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Lipid management in patients with chronic kidney disease

An Author Correction to this article was published on 11 December 2018

This article has been updated

Abstract

An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations.

Key points

  • An independent, graded inverse relationship exists between cardiovascular risk and estimated glomerular filtration rate (eGFR); patients with end-stage renal disease (ESRD) are at extremely high risk of cardiovascular events.

  • In chronic kidney disease (CKD) and ESRD, dysregulation of lipid metabolism results in increased levels of triglycerides and oxidised lipoproteins and reduced levels of HDL cholesterol; LDL cholesterol levels are usually normal.

  • As eGFR declines, there is a trend towards smaller relative risk reductions for major vascular events with statin-based therapy with little evidence of benefit in patients on dialysis.

  • Deteriorating renal function results in a unique cardiovascular phenotype with an increasing proportion of cardiovascular deaths due to heart failure and arrhythmias, rather than due to atherosclerotic events.

  • Several novel therapies are being developed to treat dyslipidaemias and their associated risks; most of these agents are biologics, which are very expensive to produce.

  • Currently there is very little evidence to support the use of novel lipid-lowering agents in patients with CKD or ESRD; however, a need exists for further studies of these therapies.

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Fig. 1: Derangements in lipoprotein metabolism in chronic kidney disease.
Fig. 2: Role of PCSK9 in cholesterol transport.
Fig. 3: Role of CETP in cholesterol transport.

Change history

  • 11 December 2018

    In the acknowledgements section of this article as originally published, information on the authors’ roles as EURECAm members is missing. The correct acknowledgement is as follows: “This Review was planned as part of the activity of the European Renal and Cardiovascular Medicine working (EURECAm) group and all authors are EURECAm members. A.O.’s work was supported by Spanish Government ISCIII FEDER funds (PI16/02057, ISCIII-RETIC REDinREN RD16/0009) and Community of Madrid (B2017/BMD-3686 CIFRA2-CM). P.R.’s work is supported by a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program FIGHT-HF (reference: ANR-15-RHU-0004) and by the French PIA project “Lorraine Université d’Excellence”, reference ANR-15-IDEX-04-LUE.” The omission has been corrected in the PDF and HTML versions of the article.

References

  1. 1.

    Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Working Group. KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int. Suppl. 3, 263–305 (2013).

    Google Scholar 

  2. 2.

    The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Atherosclerosis 253, 281–344 (2016).

    Google Scholar 

  3. 3.

    The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Atherosclerosis 252, 207–274 (2016).

    Google Scholar 

  4. 4.

    Jellinger, P. S. et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidaemia and prevention of cardiovascular disease. Endocr. Practice 23, 1–87 (2017).

    Google Scholar 

  5. 5.

    Stone, N. J. et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J. Am. Coll. Cardiol. 63, 2889–2934 (2014).

    PubMed  Google Scholar 

  6. 6.

    US Preventive Services Task Force. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA 316, 1997–2007 (2016).

    Google Scholar 

  7. 7.

    Chou, R., Dana, T., Blazina, I., Daeges, M. & Jeanne, T. L. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA 316, 2008–2024 (2016).

    PubMed  Google Scholar 

  8. 8.

    Board, J. B. S. Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 100 Suppl. 2, ii1–ii67 (2014).

    Google Scholar 

  9. 9.

    Anderson, T. J. et al. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can. J. Cardiol. 32, 1263–1282 (2016).

    PubMed  Google Scholar 

  10. 10.

    National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modifification: Guideline 181. NICE https://www.Nice.org.uk/Guidance/cg181 (2014).

  11. 11.

    Hohenstein, B. Lipoprotein(a) in nephrological patients. Clin. Res. Cardiol. Suppl. 12, 27–30 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Heine, G. H., Rogacev, K. S., Weingartner, O. & Marsche, G. Still a reasonable goal: targeting cholesterol in dialysis and advanced chronic kidney disease patients. Semin. Dial. 30, 390–394 (2017).

    PubMed  Google Scholar 

  13. 13.

    Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).

    CAS  PubMed  Google Scholar 

  14. 14.

    Matsushita, K. et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375, 2073–2081 (2010).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Vanholder, R. et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol. Dial. Transplant. 20, 1048–1056 (2005).

    CAS  PubMed  Google Scholar 

  16. 16.

    United States Renal Data System. 2015 USRDS Annual Data Report volume 2: ESRD in the United States. USRDS https://www.usrds.org/2015/download/vol2_USRDS_ESRD_15.pdf (2015).

  17. 17.

    de Jager, D. J. et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 302, 1782–1789 (2009).

    PubMed  Google Scholar 

  18. 18.

    Steenkamp, R., Rao, A. & Roderick, P. UK Renal Registry 17th annual report: chapter 5 survival and cause of death in UK adult patients on renal replacement therapy in 2013: national and centre-specific analyses. Nephron 129 (Suppl. 1), 99–129 (2015).

    PubMed  Google Scholar 

  19. 19.

    Bottomley, M. J. & Harden, P. N. Update on the long-term complications of renal transplantation. Br. Med. Bull. 106, 117–134 (2013).

    CAS  PubMed  Google Scholar 

  20. 20.

    Neale, J. & Smith, A. C. Cardiovascular risk factors following renal transplant. World J. Transplant. 5, 183–195 (2015).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Vanholder, R. et al. Reducing the costs of chronic kidney disease while delivering quality health care: a call to action. Nat. Rev. Nephrol. 13, 393–409 (2017).

    PubMed  Google Scholar 

  22. 22.

    Jardine, A. G., Gaston, R. S., Fellstrom, B. C. & Holdaas, H. Prevention of cardiovascular disease in adult recipients of kidney transplants. Lancet 378, 1419–1427 (2011).

    Google Scholar 

  23. 23.

    Hart, A., Weir, M. R. & Kasiske, B. L. Cardiovascular risk assessment in kidney transplantation. Kidney Int. 87, 527–534 (2015).

    PubMed  Google Scholar 

  24. 24.

    Pilmore, H., Dent, H., Chang, S., McDonald, S. P. & Chadban, S. J. Reduction in cardiovascular death after kidney transplantation. Transplantation 89, 851–857 (2010).

    PubMed  Google Scholar 

  25. 25.

    Hager, M. R., Narla, A. D. & Tannock, L. R. Dyslipidemia in patients with chronic kidney disease. Rev. Endocr. Metab. Disord. 18, 29–40 (2017).

    CAS  PubMed  Google Scholar 

  26. 26.

    Zheng-Lin, B. & Ortiz, A. Lipid management in chronic kidney disease: systematic review of PCSK9 targeting. Drugs 78, 215–229 (2018).

    PubMed  Google Scholar 

  27. 27.

    Visconti, L. et al. Lipid disorders in patients with renal failure: role in cardiovascular events and progression of chronic kidney disease. J. Clin. Transl Endocrinol. 6, 8–14 (2016).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Florens, N., Calzada, C., Lyasko, E., Juillard, L. & Soulage, C. O. Modified lipids and lipoproteins in chronic kidney disease: a new class of uremic toxins. Toxins (Basel) 8, 1–27 (2016).

    Google Scholar 

  29. 29.

    Deighan, C. J., Caslake, M. J., McConnell, M., Boulton-Jones, J. M. & Packard, C. J. The atherogenic lipoprotein phenotype: small dense LDL and lipoprotein remnants in nephrotic range proteinuria. Atherosclerosis 157, 211–220 (2001).

    CAS  PubMed  Google Scholar 

  30. 30.

    Vaziri, N. D., Sato, T. & Liang, K. Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous focal glomerulosclerosis. Kidney Int. 63, 1756–1763 (2003).

    CAS  PubMed  Google Scholar 

  31. 31.

    Mesquita, J., Varela, A. & Medina, J. L. Dyslipidemia in renal disease: causes, consequences and treatment. Endocrinol. Nutr. 57, 440–448 (2010).

    PubMed  Google Scholar 

  32. 32.

    Kaysen, G. A. New insights into lipid metabolism in chronic kidney disease. J. Ren Nutr. 21, 120–123 (2011).

    CAS  PubMed  Google Scholar 

  33. 33.

    Reiss, A. B., Voloshyna, I., De Leon, J., Miyawaki, N. & Mattana, J. Cholesterol metabolism in CKD. Am. J. Kidney Dis. 66, 1071–1082 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Vaziri, N. D. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am. J. Physiol. Renal Physiol. 290, F262–F272 (2006).

    CAS  PubMed  Google Scholar 

  35. 35.

    Kronenberg, F. HDL in CKD-the devil is in the detail. J. Am. Soc. Nephrol. 29, 1356–1371 (2018).

    PubMed  Google Scholar 

  36. 36.

    Annema, W. & von Eckardstein, A. Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy. Transl Res. 173, 30–57 (2016).

