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Update - Week 44, 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

The reality of TG associated residual risk
The US Optum Research database was used to explore the “Real World” residual CV risk of elevated triglycerides (TG) in statin treated individuals. This administrative claim registry allowed for a retrospective observational analysis of patients (>45 years) with diabetes or ASCVD, treated with statins and TG values between 2.26 mmol/l – 5.64 mmol/l (HTG) (N=13 411). Using a propensity score matching procedure these patients were compared to individuals with TG < 1.69 mmol/l and HDL-C > 1.04 mmol/l (N=32 506). Major CV events (MACE) were significantly increased in the HTG patients. MACE HR: 1.35; (1.225–1.485; P<0.001). This was also observed for nonfatal MI, HR: 1.35 (1.19–1.52; P<0.001), nonfatal stroke, HR: 1.27 (1.14–1.42; P<0.001), and coronary revascularization, HR: 1.51; (1.34–1.69; P<0.001). No difference was observed for unstable angina or cardiovascular death. Adding HDL-c plasma concentrations to the multivariate risk model showed similar outcomes in the high and low HDL-c sub groups. Patients with increased TG were also more expensive to care for. Based on total health care costs per month the cost HR for the HTG group was 1.17 (1.084-1.210; p<0.001) as was the HR of hospital admissions/stay; HR: 1.17 (1.113-1.223; p<0.001). In well managed high CV risk patients elevated TG were associated with worse cardiovascular consequences as well as health economic outcomes.
Toth PP, Granowitz C, Hull M et al. High Triglycerides Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: A Real-World Administrative Claims Analysis of Statin-Treated Patients With High Residual Cardiovascular Risk. J Am Heart Assoc 2018; 7:e008740. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371242
Statins First!
The ASCVD risk reducing effects of LDL-c lowering treatments have been established with solid evidence from RCT’s, meta-analyses of RCT’s and acknowledged as such in all major guidelines. Despite the shared LDL-lowering effects of different lipid lowering therapeutic compounds there are controversial differences when evaluating the so-called non-lipid lowering effects. In this real-world retrospective analysis, thrombogenic markers were evaluated in statin intolerant FH patients treated with PCSK9ab mono-therapy by specialists from the Erasmus Medical Center - Lipid Clinic in Rotterdam. Patient received evolocumab (N=19) or Alirocumab (N=18) for a median period of 28 days (14-343). D-Dimer and Fibrinogen plasma levels were measured at baseline and during follow-up visits   No significant differences could be discerned between the baseline levels and subsequent measurement of both biomarkers. These results confirm the absence of substantial anti-thrombotic effects of PCSK9ab therapy. In contrast with statins LDL-c independent anti thrombotic effects, reflected by lower fibrinogen and D-dimer plasma concentrations.  These results re-affirm the importance of prioritizing statin therapy in high CVD risk patients before considering alternative LDL-lowering strategies.
Schol-Gelok S, Galema-Boers J, van Gelder T et al. No effect of PCSK9 inhibitors on D-dimer and fibrinogen levels in patients with familial hypercholesterolemia. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 108:1412-1414. http://www.ncbi.nlm.nih.gov/pubmed/?term=30372843
A new indication for statins?
The role of statins in CVD beyond the canonical ASCVD manifestations is an intriguing one.  The disease of interest in this review was Abdominal Aortic Aneurysm (AAA) related complications. Despite the lack of randomized clinical trials and the observational nature of all studies, the results of this meta-analysis are worthwhile to take note of. The authors screened COCHRANE, MEDLINE and EMBASE libraries from inception until June 15 2018. In all, 911 studies on this topic were uncovered and 1 case control + 21 cohort studies (N=80 42), were included in this systematic review and meta-analysis. Statin use was associated with improved disease progression, rupture and mortality. Mean AAA growth rate reduction of 0.82 mm/year (0.33-1.32; P=0.001, I2 =27%). A reduced risk of AAA rupture, OR: 0.63 (0.51-0.78; P<0.0001, I2=27%) and a lower 30-day mortality after (elective) AAA surgery, OR: 0.55 (0.36-0.83; P=0.005; I2=57%). The compelling result of this meta-analysis indicates the use of statins in AAA patients who do not meet inclusion criteria as dictated by lipid lowering guidelines. The excellent safety profile and low costs reinforces high intensity statin initiation in individuals diagnosed with abdominal aneurysms, even in the absence of hard evidence from RCT’s.
Salata K, Syed M, Hussain MA et al. Statins Reduce Abdominal Aortic Aneurysm Growth, Rupture, and Perioperative Mortality: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2018; 7:e008657. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371297
Barshes NR. Nascent Medical Therapies for Abdominal Aneurysms. J Am Heart Assoc 2018; 7:e010458. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371312
CoQ10 is back (but not with a bang)!
