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Update - Week 11, 2019
 
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

CVD risk in PAD patients with an LDL-c >100 mg/dl vs < 100 mg/dl
The CV risk associated with peripheral artery disease (PAD) is substantial. Management strategies in PAD are directed at reducing ischemia related complaints as well as minimizing PAD progression as well as lowering the risk for additional ASCVD complications. The impact of lowering cholesterol, by means of statin prescription, was evaluated in this study. Between 2010 and 2016, 1324 Japanese PAD patients had an endovascular procedure because of severe claudication complaints (Rutherford category 1-3). Eligibility for the proposed analysis was confirmed in 935 patients (average age 72.1 years and 75% were men). Statins were used by 509 (54.4%) of the included patients; no data was available on statin type and intensity. LDL-c levels were analyzed at 3- and 6-months post-procedure and correlated with CV events at 5-years. Median LDL-c in this cohort was 94 mg/dl.  Based on this value, a cut-off level of 100 mg/dl was selected as stratifying factor. After a median follow-up period of 30.7 months, 83 (8.9%) of the patients suffered a CVD related complication. After 5 years CVD complications were more frequently observed in patients with an LDL-c > 100 mg/dl (at 3 and 6 months) compared to those with an LDL-c < 100 mg/dl.; 23.5% vs 13.5% (P=0.003). CVD risk was also significantly increased In patients that not used statins; 25.2% vs 10.9% (P=0.02). Based on multivariate statistical analysis, an LDL-c ≥100 mg/dl, 3 and 6 months after a vascular surgical intervention, was associated with a substantially elevated CVD risk. This risk was also observed in sub-optimally treated statin users, as reflected by an LDL-c ≥100 mg/dl. To improve clinical outcomes in PAD patients, strategies directed at more intensive treatment regimens need to be updated and improved.
Tomoi Y, Yamaji K, Soga Y et al. Serum Low-Density Lipoprotein Cholesterol Level After Endovascular Therapy in Patients With Claudication. Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists 2019:1526602819836382. http://www.ncbi.nlm.nih.gov/pubmed/?term=30873910
 
Remnant cholesterol predictive of AS risk – even when LDL<70mg/dl
Despite optimal statin therapy, reflected by achieving an LDL-c < 70 mg/dl, a significant percentage of patients are not fully protected from CVD complications. This so-called residual risk is partly related to remnant particles; triglyceride-rich lipoproteins. In this multi-center retrospective, observational study, 587 Australian patients that, between 2010 and 2016, had a CT-angiography (CTA), were evaluated. Lipid profiles were obtained <3 months prior to the angiographic procedure. Remnant cholesterol was defined as total cholesterol minus LDL-cholesterol and HDL-cholesterol. Optimal LDL-c was defined as <70 mg/dl, this was observed in 134 patients (23%); 82% of those were using a statin. Significant AS burden was defined as a CT Lehman score >5 (CT-LeSc). Patients with a CT-LeSc >5 had a significant higher remnant concentration, compared to patients with a CT-LeSc ≤5; 0.76 ± 0.36 mmol/L vs. 0.58 ± 0.33 mmol/L (p=0.01), respectively. In patients with optimal LDL-c levels, remnant concentrations remained predictive of having a CT-LeSc >5; OR 3.87 (1.34–7.55, p=0.004). After univariate analysis, remnant cholesterol (P0.001) LDL-c, HDL-c, LDLC (p=0.002) and HDLC (p < 0.001) levels predicted CT-LeSc>5. triglycerides (p=0.79) were not associated with a CT-LeSc>5. Multivariate analyses corrected for HDL-c and traditional risk factors. In the subset of patients with optimal LDLC, remnant cholesterol levels remained predictive of a CTLeSc >5; OR 3.87 (1.34–7.55, p=0.004). The authors concluded that remnant cholesterol concentrations were predictive for more severe atherosclerosis, even in patients with optimal LDL-c levels. If lowering remnant cholesterol reduces AS progression and CVD risk will need to be evaluated in prospective randomized clinical trials.