    CAS  PubMed  Google Scholar 

  37. 37.

    Julve, J., Martin-Campos, J. M., Escola-Gil, J. C. & Blanco-Vaca, F. Chylomicrons: advances in biology, pathology, laboratory testing, and therapeutics. Clin. Chim. Acta 455, 134–148 (2016).

    CAS  PubMed  Google Scholar 

  38. 38.

    Kaysen, G. A. Lipid and lipoprotein metabolism in chronic kidney disease. J. Ren Nutr. 19, 73–77 (2009).

    CAS  PubMed  Google Scholar 

  39. 39.

    Tsimihodimos, V., Mitrogianni, Z. & Elisaf, M. Dyslipidemia associated with chronic kidney disease. Open Cardiovasc. Med. J. 5, 41–48 (2011).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Gaudet, D., Drouin-Chartier, J. P. & Couture, P. Lipid metabolism and emerging targets for lipid-lowering therapy. Can. J. Cardiol. 33, 872–882 (2017).

    PubMed  Google Scholar 

  41. 41.

    Bermudez-Lopez, M. et al. New perspectives on CKD-induced dyslipidemia. Expert Opin. Ther. Targets 21, 967–976 (2017).

    CAS  PubMed  Google Scholar 

  42. 42.

    Kwan, B. C., Kronenberg, F., Beddhu, S. & Cheung, A. K. Lipoprotein metabolism and lipid management in chronic kidney disease. J. Am. Soc. Nephrol. 18, 1246–1261 (2007).

    CAS  PubMed  Google Scholar 

  43. 43.

    Chen, H. et al. Combined clinical phenotype and lipidomic analysis reveals the impact of chronic kidney disease on lipid metabolism. J. Proteome Res. 16, 1566–1578 (2017).

    CAS  PubMed  Google Scholar 

  44. 44.

    Chu, M., Wang, A. Y., Chan, I. H., Chui, S. H. & Lam, C. W. Serum small-dense LDL abnormalities in chronic renal disease patients. Br. J. Biomed. Sci. 69, 99–102 (2012).

    CAS  PubMed  Google Scholar 

  45. 45.

    Chait, A., Brazg, R. L., Tribble, D. L. & Krauss, R. M. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am. J. Med. 94, 350–356 (1993).

    CAS  PubMed  Google Scholar 

  46. 46.

    Gardner, C. D., Fortmann, S. P. & Krauss, R. M. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA 276, 875–881 (1996).

    CAS  PubMed  Google Scholar 

  47. 47.

    Kwiterovich, P. O. Jr. Lipoprotein heterogeneity: diagnostic and therapeutic implications. Am. J. Cardiol. 90, 1i–10i (2002).

    CAS  PubMed  Google Scholar 

  48. 48.

    Gelissen, I. C. et al. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler. Thromb. Vasc. Biol. 26, 534–540 (2006).

    CAS  PubMed  Google Scholar 

  49. 49.

    Voloshyna, I. & Reiss, A. B. The ABC transporters in lipid flux and atherosclerosis. Prog. Lipid Res. 50, 213–224 (2011).

    CAS  PubMed  Google Scholar 

  50. 50.

    Cardinal, H., Raymond, M. A., Hebert, M. J. & Madore, F. Uraemic plasma decreases the expression of ABCA1, ABCG1 and cell-cycle genes in human coronary arterial endothelial cells. Nephrol. Dial. Transplant. 22, 409–416 (2007).

    CAS  PubMed  Google Scholar 

  51. 51.

    Guarnieri, G. F. et al. Lecithin-cholesterol acyltransferase (LCAT) activity in chronic uremia. Kidney Int. Suppl. S26–S30 (1978).

  52. 52.

    Attman, P. O., Alaupovic, P. & Gustafson, A. Serum apolipoprotein profile of patients with chronic renal failure. Kidney Int. 32, 368–375 (1987).

    CAS  PubMed  Google Scholar 

  53. 53.

    Vaziri, N. D., Liang, K. & Parks, J. S. Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure. Kidney Int. 59, 2192–2196 (2001).

    CAS  PubMed  Google Scholar 

  54. 54.

    Barter, P. J. et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23, 160–167 (2003).

    CAS  PubMed  Google Scholar 

  55. 55.

    Kimura, H. et al. Hepatic lipase mutation may reduce vascular disease prevalence in hemodialysis patients with high CETP levels. Kidney Int. 64, 1829–1837 (2003).

    CAS  PubMed  Google Scholar 

  56. 56.

    Beddhu, S., Kimmel, P. L., Ramkumar, N. & Cheung, A. K. Associations of metabolic syndrome with inflammation in CKD: results from the Third National Health and Nutrition Examination Survey (NHANES III). Am. J. Kidney Dis. 46, 577–586 (2005).

    PubMed  Google Scholar 

  57. 57.

    Seiler, S. et al. Cholesteryl ester transfer protein activity and cardiovascular events in patients with chronic kidney disease stage V. Nephrol. Dial. Transplant. 23, 3599–3604 (2008).

    CAS  PubMed  Google Scholar 

  58. 58.

    Navab, M. et al. Oxidized lipids as mediators of coronary heart disease. Curr. Opin. Lipidol. 13, 363–372 (2002).

    CAS  PubMed  Google Scholar 

  59. 59.

    Yamamoto, S. et al. Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. J. Am. Coll. Cardiol. 60, 2372–2379 (2012).

    CAS  PubMed  Google Scholar 

  60. 60.

    Shroff, R. et al. HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype. J. Am. Soc. Nephrol. 25, 2658–2668 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Thompson, M. et al. Kidney function as a determinant of HDL and triglyceride concentrations in the Australian population. J. Clin. Med. 5, E35 (2016).

    PubMed  Google Scholar 

  62. 62.

    Batista, M. C. et al. Apolipoprotein A-I, B-100, and B-48 metabolism in subjects with chronic kidney disease, obesity, and the metabolic syndrome. Metabolism 53, 1255–1261 (2004).

    CAS  PubMed  Google Scholar 

  63. 63.

    Cheung, A. K., Parker, C. J., Ren, K. & Iverius, P. H. Increased lipase inhibition in uremia: identification of pre-beta-HDL as a major inhibitor in normal and uremic plasma. Kidney Int. 49, 1360–1371 (1996).

    CAS  PubMed  Google Scholar 

  64. 64.

    Ginsberg, H. N. et al. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J. Clin. Invest. 78, 1287–1295 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Mead, J. R., Irvine, S. A. & Ramji, D. P. Lipoprotein lipase: structure, function, regulation, and role in disease. J. Mol. Med. (Berl.) 80, 753–769 (2002).

    CAS  Google Scholar 

  66. 66.

    Liang, K., Oveisi, F. & Vaziri, N. D. Role of secondary hyperparathyroidism in the genesis of hypertriglyceridemia and VLDL receptor deficiency in chronic renal failure. Kidney Int. 53, 626–630 (1998).

    CAS  PubMed  Google Scholar 

  67. 67.

    Liang, K. & Vaziri, N. D. Acquired VLDL receptor deficiency in experimental nephrosis. Kidney Int. 51, 1761–1765 (1997).

    CAS  PubMed  Google Scholar 

  68. 68.

    Vaziri, N. D. & Liang, K. Down-regulation of VLDL receptor expression in chronic experimental renal failure. Kidney Int. 51, 913–919 (1997).

    CAS  PubMed  Google Scholar 

  69. 69.

    Li, P. K. et al. Randomized, controlled trial of glucose-sparing peritoneal dialysis in diabetic patients. J. Am. Soc. Nephrol. 24, 1889–1900 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Barbagallo, C. M. et al. Heparin induces an accumulation of atherogenic lipoproteins during hemodialysis in normolipidemic end-stage renal disease patients. Hemodial. Int. 19, 360–367 (2015).

    PubMed  Google Scholar 

  71. 71.

    Bugeja, A. L. & Chan, C. T. Improvement in lipid profile by nocturnal hemodialysis in patients with end-stage renal disease. ASAIO J. 50, 328–331 (2004).

    CAS  PubMed  Google Scholar 

  72. 72.

    Nordestgaard, B. G. & Varbo, A. Triglycerides and cardiovascular disease. Lancet 384, 626–635 (2014).

    CAS  PubMed  Google Scholar 

  73. 73.

    Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 375, 1634–1639 (2010).

    PubMed Central  Google Scholar 

  74. 74.

    Lamprea-Montealegre, J. A. et al. Chronic kidney disease, plasma lipoproteins, and coronary artery calcium incidence: the multi-ethnic study of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 33, 652–658 (2013).

    CAS  PubMed  Google Scholar 

  75. 75.

