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Update - Week 26,  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

Is the LDL-receptor to blame for the NODM effects of statins?
In this concise review on the pro-diabetogenic effects of statin, the central role of the LDL-receptor is highlighted. The regulation of cholesterol in the pancreatic island cells is targeted as pivotal and the authors suggest that the increased cholesterol uptake in Beta cells, caused by the increase of LDL-r. expression seems to have a damaging effect on insulin secretion and even beta cell apoptosis. The molecular mechanisms explaining the pro diabetogenic effects focus on the liver X receptor and sterol regulatory element-binding protein 2 (SREBP-2). What is discussed but not explained is why the effects of bile acid sequestrants on glucose metabolism; in contrast with statins seem to have an anti-diabetogenic effect. The new class of PCSK9ab were discussed as well. The Mendelian randomization studies by Ference, highlighted in this review suggest that these drugs should, like statins, also increase the risk of new onset diabetes. However, this was not observed in the meta-analysis of the phase 3 studies of both evolocumab and alirocumab and the recently published Fourier hard clinical endpoint trial. Fourier included >27 000 patients achieved a mean LDL-C reduction of 59% and 2.2 years follow-up; In contrast with Jupiter trial >17 000 patients with mean LDL-C reduction of 50% and 1.9 of follow-up that showed a clear signal of NODM. The question why statins use is related to NODM remains to be elucidated.
Yu Q, Chen Y, Xu CB. Statins and New-Onset Diabetes Mellitus: LDL Receptor May Provide a Key Link. Frontiers in pharmacology 2017; 8:372. http://www.ncbi.nlm.nih.gov/pubmed/?term=28659805 
 
Can SLE patients, at risk for thrombosis, reduce that risk by taking statins?
In this Japanese retrospective cohort study, newly diagnosed SLE patients, between April 1997 and February 2014, were included. Primary outcome was a first thrombotic event or death due to a thrombotic event. A total of 152 patients, 80 positive and 72 negative for antiphospholipid antibodies (aPL). In aPL positive patients there were 15, Arterial (6) and venous (9) thrombotic complications manifested during a median follow up of 69 months. SLE onset at an older age and IgG-anticardiolipin antibodies increased the risk, statin use decreased that risk significantly; HR 0.12 (0.01-0.98). Thrombosis developed in 7 Patients, arterial (5) and venous (2), negative for aPL. This risk was not influenced by age of SLE onset, circulating IgG-anticardiolipin antibodies and statin use. The authors concluded that statins appeared to be protective for the development of thrombotic complications in aPL positive SLE patients.
Watanabe T, Oku K, Amengual O et al. Effects of statins on thrombosis development in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus 2017:961203317716787. http://www.ncbi.nlm.nih.gov/pubmed/?term=28659045
 
Should acute intracerebral hemorrhage patients use a statin?
Using data collected in the American ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage study. This is a multi-center, prospective recruitment, multi ethnic study of intra cerebral hemorrhage (ICH) was analyzed to explore the effect of statins on ICH mortality, 3-month disability and initial hematoma volume plus subsequent expansion. Statin use was examined in 3 sub-categories: prior, continued and new use. A complete data set was available for 2457 cases. Statin use was recorded in 1093 cases (prior N=268; continued N=423 and new n=402). Statin used was associated with improved mortality and disability. No effect could be demonstrated for hematoma growth. However, statin use might have been continued/started more frequently in patients with less severe disease. The authors developed a propensity score based on factors that could influence a physician’s decision to prescribe a statin, after which statin use was no longer a significant predictor of good outcome. Although a severe ICH with a detrimental outcome would outweigh the potential benefits of statin, the number of patients were not sufficient to determine if a patient with less severe disease + a statin had an improved prognosis compared to a patient with similar clinical features but who was not started on or discontinued a statin. To properly address this important clinical dilemma only a well-designed randomized clinical trial can provide a definite answer to this question.
Siddiqui FM, Langefeld CD, Moomaw CJ et al. Use of Statins and Outcomes in Intracerebral Hemorrhage Patients. Stroke 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28663510
 
