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Update - Week 47,  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

Smart tools to predict who will be non-adherent to statins
The emphasis in managing patients at risk for CVD has mostly been directed at initiating the right statin to achieve a guideline dictated LDL-C goal. The fact that many, some even suggest the majority, of the patients stop their medication has been undervalued and needs to be attended to. Improving medication adherence is a time and resource intensive activity, being able to predict and identify non-adherent patients would allow for more efficient resource allocation. In this study, the authors created a be spoked electronic health record (HER) based model and link statin adherence to biological and clinical outcome data. They had access to the US Military Health System that collects medical data from all active and non-active military personnel plus their dependents. Patients that started statins between 2005 and 2006 were included in this analysis. Adherence was defined as filling prescriptions > 80% of days covered. Adherence rates were coupled with cholesterol reductions and CVD hospitalizations for the following 5 years after statin initiation. In total data of 138 731 patients were included and screened for 30 independent EHR factors. The model produced a C-statistics result of 0.73 for classifying statin non-adherence. Statin adherence was associated with greater cholesterol reduction; correlation 0.14 p<1 e-20) and lower hospitalizations for CVD and stroke; HR 0.84 p< 0.00001). Using this model would enable physicians to predict statin adherence and related cardiovascular benefits. They would be able to target specific patients at risk for non-adherence such as patients with chronic pain and start with personalized approaches to improve adherence.
Lucas JE, Bazemore TC, Alo C et al. An electronic health record based model predicts statin adherence, LDL cholesterol, and cardiovascular disease in the United States Military Health System. PLoS One 2017; 12:e0187809. http://www.ncbi.nlm.nih.gov/pubmed/?term=29155848
 
Is measuring β-sitosterol relevant in FH patients?
Sitosterolemia, increased absorption of plant sterol is more common that previously assumed. In this US investigation of 451,843 blood samples analysed for lipids and lipoproteins by Boston Heart Diagnostics over a 30-month period. After filtering exclusion criteria 207 926 samples remained for further analysis. Elevated LDL-C (>190 mg/dl) was discovered in 4.3% of the samples in those individuals and a plasma β-sitosterol concentrations >8.0 mg/L (99th percentile) was found in 4.3%. Only 0.72% of participants with an LDL-C <130 mg/dl. Very elevated β-sitosterol concentrations >15.0 mg/L, reflecting sitosterolemia, was found in only 0.050% of all ± 208 000 samples. Selecting samples with LDL-C >190 mg/dl resulted in 0.334% with a sitosterolemia phenotype. Based on this study approximately 4% of patients with LDL-C >190 mg/dl, reflecting a potential FH cholesterol, have elevated β-sitosterol concentrations (>99th percentile). Sitosterolemia can be a problem for ± 1:300 of these hypercholesterolemic patients. Since treatment strategies for elevated β-sitosterol concentrations require cholesterol absorption inhibitors (ezetimibe) measuring this plant sterol concentrations could be clinically relevant.
Brinton EA, Hopkins PN, Hegele RA et al. The association between hypercholesterolemia and sitosterolemia, and report of a sitosterolemia kindred. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29169939
 
Diabetics hyper-coaguability reduced by statins and/or ACEi-ARB’s
The ASCVD risk reducing effects of statins are not only reflected by their LDL-C reducing properties. Other mechanisms could play a role and are subject of numerous investigations. In this relatively small Turkish study, 95 diabetic patients were divided in 4 groups: only statin use (N=15); Only ACEi/ARB use (N=31); Statin + ACEi/ARB use (N=23) and neither statin or ACEi/ARB use (N=26). The coagulant parameters:  protein C, protein S, fibrinogen, D-dimer, INR, PTT and aPTT were evaluated in the 4 groups. No differences between the four groups were discernable for protein S, INR, aPTT, and D-dimer levels. Protein C levels were statistically significantly higher in patients using statins ACEi/ARBs or a both as compared to patients that used neither medications (P<0.01). Fibrinogen plasma concentrations were higher in patients that used both regimens as compared to neither, as well. The authors suggested that the observed anti-coaguable effects in patients using statins and/or ACEi/ARB’s could contribute to ASCVD risk reduction observed in diabetic patients using these types of drugs.