Lin A, Nerlekar N, Rajagopalan A et al. Remnant cholesterol and coronary atherosclerotic  plaque burden assessed by computed tomography coronary angiography. Atherosclerosis 2019; 284:24-30. http://www.ncbi.nlm.nih.gov/pubmed/?term=30870704
 
Statin in diabetics produced similar improved plaque characteristics as in non-diabetics
In this study the authors compared diabetic patients with non-diabetic patients to evaluate the effects of statin on plaque changes, using optical coherence tomography (OCT). Patients were included from the Massachusetts General Hospital OCT Registry and a prospective randomized trial entitled “Evaluation of Statin-induced Lipid-rich Plaque Progression by Optical Coherence Tomography (OCT) Combined With Intravascular Ultrasound (IVUS).  In total 90 patients (41 diabetics/54 plaques and 49 non-diabetics. 63 plaques) that underwent serial OCT examinations and treated with statins, were included in this retrospective analysis. After a mean follow-up period of 362 ±38 days, changes in minimum fibrous cap thickness (FCT) and lipid index were compared. Both diabetics and non-diabetics showed improved FCT and lipid index. Percent changes of minimum FCT (p = 0.796) and lipid index (p = 0.336) were comparable in both groups. Statin therapy was able to produce a significant FCT increase as well as lipid index decrease, in both groups. Kurihara O, Thondapu V, Kim HO et al. Comparison of Vascular Response to Statin Therapy in Patients With Versus Without Diabetes Mellitus. Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30851939
 
Statin-on-board improves survival in patients that suffered cardiac arrest
The National Health Insurance (NHI) program was launched in 1995 and includes >99% of the Taiwanese population of 23.74 million people. This registry was used to evaluate the effects of “statin-on-board” in patients that suffered a cardiac arrest. Between 2004 and 2011, 142,131 adult patients suffered a cardiac arrest. Patients were grouped in the statin group if they used statins > 30 days prior to the cardiac arrest and statin naïve if no statins were used within 30 days of the event. Survival between the arrest and hospital discharge was superior in the patients that used statins vs the statin naïve patients, 6.1% vs 4.3%, (p <0.0001), respectively. An improved survival remained significant after 1-year in statin users, 4.8% vs 3.2% (p <0.0001). Using a propensity score matching model, the calculated odds ratio of 1-year survival showed a significantly better outcome in the statin-users group; OR 1.41 (1.16-1.71; p = 0.001). In patients with Diabetes, CKD and a Charlson Comorbidity Index score greater than 5, the improved outcomes in statin users were preserved. The authors concluded that statin use before a cardiac arrest is associated with a significant survival benefit, a surprising benefit in patients at risk for cardiac arrest.  
Huang CH, Yu PH, Tsai MS et al. Relationship Between Statin Use and Outcomes in Patients Having Cardiac Arrest (from a Nationwide Cohort Study in Taiwan). Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30851940
 
Goals in lipid management; comparing percentage- vs absolute targets
In several of the updated lipid management guidelines, a dual strategy is proposed to optimally treat LDL-c, aiming for therapeutic targets of an LDL-c < 2.3/1.8 mmol/l and/or a percentage LDL-c reduction > 30/50%. The authors of this article aimed to evaluate the success of reaching targets in a real world setting when comparing both strategies. The study was conducted in 583 family physician practices as well as 101 specialists; they evaluated 5652patients (median age 60.6 years; 48% males). The treat to target approach was observed in 4302 patients and the remaining 1350 aimed for a percentage reduction. Patients were treated, in non-randomized fashion, with rosuvastatin and followed for 52 weeks. Visits were planned at 2, 6 and 12 months. In very high-risk patients, using a treat to target (<1.8 mmol/dl) vs > 50% LDL-c reductions were successful in  30.1% vs 23.2%. In the patients categorized as high risk, the patients that successfully reached the respective targets were 68.6% vs 58.1%. When comparing the dosages used in the two treatment strategies no difference was observed for patients using the 10 mg dosage (25% vs 23%), the 20 mg dosage was less frequently used by patients aiming for an absolute target of an LDL-c <2.3 mmol/l, 58% vs 64%. The 40 mg dosage was used more often in this group, 15% vs 12%. However, the superior percentages reduction could not be explained by a higher statin dosage. Higher baseline LDL-c (>3.9 mmol/l) was more frequently observed in the statin naïve high-risk patients compared to the previously statin-treated patients (LDL-c 3.6 mmol/l,) this partly explained that the percentage reduction strategy was superior. In the very high-risk patients, no statistical difference was observed between the two strategies, despite a similar higher LDL-c in the statin naïve vs previous statin users. The authors concluded that the percentage reduction strategy was superior in the high risk, statin naïve patients with an LDL-c ≥3.9 mmol/l.