MEGA study participants, allocated pravastatin, had a 10% lower risk of developing hypertension
In this sub-analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, the effects of 10-20 mg of pravastatin on hypertension development was studied. When the MEGA study started there were 3397 patients with normal blood pressure. During the 4 years follow up, 1595 patients developed hypertension (49.1% in the diet alone group and 44.7% in the diet plus pravastatin group). The authors show that, after adjusting for multiple covariates, pravastatin uses had a 10% lower risk of developing hypertension; HR 0.9 (0.81-0.998) compared with the individuals randomized to the diet only group. patients >60 years (HR 0.78, 95%CI 0.66–0.91), men (HR 0.82, 95% CI 0.68–0.99), those with chronic kidney disease (HR 0.79, 95% CI 0.65–0.97) or diabetes (HR 0.79, 95% CI0.69–0.98), and those without obesity (HR 0.86, 95% CI 0.77–0.99) showed more pronounced benefit of pravastatin use. The incidence rate of hypertension in this study (45%–49% during 3 years of follow-up) was markedly higher than in observed in previous cohort studies (15%–36% during 4–14 years of follow-up).
Otsuka T, Mizuno K, Shinozaki T et al. Preventive effect of pravastatin on the development of hypertension in patients with hypercholesterolemia: A post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28655522
 
CVD risk in Norwegian FH relatives identified by cascade screening
Relatives of FH patients identified by the Norwegian cascade screening program (1992-1994) and having an LDL-r mutation as well as statin treatment were evaluated for death or MACE. Identified relatives (N=220) had a median age of 37 yrs. An LDLr mutation was found in 188 FH patients (54%). Prescription data was available from 2004 and 89% of the mutation positive individuals used a statin. This resulted in an adjusted HR: 1.65 (0.56-1.59) when compared to a Danish general population cohort. In non-mutation carrying FH relatives the CVD risk was comparable to the general population cohort HR: 0.85 (0.56-1.29). When mutation carrying relatives were compared to non-mutation carrying relatives the adjusted risk was almost doubled; HR 1.94 (1.14-3.31), most of the risk was associated with non-fatal events. The authors concluded that in Norwegian FH families, the individuals that are carrying an LDL-r mutation, despite being treated with statins, remain to show an increased long-term risk of CVD events. The reason for this increased risk could be related to insufficient treatment, e.g. not able to reach LDL-C targets even when employing the maximum dosage of high intensity statins and/or initiating LDL-C treatment too late, the lifelong exposure and associated cholesterol burden needs to be addressed early in life.  Intriguingly total mortality was not increased and even reduced in both mutation carrying as non-mutation carrying FH relatives. The reason for this, as the authors point out, could be chance; the number included FH patients is too small. A similar observation was made in the Simon Broom registry study, they were able to show more specific data on non-cardiovascular mortality and observed an almost 50-60% lower risk in two specific forms of cancer: lung cancer and colon cancer. This was potentially attributed to better lifestyle in terms of lower animal fat consumption and not smoking.    
Kjaergaard KA, Christiansen MK, Schmidt M et al. Long-Term Cardiovascular Risk in Heterozygous Familial Hypercholesterolemia Relatives Identified by Cascade Screening. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=28652386
 