Aktas S, Ucak S, Kurt F et al. Evaluation of protein c and protein s levels in patients with diabetes mellitus receiving therapy with statins and ace inhibitors or angiotensin II receptor blockers. Diabetes Res Clin Pract 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29155121
 
Statins for …… Are you crazy?
The issue of cognitive impairment and CNS side effects of lipid lowering drugs in general but specifically statins and PCSK9ab have challenged patient – doctor relationships when discussing the benefits and potential harms. Especially prominent are the claims of the so called “cholesterol sceptics”, who voice their, predominantly unscientific, opinion using social media and YouTube channels. This week the statin literature update included a meta-analysis examining the benefits of statins in schizophrenic patients. Not only do anti-psychotics have a negative impact on plasma lipids, schizophrenia by itself is also associated with dyslipidemia and increased inflammatory markers. Inflammation not only plays a role in expression of this disease but treatment, using anti-inflammatory drugs, have shown improvements. For this meta-analysis the authors used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of the 324 unique articles identified, only 5 randomized, placebo controlled clinical trials, of sufficient quality, were included in this meta-analysis.  Overall 236 adult patients participated in trials with an average duration of 9.2 weeks. Placebo was used by 117 patients and statins by 119. In the pooled analysis statins were significantly superior, compared to placebo, based on the improvements of the Positive and Negative Syndrome Scale (PANSS). No significant changes in additional secondary endpoints were noted; but number of participants was quite small when subgroups were analyzed. The authors concluded that based on their aggregated data statins seem to have substantial potential to be used as add on to anti-psychotic medication as well as reducing the substantial CVD risk associated reflected by their significant hyperlipidemia.
Nomura I, Kishi T, Ikuta T, Iwata N. Statin add-on therapy in the antipsychotic treatment of schizophrenia: A meta-analysis. Psychiatry research 2017; 260:41-47. http://www.ncbi.nlm.nih.gov/pubmed/?term=29172097
 
Did women IMPROVE(-IT) with a statin + Ezetimibe?
Women and CHD risk has been a neglected topic in CVD research and clinical trials. Publications, such as this sub-analysis of the IMPROVE-IT trial, highlight the importance of aggressively addressing CVD risk factors women as well the impressive impact this can have. Although women are less prone to ASCVD complications before menopause, they catch up, and numerical more women succumb to CVD than men. The risk for recurrence in female ACS survivors is much higher compared to men as well. They are older and have a higher prevalence of CVD risk factors such as hypertension, hypercholesterolemia and diabetes. In secondary prevention, lowering LDL-c in women provides comparable relative risk reductions however the impact on absolute risk is more striking. The IMPROVE-IT study included 18 144 post ACS patients and 4 416 (24%) were women. Overall women experienced a 12% relative risk reduction; HR, 0.88(0.79–0.99), vs 5%; HR 0.95 (0.90–1.01; P=0.26 for interaction) in men. In women the total number of events was reduced by 18% HR 0.81 (0.71–0.94) vs. 6%; HR 0.94 (0.87–1.01; P=0.08 for interaction) in men. In women with ≥3 CVD risk factors the event rate was ≈3 times greater compared to women ≤1 risk factor. In these high-risk women, the impact of statin + ezetimibe not only started early but showed a 27% relative risk and an impressive 7.4% absolute risk reduction of the primary endpoint. No increased safety events were recorded in the men and female participants. The authors concluded that the combination of simvastatin + ezetimibe was a safe and efficacious intensive lipid lowering intervention that significantly reduced recurrent ASCVD events in men as well as in women.
Kato ET, Cannon CP, Blazing MA et al. Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29151034
 
Do Statins protect after an MI? Depends on NP levels and LVEF!