Csaszar A. The characteristics of two LDL-cholesterol level reduction treatment strategies, "treat-to-target" and "percent reduction": an observational study without intervention. BMC Cardiovasc Disord 2019; 19:57. http://www.ncbi.nlm.nih.gov/pubmed/?term=30857520
 
 
Relevant publications
  1. Thondapu V, Kurihara O, Yonetsu T et al. Comparison of Rosuvastatin Versus Atorvastatin for Coronary Plaque Stabilization. Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30851941
  2. Suzuki K, Oikawa T, Nochioka K et al. Elevated Serum Non-HDL (High-Density Lipoprotein) Cholesterol and Triglyceride Levels as Residual Risks for Myocardial Infarction Recurrence Under Statin Treatment. Arterioscler Thromb Vasc Biol 2019:Atvbaha119312336. http://www.ncbi.nlm.nih.gov/pubmed/?term=30866657
  3. Ray KK, Bays HE, Catapano AL et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med 2019; 380:1022-1032. http://www.ncbi.nlm.nih.gov/pubmed/?term=30865796
  4. Lutjohann D, Stellaard F, Mulder MT et al. The emerging concept of "individualized cholesterol-lowering therapy": A change in paradigm. Pharmacology & therapeutics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30877023
  5. Miedema MD, Nauffal VD, Singh A, Blankstein R. Statin therapy for young adults: A long-term investment worth considering. Trends Cardiovasc Med 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30808553
  6. Yeboah J. Statin for primary prevention of atherosclerotic cardiovascular disease in young adults: Are we there yet? Trends Cardiovasc Med 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30876793
  7. Ledru F. [Secondary cardiovascular prevention strategies]. Rev Prat 2018; 68:439-445. http://www.ncbi.nlm.nih.gov/pubmed/?term=30869397
  8. Kwak A, Kim JH, Choi CU et al. Comparative effectiveness of statins in secondary prevention among the older people aged 75 years and over. Int J Clin Pharm 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30864086
  9. Kim K, Lee CJ, Shim CY et al. Statin and clinical outcomes of primary prevention in individuals aged >75years: The SCOPE-75 study. Atherosclerosis 2019; 284:31-36. http://www.ncbi.nlm.nih.gov/pubmed/?term=30870705
  10. Khalil S, Khayyat S, Al-Khadra Y, Alraies MC. Should all diabetic patients take statin therapy regardless of serum cholesterol level? Expert Rev Cardiovasc Ther 2019:1-3. http://www.ncbi.nlm.nih.gov/pubmed/?term=30856356
  11. Jiang Y, Ni W. Economic Evaluation of the 2016 Chinese Guideline and Alternative Risk Thresholds of Initiating Statin Therapy for the Management of Atherosclerotic Cardiovascular Disease. PharmacoEconomics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30875022
  12. Ihm SH, Shin J, Park CG, Kim CH. Efficacy of a fixed dose combination of irbesartan and atorvastatin (Rovelito((R))) in Korean adults with hypertension and hypercholesterolemia. Drug design, development and therapy 2019; 13:633-645. http://www.ncbi.nlm.nih.gov/pubmed/?term=30858694
  13. Hopkin G, Au A, Collier VJ et al. Combining Multiple Treatment Comparisons with Personalized Patient Preferences: A Randomized Trial of an Interactive Platform for Statin Treatment Selection. Med Decis Making 2019:272989x19835239. http://www.ncbi.nlm.nih.gov/pubmed/?term=30873906