Chinese diabetic patients on statins half their CVD and total mortality risk
A retrospective analysis using a large central computerized database under the Hospital Authority (HA), the largest government organization in-charge of all public hospitals and out-patient clinics in Hong Kong, between 1 January 2010 and 31 December 2010. Including diabetic patients with a baseline LDL-C > 2.6 and not using statins were followed for 5 years. Total mortality and CVD events were the primary outcomes. Propensity score matching was performed between patients that initiated statins at baseline and non-statin users. Overall 10 104 pairs of diabetic patients were propensity matched. The CVD incidence in statin users vs non-statin users was 16.533 per 1000 person-years whereas comparison group had 32.387 per 1000 person-years (HR: 0.458) during a median follow-up period of 50.5 months. The numbers for total mortality: 8.138 deaths per 1000 person-years vs 19.603 deaths per 1000 person-years (HR: 0.378) Statin users that achieved and LDL-C < 2.6 mmol/L, compared to statin users who were unable to achieve this target, reduced their risk significantly as well; HR: 0.491 for CVD and 0.487 for all-cause mortality. The authors concluded that in Chinese diabetic patients statin use was associated with a significant decrease in CVD risk and all-cause mortality, especially in those that were able to achieve the target of LDL-C less than 2.6 mmol/L.
Fung CSC, Wan EYF, Chan AKC, Lam CLK. Statin use reduces cardiovascular events and all-cause mortality amongst Chinese patients with type 2 diabetes mellitus: a 5-year cohort study. BMC Cardiovasc Disord 2017; 17:166. http://www.ncbi.nlm.nih.gov/pubmed/?term=28645252
Relevant publications
  1. Kwan AC, Aronis KN, Sandfort V et al. Bridging the gap for lipid lowering therapy: plaque regression, coronary computed tomographic angiography, and imaging-guided personalized medicine. Expert Rev Cardiovasc Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28657444
  2. Wong CJ, Inouye L. What's in a Number? Risk Thresholds in Different Statin Guidelines. Journal of general internal medicine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28664259
  3. Walus-Miarka M, Czarnecka D, Kloch-Badelek M et al. Carotid artery plaques - Are risk factors the same in men and women with familial hypercholesterolemia? Int J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28663044
  4. Slomski A. Nocebo Effect May Account for Statin Adverse Events. Jama 2017; 317:2476. http://www.ncbi.nlm.nih.gov/pubmed/?term=28655010
  5. Sakamoto K, Kawamura M, Watanabe T et al. Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects. Lipids Health Dis 2017; 16:122. http://www.ncbi.nlm.nih.gov/pubmed/?term=28646901
  6. Qiu S, Zhuo W, Sun C et al. Effects of atorvastatin on chronic subdural hematoma: A systematic review. Medicine (Baltimore) 2017; 96:e7290. http://www.ncbi.nlm.nih.gov/pubmed/?term=28658127
  7. Nathan DG. Cholesterol: the debate should be terminated. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2017; 31:2722-2728. http://www.ncbi.nlm.nih.gov/pubmed/?term=28663517
  8. Lin J, Liu H, Jiang J et al. Clinical evidence of efficacy of simvastatin for aneurysmal subarachnoid hemorrhage. J Int Med Res 2017:300060517713803. http://www.ncbi.nlm.nih.gov/pubmed/?term=28661267
  9. Li R, Barton HA. Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis. Clinical pharmacokinetics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28653144
  10. Volpp KG, Troxel AB, Mehta SJ et al. Effect of Electronic Reminders, Financial Incentives, and Social Support on Outcomes After Myocardial Infarction: The HeartStrong Randomized Clinical Trial. JAMA Intern Med 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28654972
  11. Teutonico A, Libutti P, Lomonte C, Basile C. Simvastatin-induced myoglobinuric acute kidney injury following ciclosporin treatment for alopecia universalis. NDT plus 2010; 3:273-275. http://www.ncbi.nlm.nih.gov/pubmed/?term=28657046
  12. Shun-Shin MJ, Francis DP. Is this muscle pain caused by my statin? Bmj 2017; 357:j3030. http://www.ncbi.nlm.nih.gov/pubmed/?term=28645927
  13. Sapey E, Patel JM, Greenwood HL et al. Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Improved by Simvastatin. American journal of respiratory and critical care medicine 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28657793
  14. Sanchez M, Castiella A, Zapata E et al. Autoimmune Hepatitis (Immune-Mediated Liver Injury) Induced By Rosuvastatin. Gastroenterologia y hepatologia 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28655408
  15. McRae I, van Gool K, Hall J, Yen L. Role of Cost on Failure to Access Prescribed Pharmaceuticals: The Case of Statins. Applied health economics and health policy 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28660496
  16. Bays HE, Patel MD, Mavros P et al. Real-world data to assess changes in low-density lipoprotein cholesterol and predicted cardiovascular risk after ezetimibe discontinuation post reporting of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28647412
Miscellaneous publications
  1. Yim DS. Author's response to letter to the editor on: Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharmaceutics & drug disposition 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28656677
  2. Yang Y, Rong X, Lv X et al. Inhibition of mevalonate pathway prevents ischemia-induced cardiac dysfunction in rats via RhoA-independent signaling pathway. Cardiovasc Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28665545
  3. Slupski W, Trocha M, Rutkowska M. Pharmacodynamic and pharmacokinetic interactions between simvastatin and diazepam in rats. Pharmacological reports : PR 2017; 69:943-952. http://www.ncbi.nlm.nih.gov/pubmed/?term=28666152
  4. Pajohanfar NS, Mohebbi E, Hosseini-Bandegharaei A et al. Simvastatin prevents morphine-induced tolerance and dependence in mice. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2017; 93:406-411. http://www.ncbi.nlm.nih.gov/pubmed/?term=28654797
  5. Ozkok E, Yorulmaz H, Ates G et al. The impact of pretreatment with simvastatin on kidney tissue of rats with acute sepsis. Physiology international 2017; 104:158-170. http://www.ncbi.nlm.nih.gov/pubmed/?term=28665194
  6. de Kanter R, Kohl C. Letter to the Editor, Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharmaceutics & drug disposition 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28656708
  7. Jarmuzek D, Pedzinski T, Hoffmann M et al. Experimental and theoretical studies on fluvastatin primary photoproduct formation. Physical chemistry chemical physics : PCCP 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28650504
  8. Fleige M, Glorius F. alpha-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component Coupling - Direct Synthesis of a Versatile Atorvastatin Derivative. Chemistry (Weinheim an der Bergstrasse, Germany) 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=28666059
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