With the introduction of PCSK9ab, statin tolerability has surfaced as a hot debated topic that receives wide spread attention in major medical journals. In this updated meta-analysis, statin induced myopathy and the role of Co-enzyme Q10 (Co-Q10) was probed. Searching COCHRANE, MEDLINE and EMBASE libraries (2007 -2017), the authors were able to identify no less than 868(!) publications on this topic. Only 12, relatively small (N= 36-72) and short duration (30 – 90 days) RCT’s could be included in the final analysis. In total 575 patients were included in these trials; 294 patients using CoQ10 and 281 in the control arm. Patients using Co-Q10 reported improved subjective symptoms, but no changes in CK were observed. For muscle pain the weight mean difference (WMD): -1.60 (-1.75 to -1.44; P<0.001); muscle weakness WMD: -2.28 (-2.79 to -1.77; P=0.006); muscle cramp WMD:  -1.78 (-2.31 to -1.24; P<0.001), and muscle tiredness WMD: -1.75 (-2.31 to -1.19; P<0.001). Although the overall evidence, based on size duration and heterogeneity of the included clinical trials, is not overwhelming, the authors do suggest that Co-Q10 supplementation could be a complementary strategy to improve myopathy symptoms.
Qu H, Guo M, Chai H et al. Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 2018; 7:e009835. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371340
Using PCSK9ab in FH, one size fits all?
The diagnosis of FH is associated with a very high risk for ASCVD and statin eligibility embraced by all major guidelines. With the introduction of PCSK9ab’s in out therapeutic armentarium, FH patients are first and foremost indicated for this very effective LDL-c reducing treatment. However, the price for PCSK9ab is much hihger than standard statins or statins + ezetimibe. In this article coronary calcium (CAC) scoring was evaluated to improve selecting asymptomatic FH patients for intensive combination lipid lowering treatment with statins + ezetimibe and  PCSK9ab. The authors conducted a prospective follow up study that included 206 FH patients using standard lipid lowering therapy. Their mean age was 46 ±14 years, 36,4% were males and their mean baseline LDL- c was 269 ±70 mg/dl (150 ± 56 mg/dl on treatment). A positive CAC score was observed in 105 (51%) of the patients and during the mean follow up time of 3.7 years (2.6-6.8) years, 15 ASCVD events were observed in 7.2% of the participants. Patients were divided in 3 CAC score groups: 0 (n=101); 1 to 100 (N=62) and >100 (N=43). The annualized event rates, per 1000 patients, were respectively 0; 26.4 (12.9-51.8) and 44.1 (26.0-104.1). Based on a multivariate Cox regression analysis the log CAC score+1 showed a statistically significant positive correlation with ASCVD complications, HR 3.33(1.635-6.790; p=0.001). Using CAC scoring in FH patient could fulfill a dual purpose, first by filtering out the ones with a negative or 0 CAC score in whom standard therapy is sufficient versus the FH patients with a positive score were novel lipid lowering agents such as PCSK9 ab can be used to aggressively lower the LDL-c too very low levels and optimally reduce their ASCVD risk. Most likely this will be a cost-effective strategy as well!