  14. Hamoui O, Omar MI, Raal FJ et al. Increases in statin eligibility to reduce cardiovascular risk according to the 2013 ACC/AHA cholesterol guidelines in the Africa Middle East region: a sub-analysis of the Africa Middle East Cardiovascular Epidemiological (ACE) study. BMC Cardiovasc Disord 2019; 19:61. http://www.ncbi.nlm.nih.gov/pubmed/?term=30876390
  15. Dixon DL, Pamulapati LG, Bucheit JD et al. Recent Updates on the Use of PCSK9 Inhibitors in Patients with Atherosclerotic Cardiovascular Disease. Curr Atheroscler Rep 2019; 21:16. http://www.ncbi.nlm.nih.gov/pubmed/?term=30877491
  16. Chen ST, Huang ST, Shau WY et al. Long-term statin adherence in patients after hospital discharge for new onset of atherosclerotic cardiovascular disease: a population-based study of real world prescriptions in Taiwan. BMC Cardiovasc Disord 2019; 19:62. http://www.ncbi.nlm.nih.gov/pubmed/?term=30876393
  17. Abed E, LaBarbera B, Dvorak J et al. Prevalence of dyslipidemia and factors affecting dyslipidemia in young adults with type 1 diabetes: evaluation of statin prescribing. J Pediatr Endocrinol Metab 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30860978
  18. Yamamoto H, Kawamura M, Kochi I et al. Serum Anti-Apo B Antibody Level as Residual CVD Marker in DM Patients under Statin Treatment. J Atheroscler Thromb 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30867375
  19. Torres-Robles A, Wiecek E, Cutler R et al. Using Dispensing Data to Evaluate Adherence Implementation Rates in Community Pharmacy. Frontiers in pharmacology 2019; 10:130. http://www.ncbi.nlm.nih.gov/pubmed/?term=30863308
  20. Sabouret P, Farnier M, Puymirat E. [PCSK9 inhibitors: What place in the management of dyslipidemia?]. Presse medicale (Paris, France : 1983) 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30853281
  21. Riaz H, Khan SU, Rahman H et al. Effects of high-density lipoprotein targeting treatments on cardiovascular outcomes: A systematic review and meta-analysis. Eur J Prev Cardiol 2018:2047487318816495. http://www.ncbi.nlm.nih.gov/pubmed/?term=30861690
  22. Lundberg E, Hagberg O, Jahnson S, Ljungberg B. Association between occurrence of urinary bladder cancer and treatment with statin medication. Turkish journal of urology 2019; 45:97-102. http://www.ncbi.nlm.nih.gov/pubmed/?term=30875287
  23. Kluger G, von Stulpnagel-Steinbeis C, Arnold S et al. Positive Short-Term Effect of Low-Dose Rosuvastatin in a Patient with SYNGAP1-Associated Epilepsy. Neuropediatrics 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30875700
  24. Kirkegard J, Lund JL, Mortensen FV, Cronin-Fenton D. Statins and Pancreatic Cancer Risk in Patients with Chronic Pancreatitis: A Danish nationwide population-based cohort study. International journal of cancer. Journal international du cancer 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30861115
  25. Kim KM, Jung KY, Yun HM et al. Retraction Note: Effect of rosuvastatin on fasting and postprandial endothelial biomarker levels and microvascular reactivity in patients with type 2 diabetes and dyslipidemia: a preliminary report. Cardiovascular diabetology 2019; 18:32. http://www.ncbi.nlm.nih.gov/pubmed/?term=30876421
  26. Khan NNS, Kelly-Blake K, Luo Z, Olomu A. Sex Differences in Statin Prescribing in Diabetic and Heart Disease Patients in FQHCs: A Comparison of the ATPIII and 2013 ACC/AHA Cholesterol Guidelines. Health services research and managerial epidemiology 2019; 6:2333392818825414. http://www.ncbi.nlm.nih.gov/pubmed/?term=30859113