    Lamprea-Montealegre, J. A. et al. CKD, plasma lipids, and common carotid intima-media thickness: results from the multi-ethnic study of atherosclerosis. Clin. J. Am. Soc. Nephrol. 7, 1777–1785 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Lamprea-Montealegre, J. A. et al. Coronary heart disease risk associated with the dyslipidaemia of chronic kidney disease. Heart 104, 1455–1460 (2018).

    PubMed  Google Scholar 

  77. 77.

    Postorino, M., Marino, C., Tripepi, G., Zoccali, C. & CREDIT Working Group. Abdominal obesity modifies the risk of hypertriglyceridemia for all-cause and cardiovascular mortality in hemodialysis patients. Kidney Int. 79, 765–772 (2011).

    CAS  PubMed  Google Scholar 

  78. 78.

    van Capelleveen, J. C., van der Valk, F. M. & Stroes, E. S. Current therapies for lowering lipoprotein (a). J. Lipid Res. 57, 1612–1618 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Berg, K. A. New serum type system in man — the Lp system. Acta Pathol. Microbiol. Scand. 59, 369–382 (1963).

    CAS  PubMed  Google Scholar 

  80. 80.

    Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

    CAS  PubMed  Google Scholar 

  81. 81.

    Emerging Risk Factors Collaboration et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302, 412–423 (2009).

    Google Scholar 

  82. 82.

    Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Langsted, A., Kamstrup, P. R. & Nordestgaard, B. G. Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis 234, 95–101 (2014).

    CAS  PubMed  Google Scholar 

  84. 84.

    Kamstrup, P. R., Tybjaerg-Hansen, A. & Nordestgaard, B. G. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J. Am. Coll. Cardiol. 63, 470–477 (2014).

    CAS  PubMed  Google Scholar 

  85. 85.

    Zewinger, S. et al. Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol. 5, 534–543 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Bajaj, A. et al. Lipoprotein(a) and risk of myocardial infarction and death in chronic kidney disease: findings from the CRIC Study (Chronic Renal Insufficiency Cohort). Arterioscler. Thromb. Vasc. Biol. 37, 1971–1978 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Catapano, A. L. et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur. Heart J. 37, 2999–3058 (2016).

    PubMed  Google Scholar 

  88. 88.

    Agrawal, S., Zaritsky, J. J., Fornoni, A. & Smoyer, W. E. Dyslipidaemia in nephrotic syndrome: mechanisms and treatment. Nat. Rev. Nephrol. 14, 57–70 (2018).

    CAS  PubMed  Google Scholar 

  89. 89.

    Vaziri, N. D. Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences. Kidney Int. 90, 41–52 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Dounousi, E. et al. Oxidative stress is progressively enhanced with advancing stages of CKD. Am. J. Kidney Dis. 48, 752–760 (2006).

    CAS  PubMed  Google Scholar 

  91. 91.

    Garcia-Cruset, S., Carpenter, K. L., Guardiola, F., Stein, B. K. & Mitchinson, M. J. Oxysterol profiles of normal human arteries, fatty streaks and advanced lesions. Free Radic. Res. 35, 31–41 (2001).

    CAS  PubMed  Google Scholar 

  92. 92.

    Lizard, G. et al. Characterization and comparison of the mode of cell death, apoptosis versus necrosis, induced by 7beta-hydroxycholesterol and 7-ketocholesterol in the cells of the vascular wall. Arterioscler. Thromb. Vasc. Biol. 19, 1190–1200 (1999).

    CAS  PubMed  Google Scholar 

  93. 93.

    Uchida, K. Role of reactive aldehyde in cardiovascular diseases. Free Radic. Biol. Med. 28, 1685–1696 (2000).

    CAS  PubMed  Google Scholar 

  94. 94.

    Palinski, W. et al. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler. Thromb. 14, 605–616 (1994).

    CAS  PubMed  Google Scholar 

  95. 95.

    Levitan, I., Volkov, S. & Subbaiah, P. V. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid. Redox Signal. 13, 39–75 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Drozdz, D. et al. Oxidative stress biomarkers and left ventricular hypertrophy in children with chronic kidney disease. Oxid. Med. Cell. Longev. 2016, 7520231 (2016).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Reis, A. et al. Top-down lipidomics of low density lipoprotein reveal altered lipid profiles in advanced chronic kidney disease. J. Lipid Res. 56, 413–422 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Massy, Z. A. & de Zeeuw, D. LDL cholesterol in CKD — to treat or not to treat? Kidney Int. 84, 451–456 (2013).

    PubMed  Google Scholar 

  99. 99.

    Speer, T. et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38, 754–768 (2013).

    CAS  PubMed  Google Scholar 

  100. 100.

    Vaziri, N. D. HDL abnormalities in nephrotic syndrome and chronic kidney disease. Nat. Rev. Nephrol. 12, 37–47 (2016).

    CAS  PubMed  Google Scholar 

  101. 101.

    Haas, M. E. et al. The role of proprotein convertase Subtilisin/Kexin type 9 in nephrotic syndrome-associated hypercholesterolemia. Circulation 134, 61–72 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Rogacev, K. S. et al. PCSK9 plasma concentrations are independent of GFR and do not predict cardiovascular events in patients with decreased GFR. PLOS ONE 11, e0146920 (2016).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Agarwal, A. & Prasad, G. V. Post-transplant dyslipidemia: mechanisms, diagnosis and management. World J. Transplant 6, 125–134 (2016).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    de Groen, P. C. Cyclosporine, low-density lipoprotein, and cholesterol. Mayo Clin. Proc. 63, 1012–1021 (1988).

    PubMed  Google Scholar 

  105. 105.

    Princen, H. M., Meijer, P., Wolthers, B. G., Vonk, R. J. & Kuipers, F. Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis. Biochem. J. 275, 501–505 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Kramer, B. K. et al. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol. Dial. Transplant. 20, 968–973 (2005).

    PubMed  Google Scholar 

  107. 107.

    White, M. et al. Conversion from cyclosporine microemulsion to tacrolimus-based immunoprophylaxis improves cholesterol profile in heart transplant recipients with treated but persistent dyslipidemia: the Canadian multicentre randomized trial of tacrolimus versus cyclosporine microemulsion. J. Heart Lung Transplant. 24, 798–809 (2005).

    PubMed  Google Scholar 

  108. 108.

    Alghamdi, S., Nabi, Z., Skolnik, E., Alkorbi, L. & Albaqumi, M. Cyclosporine versus tacrolimus maintenance therapy in renal transplant. Exp. Clin. Transplant. 9, 170–174 (2011).

    PubMed  Google Scholar 

  109. 109.

    Massy, Z. A. et al. Hyperlipidaemia and post-heparin lipase activities in renal transplant recipients treated with sirolimus or cyclosporin A. Nephrol. Dial. Transplant. 15, 928 (2000).

    CAS  PubMed  Google Scholar 

  110. 110.

    Morrisett, J. D. et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J. Lipid Res. 43, 1170–1180 (2002).

    CAS  PubMed  Google Scholar 

  111. 111.

    Kasiske, B. L. et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am. J. Transplant. 8, 1384–1392 (2008).

    CAS  PubMed  Google Scholar 

  112. 112.

    Emerging Risk Factors Collaboration et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009).

    Google Scholar 

  113. 113.

    Lowrie, E. G. & Lew, N. L. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am. J. Kidney Dis. 15, 458–482 (1990).

    CAS  PubMed  Google Scholar 

  114. 114.

    Baigent, C., Landray, M. J. & Wheeler, D. C. Misleading associations between cholesterol and vascular outcomes in dialysis patients: the need for randomized trials. Semin. Dial. 20, 498–503 (2007).

    PubMed  Google Scholar 

  115. 115.

    Baigent, C., Burbury, K. & Wheeler, D. Premature cardiovascular disease in chronic renal failure. Lancet 356, 147–152 (2000).

    CAS  PubMed  Google Scholar 

  116. 116.

    Zoccali, C. Cardiovascular risk in uraemic patients-is it fully explained by classical risk factors? Nephrol. Dial. Transplant. 15, 454–457 (2000).

    CAS  PubMed  Google Scholar 

  117. 117.

    Saran, R. et al. US Renal Data System 2016 annual data report: epidemiology of kidney disease in the United States. Am. J. Kidney Dis. 69, S465–S480 (2017).

    Google Scholar 

  118. 118.

    Methven, S., Steenkamp, R. & Fraser, S. UK Renal Registry 19th Annual Report: chapter 5 survival and causes of death in UK adult patients on renal replacement therapy in 2015: national and centre-specific analyses. Nephron 137 (Suppl. 1), 117–150 (2017).

    PubMed  Google Scholar 

  119. 119.

    Cholesterol Treatment Trialists Collaboration et al. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol. 4, 829–839 (2016).

    Google Scholar 

  120. 120.

