJ, Owens DK. Guideline Recommendations for Statin Therapy. Jama 2017; 318:963-964. http://www.ncbi.nlm.nih.gov/pubmed/?term=28898373
  7. Giugliano D, Maiorino MI, Bellastella G, Esposito K. Type 2 diabetes and cardiovascular prevention: the dogmas disputed. Endocrine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28895030
  8. Briasoulis A, Pala M, Telila T et al. Statins and contrast-induced nephropathy: a systematic review and meta-analysis. Current pharmaceutical design 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28914202
  9. Al Hamarneh YN, Tsuyuki RT, Jones CA et al. Effectiveness of Pharmacist Interventions on Cardiovascular Risk in Patients With CKD: A Subgroup Analysis of the Randomized Controlled RxEACH Trial. American journal of kidney diseases : the official journal of the National Kidney Foundation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28912054
  10. Williams BR, Amos Bailey F, Kvale E et al. Continuation of non-essential medications in actively dying hospitalised patients. BMJ supportive & palliative care 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28904011
  11. White CM, Weeda ER, Nguyen E. Should an LDL-Cholesterol Target-Based Approach Be Readopted? The Annals of pharmacotherapy 2017:1060028017722009. http://www.ncbi.nlm.nih.gov/pubmed/?term=28915766
  12. Verma AA, Jimenez MP, Subramanian SV et al. Race and Socioeconomic Differences Associated With Changes in Statin Eligibility Under the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines. Circ Cardiovasc Qual Outcomes 2017; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=28912201
  13. Steicke M, Wang Y. Comment: Translating Guidelines Into Practice: Interpreting the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk. The Annals of pharmacotherapy 2017:1060028017732358. http://www.ncbi.nlm.nih.gov/pubmed/?term=28895424
  14. Seftel AD. Re: Statin, Testosterone and Phosphodiesterase 5-Inhibitor Treatments and Age Related Mortality in Diabetes. The Journal of urology 2017; 198:727-730. http://www.ncbi.nlm.nih.gov/pubmed/?term=28905759
  15. Schreiber K, Radin M, Sciascia S. Current insights in obstetric antiphospholipid syndrome. Current opinion in obstetrics & gynecology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28915160
  16. Radermecker RP. [Lipertance(R) The ASCOT single-pill combination has finally arrived]. Revue medicale de Liege 2017; 72:416-422. http://www.ncbi.nlm.nih.gov/pubmed/?term=28892318
  17. Pirillo A, Norata GD, Catapano AL. Strategies for the use of nonstatin therapies. Curr Opin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28914630
  18. Parhofer KG. New approaches to address dyslipidemia. Curr Opin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28902717
  19. Lin XL, Liu MH. Statin and ezetimibe combination therapy: New therapeutic options for lowering Low-Density Lipoprotein Cholesterol. Int J Cardiol 2017; 247:49. http://www.ncbi.nlm.nih.gov/pubmed/?term=28916087
  20. Lee JS, Gonzales R, Vittinghoff E et al. Appropriate Reconciliation of Cardiovascular Medications After Elective Surgery and Postdischarge Acute Hospital and Ambulatory Visits. Journal of hospital medicine 2017; 12:723-730. http://www.ncbi.nlm.nih.gov/pubmed/?term=28914276
  21. Indumathi C, Anusha N, Vinod KV et al. Atorvastatin Induced Adverse Drug Reactions among South Indian Tamils. J Clin Diagn Res 2017; 11:Fc01-fc05. http://www.ncbi.nlm.nih.gov/pubmed/?term=28892923
  22. Bravata DM, Myers LJ, Cheng E et al. Development and Validation of Electronic Quality Measures to Assess Care for Patients With Transient Ischemic Attack and Minor Ischemic Stroke. Circ Cardiovasc Qual Outcomes 2017; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=28912200
Miscellaneous publications
  1. Yu SY, Dong B, Tang L, Zhou SH. Statin regulates NLRP1 inflammasome expression through SREBP1: A novel anti-atherosclerotic mechanism. Int J Cardiol 2017; 247:11. http://www.ncbi.nlm.nih.gov/pubmed/?term=28916051
  2. Karlic H, Haider F, Thaler R et al. Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines. Int J Mol Sci 2017; 18. http://www.ncbi.nlm.nih.gov/pubmed/?term=28914765
  3. Karagkounis G, DeVecchio J, Ferrandon S, Kalady MF. Simvastatin enhances radiation sensitivity of colorectal cancer cells. Surgical endoscopy 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28916945
  4. Kang M, Lee KH, Lee HS et al. Concurrent treatment with simvastatin and NF-kappaB inhibitor in human castration-resistant prostate cancer cells exerts synergistic anti-cancer effects via control of the NF-kappaB/LIN28/let-7 miRNA signaling pathway. PLoS One 2017; 12:e0184644. http://www.ncbi.nlm.nih.gov/pubmed/?term=28910332
  5. Bleda S, de Haro J, Acin F. Statin potential Nlrp1 inflammasome gene expression modulation via Srebp-1 pathway in peripheral arterial disease. Int J Cardiol 2017; 247:12. http://www.ncbi.nlm.nih.gov/pubmed/?term=28916052
  6. Dikshit R, Tallapragada P. Statistical optimization of lovastatin and confirmation of nonexistence of citrinin under solid-state fermentation by Monascus sanguineus. Journal of food and drug analysis 2016; 24:433-440. http://www.ncbi.nlm.nih.gov/pubmed/?term=28911599
  7. Beg S, Katare OP, Singh B. Formulation by design approach for development of ultrafine self-nanoemulsifying systems of rosuvastatin calcium containing long-chain lipophiles for hyperlipidemia management. Colloids and surfaces. B, Biointerfaces 2017; 159:869-879. http://www.ncbi.nlm.nih.gov/pubmed/?term=28892871
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