The CORONA and GISI-Heart Failure trials were unable to demonstrate benefits of rosuvastatin in patients with (advanced) heart failure (HF). If patients, with less severe HF, would be protected from ASCVD complications when using a statin is still uncertain. The authors of this study used data collected (November 2005 to July 2014) in the Korean Acute Myocardial Infarction Registry (KAMIR) and the Korea Working Group on Myocardial Infarction (KorMI) registry. They evaluated the impact of statins in patients stratified by natriuretic peptide (NP), B-type NP and NT-ProBNP plasma levels as well as reduced left ventricular ejection fraction (LVEF) < 40%.  Overall data from 11 492 AMI patients could be assessed, 9 075 (79%) were discharged with a statin and 2 417 (21%) did not use a statin. Patients were evaluated after one year follow up for mortality and major coronary outcomes (MCO): cardiac death, non-cardiac death, recurrent MI, and repeat percutaneous coronary interventions or coronary artery bypass grafting. Statin therapy was associated with a 27.8 % lower MCO hazard. Only patients in the two top quartiles of NP levels showed reduced all-cause mortality as well. However improved outcomes were only observed in patients with a LVEF >40%. The authors concluded that by using a moderate – high intensity statin, MCO’s and mortality were reduced, but only if NP levels were elevated. In patients with reduced LVEF’s, statins were unable to demonstrate benefits.
Cho J, Park IB, Lee K et al. Statin has more protective effects in AMI patients with higher plasma BNP or NT-proBNP level, but not with lower left ventricular ejection fraction. J Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29158023
Relevant publications
  1. Wakabayashi K, Ikeda N, Kajimoto K et al. Trends and predictors of non-cardiovascular death in patients hospitalized for acute heart failure. Int J Cardiol 2018; 250:164-170. http://www.ncbi.nlm.nih.gov/pubmed/?term=29169753
  2. Szczepanik A, Hulbert A, Lee HJ et al. Effect of HMG CoA reductase inhibitors on the development of chronic lung allograft dysfunction. Clinical transplantation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29151274
  3. Pavlovic J, Greenland P, Deckers JW et al. Assessing gaps in cholesterol treatment guidelines for primary prevention of cardiovascular disease based on available randomised clinical trial evidence: The Rotterdam Study. Eur J Prev Cardiol 2017:2047487317743352. http://www.ncbi.nlm.nih.gov/pubmed/?term=29171772
  4. Orho-Melander M, Hindy G, Borgquist S et al. Blood lipid genetic scores, the HMGCR gene and cancer risk: a Mendelian randomization study. International journal of epidemiology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29165714
  5. Nishio T, Taura K, Nakamura N et al. Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection: a subgroup analysis of patients without chronic hepatitis viral infection. Surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29167018
  6. Nahar D. Prophylactic Management of Contrast-Induced Acute Kidney Injury in High-Risk Patients. Nephrology nursing journal : journal of the American Nephrology Nurses' Association 2017; 44:244-249. http://www.ncbi.nlm.nih.gov/pubmed/?term=29165956
  7. Mrotzek SM, Rassaf T, Totzeck M. Ticagrelor Leads to Statin-Induced Rhabdomyolysis: A Case Report. Am J Case Rep 2017; 18:1238-1241. http://www.ncbi.nlm.nih.gov/pubmed/?term=29167415
  8. Koh KK, Nam CW, Chao TH et al. A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29153823
  9. Hwong WY, Abdul Aziz Z, Sidek NN et al. Prescription of secondary preventive drugs after ischemic stroke: results from the Malaysian National Stroke Registry. BMC Neurol 2017; 17:203. http://www.ncbi.nlm.nih.gov/pubmed/?term=29169331
  10. Farnier M. Alirocumab for the treatment of hyperlipidemia in high-risk patients: an updated review. Expert Rev Cardiovasc Ther 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29171769