    Chue, C. D., Townend, J. N., Steeds, R. P. & Ferro, C. J. Arterial stiffness in chronic kidney disease: causes and consequences. Heart 96, 817–823 (2010).

    PubMed  Google Scholar 

  121. 121.

    Moody, W. E., Edwards, N. C., Chue, C. D., Ferro, C. J. & Townend, J. N. Arterial disease in chronic kidney disease. Heart 99, 365–372 (2013).

    CAS  PubMed  Google Scholar 

  122. 122.

    Edwards, N. C. et al. Defining the natural history of uremic cardiomyopathy in chronic kidney disease: the role of cardiovascular magnetic resonance. JACC Cardiovasc. Imaging 7, 703–714 (2014).

    Google Scholar 

  123. 123.

    Mall, G., Huther, W., Schneider, J., Lundin, P. & Ritz, E. Diffuse intermyocardiocytic fibrosis in uraemic patients. Nephrol. Dial. Transplant. 5, 39–44 (1990).

    CAS  PubMed  Google Scholar 

  124. 124.

    Aoki, J. et al. Clinical and pathologic characteristics of dilated cardiomyopathy in hemodialysis patients. Kidney Int. 67, 333–340 (2005).

    PubMed  Google Scholar 

  125. 125.

    Storey, B. C. et al. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney Int. 93, 1000–1007 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Kilpatrick, R. D. et al. Association between serum lipids and survival in hemodialysis patients and impact of race. J. Am. Soc. Nephrol. 18, 293–303 (2007).

    CAS  PubMed  Google Scholar 

  127. 127.

    Liu, Y. et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 291, 451–459 (2004).

    CAS  PubMed  Google Scholar 

  128. 128.

    Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. & Dawber, T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707–714 (1977).

    CAS  PubMed  Google Scholar 

  129. 129.

    Arntzenius, A. C. et al. Diet, lipoproteins, and the progression of coronary atherosclerosis. The Leiden Intervention Trial. N. Engl. J. Med. 312, 805–811 (1985).

    CAS  PubMed  Google Scholar 

  130. 130.

    Castelli, W. P. et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 256, 2835–2838 (1986).

    CAS  PubMed  Google Scholar 

  131. 131.

    Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).

    CAS  PubMed  Google Scholar 

  132. 132.

    Investigators, A.-H. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).

    Google Scholar 

  133. 133.

    Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).

    CAS  PubMed  Google Scholar 

  134. 134.

    HPS2-THRIVE Collaborative Group et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371, 203–212 (2014).

    Google Scholar 

  135. 135.

    Lo, J. C., Go, A. S., Chandra, M., Fan, D. & Kaysen, G. A. GFR, body mass index, and low high-density lipoprotein concentration in adults with and without CKD. Am. J. Kidney Dis. 50, 552–558 (2007).

    CAS  PubMed  Google Scholar 

  136. 136.

    Ganda, A. et al. Mild renal dysfunction and metabolites tied to low HDL cholesterol are associated with monocytosis and atherosclerosis. Circulation 127, 988–996 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Anderson, J. L. et al. High density lipoprotein (HDL) particles from end-stage renal disease patients are defective in promoting reverse cholesterol transport. Sci. Rep. 7, 41481 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Zewinger, S. et al. HDL cholesterol is not associated with lower mortality in patients with kidney dysfunction. J. Am. Soc. Nephrol. 25, 1073–1082 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Silbernagel, G. et al. HDL cholesterol, apolipoproteins, and cardiovascular risk in hemodialysis patients. J. Am. Soc. Nephrol. 26, 484–492 (2015).

    PubMed  Google Scholar 

  140. 140.

    Moradi, H. et al. Elevated high-density lipoprotein cholesterol and cardiovascular mortality in maintenance hemodialysis patients. Nephrol. Dial. Transplant. 29, 1554–1562 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Moradi, H. et al. Association of serum lipids with outcomes in Hispanic hemodialysis patients of the west versus east coasts of the United States. Am. J. Nephrol. 41, 284–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Chang, T. I. et al. Inverse association between serum non-high-density lipoprotein cholesterol levels and mortality in patients undergoing incident hemodialysis. J. Am. Heart Assoc. 7, e009096 (2018).

    PubMed  Google Scholar 

  143. 143.

    Sarwar, N. et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 115, 450–458 (2007).

    CAS  PubMed  Google Scholar 

  144. 144.

    Levy, R. I. & Glueck, C. J. Hypertriglyceridemia, diabetes mellitus, and coronary vessel disease. Arch. Intern. Med. 123, 220–228 (1969).

    CAS  PubMed  Google Scholar 

  145. 145.

    Shoji, T., Nishizawa, Y., Nishitani, H., Yamakawa, M. & Morii, H. Roles of hypoalbuminemia and lipoprotein lipase on hyperlipoproteinemia in continuous ambulatory peritoneal dialysis. Metabolism 40, 1002–1008 (1991).

    CAS  PubMed  Google Scholar 

  146. 146.

    Vaziri, N. D. Causes of dysregulation of lipid metabolism in chronic renal failure. Semin. Dial. 22, 644–651 (2009).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Zammit, A. R., Katz, M. J., Derby, C., Bitzer, M. & Lipton, R. B. Chronic kidney disease in non-diabetic older adults: associated roles of the metabolic syndrome, inflammation, and insulin resistance. PLOS ONE 10, e0139369 (2015).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).

    Google Scholar 

  149. 149.

    Sacks, F. M. et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N. Engl. J. Med. 335, 1001–1009 (1996).

    CAS  PubMed  Google Scholar 

  150. 150.

    Colhoun, H. M. et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364, 685–696 (2004).

    CAS  Google Scholar 

  151. 151.

    Collins, R. et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361, 2005–2016 (2003).

    PubMed  PubMed Central  Google Scholar 

  152. 152.

    Cholesterol Treatment Trialists Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376, 1670–1681 (2010).

    Google Scholar 

  153. 153.

    Cholesterol Treatment Trialists Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 385, 1397–1405 (2015).

    Google Scholar 

  154. 154.

    Collins, R. et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 388, 2532–2561 (2016).

    CAS  PubMed  Google Scholar 

  155. 155.

    Cholesterol Treatment Trialists Collaboration. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380, 581–590 (2012).

    Google Scholar 

  156. 156.

    Shepherd, J. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med. 333, 1301–1307 (1995).

    CAS  PubMed  Google Scholar 

  157. 157.

    Ridker, P. M. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359, 2195–2207 (2008).

    CAS  PubMed  Google Scholar 

  158. 158.

    Tonelli, M. et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 110, 1557–1563 (2004).

    CAS  PubMed  Google Scholar 

  159. 159.

    Ridker, P. M. et al. Rosuvastatin for primary prevention among individuals with elevated high-sensitivity c-reactive protein and 5% to 10% and 10% to 20% 10-year risk. Implications of the justification for use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) trial for “intermediate risk”. Circ. Cardiovasc. Qual. Outcomes 3, 447–452 (2010).

    PubMed  Google Scholar 

  160. 160.

    Shepherd, J. et al. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J. Am. Coll. Cardiol. 51, 1448–1454 (2008).

    CAS  PubMed  Google Scholar 

  161. 161.

    Holdaas, H. et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 361, 2024–2031 (2003).

    CAS  PubMed  Google Scholar 

  162. 162.

    Holdaas, H. et al. Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study. Am. J. Transplant. 5, 2929–2936 (2005).

    CAS  PubMed  Google Scholar 

  163. 163.

    Fellstrom, B. C. et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N. Engl. J. Med. 360, 1395–1407 (2009).

    CAS  PubMed  Google Scholar 

  164. 164.

    Wanner, C. et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 353, 238–248 (2005).

    CAS  PubMed  Google Scholar 

  165. 165.

    Marz, W. et al. Atorvastatin and low-density lipoprotein cholesterol in type 2 diabetes mellitus patients on hemodialysis. Clin. J. Am. Soc. Nephrol. 6, 1316–1325 (2011).

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    Sleight, P. Debate: subgroup analyses in clinical trials: fun to look at - but don’t believe them! Curr. Control. Trials Cardiovasc. Med. 1, 25–27 (2000).

    PubMed  PubMed Central  Google Scholar 

  167. 167.

    Brookes, S. T. et al. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol. Assess. 5, 1–56 (2001).

    CAS  PubMed  Google Scholar 

  168. 168.

    Peto, R. Current misconception 3: that subgroup-specific trial mortality results often provide a good basis for individualising patient care. Br. J. Cancer 104, 1057–1058 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Baigent, C. et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377, 2181–2192 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    De Nicola, L. et al. Prognostic role of LDL cholesterol in non-dialysis chronic kidney disease: multicenter prospective study in Italy. Nutr. Metab. Cardiovasc. Dis. 25, 756–762 (2015).

    PubMed  Google Scholar 

  171. 171.