  27. Cook MJ, Sorial AK, Lunt M et al. Effect of timing and duration of statin exposure on risk of hip or knee revision arthroplasty: a population-based cohort study. The Journal of rheumatology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30877207
  28. Bouitbir J, Sanvee GM, Panajatovic MV et al. Mechanisms of statin-associated skeletal muscle-associated symptoms. Pharmacol Res 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30877064  
Basic Science publications
 
 
  1. Zhu P, Huang G, Zhang B et al. Assessment of fracture healing properties of lovastatin loaded nanoparticles: preclinical study in rat model. Acta biochimica Polonica 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30856636
  2. Zhu K, Qian L, Lin Y et al. Pioglitazone Ameliorates Atorvastatin-Induced Islet Cell Dysfunction through Activation of FFA1 in INS-1 Cells. Journal of diabetes research 2019; 2019:5245063. http://www.ncbi.nlm.nih.gov/pubmed/?term=30863781
  3. Watanabe K, Oda S, Matsubara A et al. Establishment and characterization of a mouse model of rhabdomyolysis by coadministration of statin and fibrate. Toxicology letters 2019; 307:49-58. http://www.ncbi.nlm.nih.gov/pubmed/?term=30853469
  4. Wang J, Cheng X, Zhang X et al. A combination of indomethacin and atorvastatin ameliorates cognitive and pathological deterioration in PrP-hAbetaPPswe/PS1(DeltaE9) transgenic mice. Journal of neuroimmunology 2019; 330:108-115. http://www.ncbi.nlm.nih.gov/pubmed/?term=30870684
  5. Tradtrantip L, Duan T, Yeaman MR, Verkman AS. CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica. Journal of neuroinflammation 2019; 16:57. http://www.ncbi.nlm.nih.gov/pubmed/?term=30851734
  6. Naserzadeh R, Abad N, Ghorbanzadeh B et al. Simvastatin exerts antidepressant-like activity in mouse forced swimming test: Role of NO-cGMP-KATP channels pathway and PPAR-gamma receptors. Pharmacology, biochemistry, and behavior 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30857920
  7. Kanda T, Sugihara T, Takata T et al. Low-density lipoprotein receptor expression is involved in the beneficial effect of photodynamic therapy using talaporfin sodium on gastric cancer cells. Oncology letters 2019; 17:3261-3266. http://www.ncbi.nlm.nih.gov/pubmed/?term=30867758
  8. Huai J, Yang Z, Yi YH, Wang GJ. Role of mammalian target of rapamycin signaling pathway in regulation of fatty acid oxidation in a preeclampsia-like mouse model treated with pravastatin. Chinese medical journal 2019; 132:671-679. http://www.ncbi.nlm.nih.gov/pubmed/?term=30855348
  9. Curry L, Almukhtar H, Alahmed J et al. Simvastatin inhibits L-type Ca2+-channel activity through impairment of mitochondrial function. Toxicological sciences : an official journal of the Society of Toxicology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30859212
  10. Chang CC, Huang KH, Hsu SP et al. Simvastatin reduces the carcinogenic effect of 3-methylcholanthrene in renal epithelial cells through histone deacetylase 1 inhibition and RhoA reactivation. Scientific reports 2019; 9:4606. http://www.ncbi.nlm.nih.gov/pubmed/?term=30872677
  11. Araya-Sibaja AM, Vega-Baudrit JR, Guillen-Giron T et al. Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids. Pharmaceutics 2019; 11. http://www.ncbi.nlm.nih.gov/pubmed/?term=30857331
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