  11. Eindhoven DC, Hilt AD, Zwaan TC et al. Age and gender differences in medical adherence after myocardial infarction: Women do not receive optimal treatment - The Netherlands claims database. Eur J Prev Cardiol 2017:2047487317744363. http://www.ncbi.nlm.nih.gov/pubmed/?term=29164916
  12. Wallemacq C. [Evolocumab (Repatha(R)) : a human monoclonal antibody against PCSK9 protein as potent cholesterol-lowering therapy]. Revue medicale de Liege 2017; 72:505-512. http://www.ncbi.nlm.nih.gov/pubmed/?term=29171950
  13. Tshongo Muhindo C, Ahn SA, Rousseau MF et al. Efficacy and safety of a combination of red yeast rice and olive extract in hypercholesterolemic patients with and without statin-associated myalgia. Complementary therapies in medicine 2017; 35:140-144. http://www.ncbi.nlm.nih.gov/pubmed/?term=29154060
  14. Stefanutti C, Mazza F, Mesce D et al. Corrigendum to "Monascus purpureus for statin and ezetimibe intolerant heterozygous familial hypercholesterolaemia patients: A clinical study" [Atherosclerosis (Supplements) 30C (2017) 86-91]. Atherosclerosis. Supplements 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29153764
  15. Pascual Fuster V. [Usefulness of plant sterols in the treatment of hypercholesterolemia]. Nutricion hospitalaria 2017; 34:62-67. http://www.ncbi.nlm.nih.gov/pubmed/?term=29156935
  16. Kodera S, Kiyosue A, Ando J et al. Cost-Effectiveness Analysis of Cardiovascular Disease Treatment in Japan. Int Heart J 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29151496
  17. Kang WY, Seong SJ, Ohk B et al. Pharmacokinetics and bioequivalence of a rosuvastatin/ezetimibe fixed-dose combination tablet versus single agents in healthy male subjects. International journal of clinical pharmacology and therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29162214
  18. Escobar C, Barrios V, Perez de Isla L. [Optimal cholesterol levels in patients in real-life. A systematic review]. Semergen / Sociedad Espanola de Medicina Rural y Generalista 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29153337
Miscellaneous publications
  1. Yu P, Xiong T, Tenedero CB et al. Rosuvastatin Reduces Aortic Sinus and Coronary Artery Atherosclerosis in SR-B1 (Scavenger Receptor Class B Type 1)/ApoE (Apolipoprotein E) Double Knockout Mice Independently of Plasma Cholesterol Lowering. Arterioscler Thromb Vasc Biol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29162602
  2. Song M, Chen FF, Li YH et al. Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury. Journal of cachexia, sarcopenia and muscle 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29152896
  3. Marques NF, Castro AA, Mancini G et al. Atorvastatin Prevents Early Oxidative Events and Modulates Inflammatory Mediators in the Striatum Following Intranasal 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Administration in Rats. Neurotox Res 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29164519
  4. Madasamy S, Liu D, Lundry J et al. Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles. Journal of visualized experiments : JoVE 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29155776
  5. Li H, Zhao Q, Liu R et al. Protective Effect and Potential Mechanism of Simvastatin on Myocardial Injury Induced by Diabetes with Hypoglycemia. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29165724
  6. Bonnet F. [Should statin therapy be discontinued in the elderly?]. La Revue de medecine interne / fondee ... par la Societe nationale francaise de medecine interne 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29157754
  7. Yao H, Lv J. Statin Attenuated Myocardial Inflammation Induced by PM2.5 in Rats. Acta Cardiologica Sinica 2017; 33:637-645. http://www.ncbi.nlm.nih.gov/pubmed/?term=29167617
  8. Porfire A, Muntean DM, Rus L et al. A quality by design approach for the development of lyophilized liposomes with simvastatin. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 2017; 25:981-992. http://www.ncbi.nlm.nih.gov/pubmed/?term=29158704
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This activity is supported by an educational grant from Pfizer.