    Haynes, R. et al. Effects of lowering LDL cholesterol on progression of kidney disease. J. Am. Soc. Nephrol. 25, 1825–1833 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Su, X. et al. Effect of statins on kidney disease outcomes: a systematic review and meta-analysis. Am. J. Kidney Dis. 67, 881–892 (2016).

    CAS  PubMed  Google Scholar 

  173. 173.

    Krumholz, H. M. Statins evidence: when answers also raise questions. BMJ 354, i4963 (2016).

    PubMed  Google Scholar 

  174. 174.

    Tonelli, M. et al. Association between LDL-C and risk of myocardial infarction in CKD. J. Am. Soc. Nephrol. 24, 979–986 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Tsimikas, S. A. Test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol. 69, 692–711 (2017).

    CAS  PubMed  Google Scholar 

  176. 176.

    Hopewell, J. C., Haynes, R. & Baigent, C. The role of lipoprotein(a) in chronic kidney disease. J. Lipid Res. 59, 577–585 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Palmer, S. C. et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst. Rev. 5, CD007784 (2014).

    Google Scholar 

  178. 178.

    Palmer, S. C. et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst. Rev. CD004289 (2013).

  179. 179.

    Palmer, S. C. et al. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst. Rev. 1, CD005019 (2014).

    Google Scholar 

  180. 180.

    Major, R. W., Cheung, C. K., Gray, L. J. & Brunskill, N. J. Statins and cardiovascular primary prevention in CKD: a meta-analysis. Clin. J. Am. Soc. Nephrol. 10, 732–739 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Green, D., Ritchie, J. P. & Kalra, P. A. Meta-analysis of lipid-lowering therapy in maintenance dialysis patients. Nephron Clin. Pract. 124, 209–217 (2013).

    CAS  PubMed  Google Scholar 

  182. 182.

    Hou, W. et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur. Heart J. 34, 1807–1817 (2013).

    CAS  PubMed  Google Scholar 

  183. 183.

    Libby, P. Inflammation in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 32, 2045–2051 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    McCausland, F. R. et al. C-reactive protein and risk of ESRD: results from the trial to reduce cardiovascular events with aranesp therapy (TREAT). Am. J. Kidney Dis. 68, 873–881 (2016).

    CAS  Google Scholar 

  185. 185.

    Handelman, G. J. et al. Elevated plasma F2-isoprostanes in patients on long-term hemodialysis. Kidney Int. 59, 1960–1966 (2001).

    CAS  PubMed  Google Scholar 

  186. 186.

    Gupta, J. et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin. J. Am. Soc. Nephrol. 7, 1938–1946 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Akchurin, O. M. & Kaskel, F. Update on inflammation in chronic kidney disease. Blood Purif. 39, 84–92 (2015).

    CAS  PubMed  Google Scholar 

  188. 188.

    Amdur, R. L. et al. Inflammation and progression of CKD: The CRIC Study. Clin. J. Am. Soc. Nephrol. 11, 1546–1556 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Oesterle, A., Laufs, U. & Liao, J. K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res. 120, 229–243 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Ridker, P. M. et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 373, 1175–1182 (2009).

    CAS  PubMed  Google Scholar 

  191. 191.

    Ridker, P. M., MacFadyen, J., Cressman, M. & Glynn, R. J. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial. J. Am. Coll. Cardiol. 55, 1266–1273 (2010).

    CAS  PubMed  Google Scholar 

  192. 192.

    Rubins, H. B. et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N. Engl. J. Med. 341, 410–418 (1999).

    CAS  PubMed  Google Scholar 

  193. 193.

    Frick, M. H. et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317, 1237–1245 (1987).

    CAS  PubMed  Google Scholar 

  194. 194.

    Robins, S. J. et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 285, 1585–1591 (2001).

    CAS  PubMed  Google Scholar 

  195. 195.

    Broeders, N., Knoop, C., Antoine, M., Tielemans, C. & Abramowicz, D. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent? Nephrol. Dial. Transplant. 15, 1993–1999 (2000).

    CAS  PubMed  Google Scholar 

  196. 196.

    Lipscombe, J., Lewis, G. F., Cattran, D. & Bargman, J. M. Deterioration in renal function associated with fibrate therapy. Clin. Nephrol. 55, 39–44 (2001).

    CAS  PubMed  Google Scholar 

  197. 197.

    Lipscombe, J. & Bargman, J. M. Fibrate-induced increase in blood urea and creatinine. Nephrol. Dial. Transplant. 16, 1515 (2001).

    CAS  PubMed  Google Scholar 

  198. 198.

    Sica, D. A. Fibrate therapy and renal function. Curr. Atheroscler. Rep. 11, 338–342 (2009).

    CAS  PubMed  Google Scholar 

  199. 199.

    Markossian, T. et al. Controversies regarding lipid management and statin use for cardiovascular risk reduction in patients with CKD. Am. J. Kidney Dis. 67, 965–977 (2016).

    CAS  PubMed  Google Scholar 

  200. 200.

    Insull, W. Jr. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med. J. 99, 257–273 (2006).

    PubMed  Google Scholar 

  201. 201.

    Grundy, S. M., Ahrens, E. H. Jr & Salen, G. Interruption of the enterohepatic circulation of bile acids in man: comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J. Lab. Clin. Med. 78, 94–121 (1971).

    CAS  PubMed  Google Scholar 

  202. 202.

    Couture, P. & Lamarche, B. Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond. Curr. Opin. Lipidol. 24, 227–232 (2013).

    CAS  PubMed  Google Scholar 

  203. 203.

    Hou, R. & Goldberg, A. C. Lowering low-density lipoprotein cholesterol: statins, ezetimibe, bile acid sequestrants, and combinations: comparative efficacy and safety. Endocrinol. Metab. Clin. North Am. 38, 79–97 (2009).

    CAS  PubMed  Google Scholar 

  204. 204.

    Jacobson, T. A., Armani, A., McKenney, J. M. & Guyton, J. R. Safety considerations with gastrointestinally active lipid-lowering drugs. Am. J. Cardiol. 99, 47C–55C (2007).

    CAS  PubMed  Google Scholar 

  205. 205.

    Lloyd-Jones, D. M. et al. 2017 focused update of 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: a report of the American College of Cardiology Task Force on expert consensus decision pathways. J. Am. Coll. Cardiol. 70, 1785–1822 (2017).

    PubMed  Google Scholar 

  206. 206.

    Koskinas, K. C. et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur. Heart J. 39, 1172–1180 (2018).

    PubMed  Google Scholar 

  207. 207.

    Harper, C. R. & Jacobson, T. A. Managing dyslipidemia in chronic kidney disease. J. Am. Coll. Cardiol. 51, 2375–2384 (2008).

    CAS  PubMed  Google Scholar 

  208. 208.

    Friedman, A. & Moe, S. Review of the effects of omega-3 supplementation in dialysis patients. Clin. J. Am. Soc. Nephrol. 1, 182–192 (2006).

    CAS  PubMed  Google Scholar 

  209. 209.

    Svensson, M., Schmidt, E. B., Jorgensen, K. A. & Christensen, J. H. The effect of n-3 fatty acids on lipids and lipoproteins in patients treated with chronic haemodialysis: a randomized placebo-controlled intervention study. Nephrol. Dial. Transplant. 23, 2918–2924 (2008).

    CAS  PubMed  Google Scholar 

  210. 210.

    Hassan, K. S., Hassan, S. K., Hijazi, E. G. & Khazim, K. O. Effects of omega-3 on lipid profile and inflammation markers in peritoneal dialysis patients. Ren. Fail. 32, 1031–1035 (2010).

    CAS  PubMed  Google Scholar 

  211. 211.

    Weintraub, H. S. Overview of prescription omega-3 fatty acid products for hypertriglyceridemia. Postgrad. Med. 126, 7–18 (2014).

    PubMed  Google Scholar 

  212. 212.

    Wu, L. & Parhofer, K. G. Diabetic dyslipidemia. Metabolism 63, 1469–1479 (2014).

    CAS  PubMed  Google Scholar 

  213. 213.

    Ballantyne, C. M. et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am. J. Cardiol. 110, 984–992 (2012).

    CAS  PubMed  Google Scholar 

  214. 214.

    Bays, H. E. et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, placebo-controlled, randomized, double-blind, 12-week study with an open-label extension [MARINE] trial). Am. J. Cardiol. 108, 682–690 (2011).

    CAS  PubMed  Google Scholar 

  215. 215.

    Kastelein, J. J. et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the epanova for lowering very high triglycerides (EVOLVE) trial. J. Clin. Lipidol. 8, 94–106 (2014).

    PubMed  Google Scholar 

  216. 216.

    Wei, M. Y. & Jacobson, T. A. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Curr. Atheroscler. Rep. 13, 474–483 (2011).