Miname MH, Bittencourt MS, Moraes SR et al. Coronary Artery Calcium and Cardiovascular Events in Patients With Familial Hypercholesterolemia Receiving Standard Lipid-Lowering Therapy. JACC Cardiovasc Imaging 2018. PM: http://www.ncbi.nlm.nih.gov/pubmed/?term=30448145
Relevant publications
  1. Vallejo-Vaz AJ, Ginsberg HN, Davidson MH et al. Lower On-Treatment Low-Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials. J Am Heart Assoc 2018; 7:e009221. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371190
  2. Tuteja S, Qu L, Vujkovic M et al. Genetic Variants Associated With Plasma Lipids Are Associated With the Lipid Response to Niacin. J Am Heart Assoc 2018; 7:e03488. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371334
  3. Tryggvadottir H, Huzell L, Gustbee E et al. Interactions Between ABCB1 Genotype and Preoperative Statin Use Impact Clinical Outcomes Among Breast Cancer Patients. Frontiers in oncology 2018; 8:428. http://www.ncbi.nlm.nih.gov/pubmed/?term=30370250
  4. Takaguri A. [Elucidation of a New Mechanism of Onset of Insulin Resistance: Effects of Statins and Tumor Necrosis Factor-alpha on Insulin Signal Transduction]. Yakugaku Zasshi 2018; 138:1329-1334. http://www.ncbi.nlm.nih.gov/pubmed/?term=30381640
  5. Srivanichakorn W, Godsland IF, Washirasaksiri C et al. Cardiometabolic risk factors in Thai individuals with prediabetes treated in a high-risk, prevention clinic - unexpected relationship between HDL cholesterol and glycaemia in men. Journal of diabetes investigation 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30387292
  6. Shah T, Virani SS. Lipid-Lowering Therapies: Risks in Women and Evidence-Based Options. Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 2018; 45:238-239. http://www.ncbi.nlm.nih.gov/pubmed/?term=30374235
  7. Lowenstern AM, Li S, Navar AM et al. Measurement of Low-Density Lipoprotein Cholesterol Levels in Primary and Secondary Prevention Patients: Insights From the PALM Registry. J Am Heart Assoc 2018; 7:e009251. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371214
  8. Kim J, Park KT, Jang MJ et al. High-Intensity Versus Non-High-Intensity Statins in Patients Achieving Low-Density Lipoprotein Cholesterol Goal After Percutaneous Coronary Intervention. J Am Heart Assoc 2018; 7:e009517. http://www.ncbi.nlm.nih.gov/pubmed/?term=30376751
  9. Havers FP, Chung JR, Belongia EA et al. Influenza Vaccine Effectiveness and Statin Use Among Adults in the United States, 2011-2017. Clin Infect Dis 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30371753
  10. Kajinami K, Ozaki A, Tajima Y et al. Real-World Data to Identify Hypercholesterolemia Patients on Suboptimal Statin Therapy. J Atheroscler Thromb 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30369517
  11. Hussain MA, Saposnik G, Raju S et al. Association Between Statin Use and Cardiovascular Events After Carotid Artery Revascularization. J Am Heart Assoc 2018; 7:e009745. http://www.ncbi.nlm.nih.gov/pubmed/?term=30369318
  12. Firouzi A, Kazem Moussavi A, Mohebbi A et al. Comparison between rosuvastatin and atorvastatin for the prevention of contrast-induced nephropathy in patients with STEMI undergoing primary percutaneous coronary intervention. Journal of cardiovascular and thoracic research 2018; 10:149-152. http://www.ncbi.nlm.nih.gov/pubmed/?term=30386535
  13. Cheng Y, Sun T, Yin C et al. Downregulation of PTEN by sodium orthovanadate protects the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment. Journal of cellular biochemistry 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30368869
  14. Cavallari I, Delli Veneri A, Maddaloni E et al. Comparison of Lipid-Lowering Medications and Risk for Cardiovascular Disease in Diabetes. Current diabetes reports 2018; 18:138. http://www.ncbi.nlm.nih.gov/pubmed/?term=30370486
  15. Schousboe JT, Kats AM, Langsetmo L et al. Central Obesity and Visceral Adipose Tissue Are Not Associated With Incident Atherosclerotic Cardiovascular Disease Events in Older Men. J Am Heart Assoc 2018; 7:e009172. http://www.ncbi.nlm.nih.gov/pubmed/?term=30369326
  16. Rahim F, Sayyah M. Effects of atorvastatin on treatment-resistant obsessive-compulsive disorder: A double-blind randomized trial. Psychiatria polska 2018; 52:719-729. http://www.ncbi.nlm.nih.gov/pubmed/?term=30368541
  17. Adhyaru BB, Jacobson TA. Safety and efficacy of statin therapy. Nat Rev Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30375494
Miscellaneous publications
  1. Park KY, Heo TH. Combination therapy with cilostazol and pravastatin improves antiatherogenic effects in LDLR KO mice. Cardiovasc Ther 2018:e12476. http://www.ncbi.nlm.nih.gov/pubmed/?term=30378752
  2. Medeiros ADC, Azevedo IM, Lima ML et al. Effects of simvastatin on 5-fluorouracil-induced gastrointestinal mucositis in rats. Revista do Colegio Brasileiro de Cirurgioes 2018; 45:e1968. http://www.ncbi.nlm.nih.gov/pubmed/?term=30379218
  3. Lin PY, Lee FY, Wallace CG et al. Corrigendum to "The therapeutic effect of rosuvastatin and propylthiouracil on ameliorating high-cholesterol diet-induced rabbit aortic atherosclerosis and stiffness" [Int. J. Cardiol. 227 (2017) 938-949]. Int J Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30384978
  4. Ahmadi Y, Karimian R, Panahi Y. Effects of statins on the chemoresistance-The antagonistic drug-drug interactions versus the anti-cancer effects. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 108:1856-1865. http://www.ncbi.nlm.nih.gov/pubmed/?term=30372891
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