    CAS  PubMed  Google Scholar 

  217. 217.

    Harris, W. S. & Bulchandani, D. Why do omega-3 fatty acids lower serum triglycerides? Curr. Opin. Lipidol. 17, 387–393 (2006).

    CAS  PubMed  Google Scholar 

  218. 218.

    Bays, H. E., Tighe, A. P., Sadovsky, R. & Davidson, M. H. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev. Cardiovasc. Ther. 6, 391–409 (2008).

    CAS  PubMed  Google Scholar 

  219. 219.

    Kotwal, S., Jun, M., Sullivan, D., Perkovic, V. & Neal, B. Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ. Cardiovasc. Qual. Outcomes 5, 808–818 (2012).

    PubMed  Google Scholar 

  220. 220.

    Aung, T. et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 3, 225–234 (2018).

    PubMed  PubMed Central  Google Scholar 

  221. 221.

    Bhatt, D. L. et al. Rationale and design of REDUCE-IT: reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin. Cardiol. 40, 138–148 (2017).

    PubMed  PubMed Central  Google Scholar 

  222. 222.

    Nicholls, S. J. et al. Assessment of omega-3 carboxylic acids in statin treated patients with high levels of triglycerides and low levels of high density lipoprotein cholesterol: rationale and design of the STRENGTH Trial. Clin. Cardiol. https://doi.org/10.1002/clc.23055 (2018).

    Article  PubMed  Google Scholar 

  223. 223.

    Barter, P. J. & Rye, K. A. New era of lipid-lowering drugs. Pharmacol. Rev. 68, 458–475 (2016).

    PubMed  PubMed Central  Google Scholar 

  224. 224.

    Marais, D. A., Blom, D. J., Petrides, F., Goueffic, Y. & Lambert, G. Proprotein convertase subtilisin/kexin type 9 inhibition. Curr. Opin. Lipidol. 23, 511–517 (2012).

    CAS  PubMed  Google Scholar 

  225. 225.

    Lambert, G., Sjouke, B., Choque, B., Kastelein, J. J. & Hovingh, G. K. The PCSK9 decade. J. Lipid Res. 53, 2515–2524 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226.

    Seidah, N. G. et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl Acad. Sci. USA 100, 928–933 (2003).

    CAS  PubMed  Google Scholar 

  227. 227.

    Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    CAS  PubMed  Google Scholar 

  228. 228.

    Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005).

    CAS  PubMed  Google Scholar 

  229. 229.

    Horton, J. D., Cohen, J. C. & Hobbs, H. H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32, 71–77 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Benn, M., Nordestgaard, B. G., Grande, P., Schnohr, P. & Tybjaerg-Hansen, A. PCSK9 R46L low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J. Am. Coll. Cardiol. 55, 2833–2842 (2010).

    CAS  PubMed  Google Scholar 

  231. 231.

    Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

    CAS  PubMed  Google Scholar 

  232. 232.

    Lepor, N. E. & Kereiakes, D. J. The PCSK9 inhibitors: a novel therapeutic target enters clinical practice. Am. Health Drug Benefits 8, 483–489 (2015).

    PubMed  PubMed Central  Google Scholar 

  233. 233.

    Colhoun, H. M. et al. Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovasc. Disord. 14, 121 (2014).

    PubMed  PubMed Central  Google Scholar 

  234. 234.

    Kastelein, J. J. et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc. Drugs Ther. 28, 281–289 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235.

    Moriarty, P. M. et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J. Clin. Lipidol. 8, 554–561 (2014).

    PubMed  Google Scholar 

  236. 236.

    Robinson, J. G. et al. Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies. Clin. Cardiol. 37, 597–604 (2014).

    PubMed  PubMed Central  Google Scholar 

  237. 237.

    Schwartz, G. G. et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am. Heart J. 168, 682–689 (2014).

    CAS  PubMed  Google Scholar 

  238. 238.

    Cannon, C. P. et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur. Heart J. 36, 1186–1194 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239.

    Bays, H. et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J. Clin. Endocrinol. Metab. 100, 3140–3148 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 240.

    Kastelein, J. J. et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J. 36, 2996–3003 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241.

    Kereiakes, D. J. et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am. Heart J. 169, 906–915.e13 (2015).

    CAS  PubMed  Google Scholar 

  242. 242.

    Roth, E. M. & McKenney, J. M. ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol. 11, 27–37 (2015).

    CAS  PubMed  Google Scholar 

  243. 243.

    Farnier, M. et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: the ODYSSEY OPTIONS II randomized trial. Atherosclerosis 244, 138–146 (2016).

    CAS  PubMed  Google Scholar 

  244. 244.

    Stein, E. A. & Raal, F. Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9. Annu. Rev. Med. 65, 417–431 (2014).

    CAS  PubMed  Google Scholar 

  245. 245.

    Robinson, J. G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).

    CAS  PubMed  Google Scholar 

  246. 246.

    Toth, P. P. et al. Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease. Kidney Int. 93, 1397–1408 (2018).

    CAS  PubMed  Google Scholar 

  247. 247.

    Steg, P., Kumbhani, D. J. & Eagle, K. A. Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab - ODYSSEY OUTCOMES. ACC http://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2018/03/09/08/02/Odyssey-Outcomes (2018).

  248. 248.

    Maki, K. C. The ODYSSEY outcomes trial: clinical implications and exploration of the limits of what can be achieved through lipid lowering. J. Clin. Lipidol. https://doi.org/10.1016/j.jacl.2018.05.016 (2018).

    Article  PubMed  Google Scholar 

  249. 249.

    Fitzgerald, G. & Kiernan, T. PCSK9 inhibitors and LDL reduction: pharmacology, clinical implications, and future perspectives. Expert Rev. Cardiovasc. Ther. 16, 567–578 (2018).

    CAS  PubMed  Google Scholar 

  250. 250.

    Robinson, J. G. et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 311, 1870–1882 (2014).

    PubMed  PubMed Central  Google Scholar 

  251. 251.

    Koren, M. J. et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J. Am. Coll. Cardiol. 63, 2531–2540 (2014).

    CAS  PubMed  Google Scholar 

  252. 252.

    Stroes, E. et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol. 63, 2541–2548 (2014).

    CAS  PubMed  Google Scholar 

  253. 253.

    Blom, D. J. et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med. 370, 1809–1819 (2014).

    CAS  PubMed  Google Scholar 

  254. 254.

    Raal, F. J. et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 385, 331–340 (2015).

    CAS  PubMed  Google Scholar 

  255. 255.

    Nicholls, S. J. et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 316, 2373–2384 (2016).

    CAS  PubMed  Google Scholar 

  256. 256.

    Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).

    CAS  Google Scholar 

  257. 257.

    Sabatine, M. S. et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. Am. Heart J. 173, 94–101 (2016).

    CAS  PubMed  Google Scholar 

  258. 258.

    Ballantyne, C. M. et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am. J. Cardiol. 115, 1212–1221 (2015).

    CAS  PubMed  Google Scholar 

  259. 259.

    Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    CAS  PubMed  Google Scholar 

  260. 260.

    Khvorova, A. Oligonucleotide therapeutics - a new class of cholesterol-lowering drugs. N. Engl. J. Med. 376, 4–7 (2017).

    CAS  PubMed  Google Scholar 

  261. 261.

    Fitzgerald, K. et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376, 41–51 (2017).

    CAS  PubMed  Google Scholar 

  262. 262.

    Ray, K. K. et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376, 1430–1440 (2017).

    CAS  PubMed  Google Scholar 

  263. 263.

    Ray, K. K. et al. Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins: pre-specified secondary end points in ORION 1. Circulation https://doi.org/10.1161/CIRCULATIONAHA.118.034710 (2018).

    Article  PubMed  Google Scholar 

  264. 264.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03060577?term=NCT03060577&rank=1 (2017).

  265. 265.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02963311?term=NCT02963311&rank=1 (2018).

  266. 266.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03399370?term=NCT03399370&rank=1 (2018).

  267. 267.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03400800?term=NCT03400800&rank=1(2018).

  268. 268.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03159416?term=NCT03159416&rank=1 (2018).

  269. 269.

    Brousseau, M. E. et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N. Engl. J. Med. 350, 1505–1515 (2004).

    CAS  PubMed  Google Scholar 

  270. 270.

    Forrest, M. J. et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br. J. Pharmacol. 154, 1465–1473 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. 271.

    Lincoff, A. M. et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N. Engl. J. Med. 376, 1933–1942 (2017).

    PubMed  Google Scholar 

  272. 272.

    Tall, A. R. & Rader, D. J. The trials and tribulations of CETP inhibitors. Circ. Res. 122, 106–112 (2018).

    CAS  PubMed  Google Scholar 

  273. 273.

    Cannon, C. P. et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N. Engl. J. Med. 363, 2406–2415 (2010).

    CAS  PubMed  Google Scholar 

  274. 274.

    REVEAL Collaborative Group. Randomized evaluation of the effects of anacetrapib through lipid-modification (REVEAL)-a large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: trial design, recruitment, and baseline characteristics. Am. Heart J. 187, 182–190 (2017).

    PubMed Central  Google Scholar 

  275. 275.

    HPS3/TIMI55–REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med. 377, 1217–1227 (2017).

    Google Scholar 

  276. 276.

    Hovingh, G. K. et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet 386, 452–460 (2015).

    CAS  PubMed  Google Scholar 

  277. 277.

    Vaziri, N. D. Role of dyslipidemia in impairment of energy metabolism, oxidative stress, inflammation and cardiovascular disease in chronic kidney disease. Clin. Exp. Nephrol. 18, 265–268 (2014).

    CAS  PubMed  Google Scholar 

  278. 278.

    Moradi, H. & Vaziri, N. D. Molecular mechanisms of disorders of lipid metabolism in chronic kidney disease. Front. Biosci. (Landmark Ed) 23, 146–161 (2018).

    Google Scholar 

  279. 279.

    Feinberg, M. W. No small task: therapeutic targeting of Lp(a) for cardiovascular disease. Lancet 388, 2211–2212 (2016).

    PubMed  Google Scholar 

  280. 280.

    Thomas, T. et al. CETP (Cholesteryl Ester Transfer Protein) inhibition with anacetrapib decreases production of lipoprotein(a) in mildly hypercholesterolemic subjects. Arterioscler. Thromb. Vasc. Biol. 37, 1770–1775 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  281. 281.

    Tsimikas, S. et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–1483 (2015).

    CAS  PubMed  Google Scholar 

  282. 282.

    Viney, N. J. et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 388, 2239–2253 (2016).

    CAS  PubMed  Google Scholar 

  283. 283.

    Hussain, M. M., Rava, P., Walsh, M., Rana, M. & Iqbal, J. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.) 9, 14 (2012).

    CAS  Google Scholar 

  284. 284.

    Raal, F. J. et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375, 998–1006 (2010).

    CAS  PubMed  Google Scholar 

  285. 285.

    Yamamoto, T., Wada, F. & Harada-Shiba, M. Development of antisense drugs for dyslipidemia. J. Atheroscler. Thromb. 23, 1011–1025 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  286. 286.

    Panta, R., Dahal, K. & Kunwar, S. Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials. J. Clin. Lipidol. 9, 217–225 (2015).

    PubMed  Google Scholar 

  287. 287.

    Samaha, F. F., McKenney, J., Bloedon, L. T., Sasiela, W. J. & Rader, D. J. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat. Clin. Pract. Cardiovasc. Med. 5, 497–505 (2008).

    CAS  PubMed  Google Scholar 

  288. 288.

    Hussain, M. M. & Bakillah, A. New approaches to target microsomal triglyceride transfer protein. Curr. Opin. Lipidol. 19, 572–578 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. 289.

    Cuchel, M. et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 381, 40–46 (2013).

    CAS  PubMed  Google Scholar 

  290. 290.

    Vuorio, A., Tikkanen, M. J. & Kovanen, P. T. Inhibition of hepatic microsomal triglyceride transfer protein - a novel therapeutic option for treatment of homozygous familial hypercholesterolemia. Vasc. Health Risk Manag. 10, 263–270 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. 291.

    Zodda, D., Giammona, R. & Schifilliti, S. Treatment strategy for dyslipidemia in cardiovascular disease prevention: focus on old and new drugs. Pharmacy (Basel) 6, E10 (2018).

    Google Scholar 

  292. 292.

    Ajufo, E. & Rader, D. J. New therapeutic approaches for familial hypercholesterolemia. Annu. Rev. Med. 69, 113–131 (2018).

    CAS  PubMed  Google Scholar 

  293. 293.

    Gordts, P. L. et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J. Clin. Invest. 126, 2855–2866 (2016).

    PubMed  PubMed Central  Google Scholar 

  294. 294.

    Pechlaner, R. et al. Very-low-density lipoprotein-associated apolipoproteins predict cardiovascular events and are lowered by inhibition of APOC-III. J. Am. Coll. Cardiol. 69, 789–800 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  295. 295.

    Brown, W. V. & Baginsky, M. L. Inhibition of lipoprotein lipase by an apoprotein of human very low density lipoprotein. Biochem. Biophys. Res. Commun. 46, 375–382 (1972).

    CAS  PubMed  Google Scholar 

  296. 296.

    Sundaram, M. et al. Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions. J. Lipid Res. 51, 150–161 (2010).

    PubMed  PubMed Central  Google Scholar 

  297. 297.

    Yao, Z. Human apolipoprotein C-III - a new intrahepatic protein factor promoting assembly and secretion of very low density lipoproteins. Cardiovasc. Hematol. Disord. Drug Targets 12, 133–140 (2012).

    CAS  PubMed  Google Scholar 

  298. 298.

    Yang, X. et al. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J. Lipid Res. 57, 706–713 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  299. 299.

    Dewey, F. E. et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377, 211–221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  300. 300.

    Graham, M. J. et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 377, 222–232 (2017).

    CAS  PubMed  Google Scholar 

  301. 301.

    Gille, A., D’Andrea, D., Tortorici, M. A., Hartel, G. & Wright, S. D. CSL112 (apolipoprotein A-I [human]) enhances cholesterol efflux similarly in healthy individuals and stable atherosclerotic disease patients. Arterioscler. Thromb. Vasc. Biol. 38, 953–963 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  302. 302.

    Michael Gibson, C. et al. Safety and tolerability of CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I, after acute myocardial infarction: the AEGIS-I trial (ApoA-I event reducing in ischemic syndromes I). Circulation 134, 1918–1930 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. 303.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03473223?term=NCT03473223&rank=1 (2018).

  304. 304.

    Tardy, C. et al. CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice. Atherosclerosis 232, 110–118 (2014).

    CAS  PubMed  Google Scholar 

  305. 305.

    Tardif, J. C. et al. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur. Heart J. 35, 3277–3286 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. 306.

    Kataoka, Y. et al. Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden. Cardiovasc. Diagn. Ther. 7, 252–263 (2017).

    PubMed  PubMed Central  Google Scholar 

  307. 307.

    Di Bartolo, B. A., Schwarz, N., Andrews, J. & Nicholls, S. J. Infusional high-density lipoproteins therapies as a novel strategy for treating atherosclerosis. Arch. Med. Sci. 13, 210–214 (2017).

    PubMed  Google Scholar 

  308. 308.

    Nicholls, S. J. et al. Effect of serial infusions of CER-001, a pre-beta high-density lipoprotein mimetic, on coronary atherosclerosis in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: a randomized clinical trial. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2018.2121 (2018).

    Article  PubMed  Google Scholar 

  309. 309.

    Rader, D. J. Apolipoprotein A-I infusion therapies for coronary disease: two outs in the ninth inning and swinging for the fences. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2018.2168 (2018).

    Article  PubMed  Google Scholar 

  310. 310.

    Chypre, M., Zaidi, N. & Smans, K. ATP-citrate lyase: a mini-review. Biochem. Biophys. Res. Commun. 422, 1–4 (2012).

    CAS  PubMed  Google Scholar 

  311. 311.

    Burke, A. C. & Huff, M. W. ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia. Curr. Opin. Lipidol. 28, 193–200 (2017).

    CAS  PubMed  Google Scholar 

  312. 312.

    Pinkosky, S. L. et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J. Lipid Res. 54, 134–151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  313. 313.

    Pinkosky, S. L. et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat. Commun. 7, 13457 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  314. 314.

    Samsoondar, J. P. et al. Prevention of diet-induced metabolic dysregulation, inflammation, and atherosclerosis in Ldlr(−/−) mice by treatment with the ATP-citrate lyase inhibitor bempedoic acid. Arterioscler. Thromb. Vasc. Biol. 37, 647–656 (2017).

    CAS  PubMed  Google Scholar 

  315. 315.

    Burke, A. C. et al. Bempedoic acid lowers low-density lipoprotein cholesterol and attenuates atherosclerosis in low-density lipoprotein receptor-deficient (LDLR(+/−) and LDLR(−/−)) Yucatan miniature pigs. Arterioscler. Thromb. Vasc. Biol. 38, 1178–1190 (2018).

    CAS  PubMed  Google Scholar 

  316. 316.

    Ballantyne, C. M. et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J. Am. Coll. Cardiol. 62, 1154–1162 (2013).

    CAS  PubMed  Google Scholar 

  317. 317.

    Gutierrez, M. J. et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 34, 676–683 (2014).

    CAS  PubMed  Google Scholar 

  318. 318.

    Thompson, P. D. et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J. Clin. Lipidol. 10, 556–567 (2016).

    PubMed  Google Scholar 

  319. 319.

    Ballantyne, C. M. et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am. J. Cardiol. 117, 1928–1933 (2016).

    CAS  PubMed  Google Scholar 

  320. 320.

    Thompson, P. D. et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J. Clin. Lipidol. 9, 295–304 (2015).

    PubMed  Google Scholar 

  321. 321.

    Stein, E., Bays, H., Koren, M., Bakker-Arkema, R. & Bisgaier, C. Efficacy and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. J. Clin. Lipidol. 10, 1212–1222 (2016).

    PubMed  Google Scholar 

  322. 322.

    Bisgaier, C. L., Oniciu, D. C. & Srivastava, R. A. K. Comparative evaluation of gemcabene and peroxisome proliferator-activated receptor ligands in transcriptional assays of peroxisome proliferator-activated receptors: implication for the treatment of hyperlipidemia and cardiovascular disease. J. Cardiovasc. Pharmacol. 72, 3–10 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  323. 323.

    Bays, H. E. et al. Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am. J. Cardiol. 92, 538–543 (2003).

    CAS  PubMed  Google Scholar 

  324. 324.

    Cheng, D. et al. Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption. J. Biol. Chem. 283, 29802–29811 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  325. 325.

    Meyers, C. D., Amer, A., Majumdar, T. & Chen, J. Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects. J. Clin. Pharmacol. 55, 1031–1041 (2015).

    CAS  PubMed  Google Scholar 

  326. 326.

    Ward, S. et al. A systematic review and economic evaluation of statins for the prevention of coronary events. Health Technol. Assess. 11, 1–160 (2007).

    PubMed  Google Scholar 

  327. 327.

    Mistry, H. et al. Cost-effectiveness of a European preventive cardiology programme in primary care: a Markov modelling approach. BMJ Open 2, e001029 (2012).

    PubMed  PubMed Central  Google Scholar 

  328. 328.

    Erickson, K. F. et al. Cost-effectiveness of statins for primary cardiovascular prevention in chronic kidney disease. J. Am. Coll. Cardiol. 61, 1250–1258 (2013).

    PubMed  PubMed Central  Google Scholar 

  329. 329.

    McConnachie, A. et al. Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study. Eur. Heart J. 35, 290–298 (2014).

    CAS  PubMed  Google Scholar 

  330. 330.

    Stam-Slob, M. C., van der Graaf, Y., Greving, J. P., Dorresteijn, J. A. & Visseren, F. L. Cost-effectiveness of intensifying lipid-lowering therapy with statins based on individual absolute benefit in coronary artery disease patients. J. Am. Heart Assoc. 6, e004648 (2017).

    PubMed  PubMed Central  Google Scholar 

  331. 331.

    Rubio-Sans, P. The cost effectiveness of statin therapies in Spain in 2010, after the introduction of generics and reference prices. Am. J. Cardiovasc. Drugs 10, 369–382 (2010).

    Google Scholar 

  332. 332.

    Mihaylova, B. et al. Cost-effectiveness of simvastatin plus ezetimibe for cardiovascular prevention in CKD: results of the Study of Heart and Renal Protection (SHARP). Am. J. Kidney Dis. 67, 576–584 (2016).

    PubMed  PubMed Central  Google Scholar 

  333. 333.

    National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. NICE https://www.nice.org.uk/guidance/ta394 (2016).

  334. 334.

    Villa, G. et al. Cost-effectiveness of evolocumab in patients with high cardiovascular risk in Spain. Clin. Ther. 39, 771–786.e3 (2017).

    CAS  PubMed  Google Scholar 

  335. 335.

    Gandra, S. R. et al. Cost-effectiveness of LDL-C lowering with evolocumab in patients with high cardiovascular risk in the United States. Clin. Cardiol. 39, 313–320 (2016).

    PubMed  PubMed Central  Google Scholar 

  336. 336.

    Pratt, C. M. & Moye, L. A. The cardiac arrhythmia suppression trial. Casting suppression in a different light. Circulation 91, 245–247 (1995).

    CAS  Google Scholar 

  337. 337.

    Besarab, A. et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N. Engl. J. Med. 339, 584–590 (1998).

    CAS  PubMed  Google Scholar 

  338. 338.

    Carlberg, B., Samuelsson, O. & Lindholm, L. H. Atenolol in hypertension: is it a wise choice? Lancet 364, 1684–1689 (2004).

    CAS  PubMed  Google Scholar 

  339. 339.

    Singh, A. K. et al. Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 355, 2085–2098 (2006).

    CAS  PubMed  Google Scholar 

  340. 340.

    Pfeffer, M. A. et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N. Engl. J. Med. 361, 2019–2032 (2009).

    PubMed  Google Scholar 

  341. 341.

    ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N. Engl. J. Med. 361, 1953–1962 (2009).

    Google Scholar 

  342. 342.

    Barrett, A., Roques, T., Small, M. & Smith, R. D. How much will Herceptin really cost? Bmj 333, 1118–1120 (2006).

    PubMed  PubMed Central  Google Scholar 

  343. 343.

    Ng, K. P., Townend, J. N. & Ferro, C. J. Randomised-controlled trials in chronic kidney disease—a call to arms! Int. J. Clin. Pract. 66, 913–915 (2012).

    CAS  PubMed  Google Scholar 

  344. 344.

    Joseph, P. D., Craig, J. C. & Caldwell, P. H. Clinical trials in children. Br. J. Clin. Pharmacol. 79, 357–369 (2015).

    PubMed  PubMed Central  Google Scholar 

  345. 345.

    Liu, K. A. & Mager, N. A. Women’s involvement in clinical trials: historical perspective and future implications. Pharm. Pract. (Granada) 14, 708 (2016).

    Google Scholar 

  346. 346.

    Downing, N. S. et al. Participation of the elderly, women, and minorities in pivotal trials supporting 2011–2013 U. S. Food and Drug Administration approvals. Trials 17, 199 (2016).

    PubMed  PubMed Central  Google Scholar 

  347. 347.

    Meier, T. et al. Healthcare costs associated with an adequate intake of sugars, salt and saturated fat in Germany: a health econometrical analysis. PLOS ONE 10, e0135990 (2015).

    PubMed  PubMed Central  Google Scholar 

  348. 348.

    Smed, S., Scarborough, P., Rayner, M. & Jensen, J. D. The effects of the Danish saturated fat tax on food and nutrient intake and modelled health outcomes: an econometric and comparative risk assessment evaluation. Eur. J. Clin. Nutr. 70, 681–686 (2016).

    CAS  PubMed  Google Scholar 

  349. 349.

    Smith-Spangler, C. M., Juusola, J. L., Enns, E. A., Owens, D. K. & Garber, A. M. Population strategies to decrease sodium intake and the burden of cardiovascular disease: a cost-effectiveness analysis. Ann. Intern. Med. 152, 481–487 (2010).

    PubMed  Google Scholar 

  350. 350.

    Palmer, S. C., Strippoli, G. F. & Craig, J. C. KHA-CARI commentary on the KDIGO clinical practice guideline for lipid management in chronic kidney disease. Nephrology (Carlton) 19, 663–666 (2014).

    Google Scholar 

  351. 351.

    Sarnak, M. J. et al. KDOQI US commentary on the 2013 KDIGO clinical practice guideline for lipid management in CKD. Am. J. Kidney Dis. 65, 354–366 (2015).

    PubMed  Google Scholar 

  352. 352.

    Schneider, M. P. et al. Implementation of the KDIGO guideline on lipid management requires a substantial increase in statin prescription rates. Kidney Int. 88, 1411–1418 (2015).

    CAS  PubMed  Google Scholar 

  353. 353.

    Eddy, D. M. et al. Individualized guidelines: the potential for increasing quality and reducing costs. Ann. Intern. Med. 154, 627–634 (2011).

    PubMed  Google Scholar 

  354. 354.

    Cooper, R. A. & Straus, D. J. Clinical guidelines, the politics of value, and the practice of medicine: physicians at the crossroads. J. Oncol. Pract. 8, 233–235 (2012).

    PubMed  PubMed Central  Google Scholar 

  355. 355.

    Glasziou, P. P. et al. Monitoring cholesterol levels: measurement error or true change? Ann. Intern. Med. 148, 656–661 (2008).

    PubMed  Google Scholar 

  356. 356.

    Takahashi, O. et al. Lipid re-screening: what is the best measure and interval? Heart 96, 448–452 (2010).

    PubMed  Google Scholar 

  357. 357.

    Hayward, R. A. & Krumholz, H. M. Three reasons to abandon low-density lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ. Cardiovasc. Qual. Outcomes 5, 2–5 (2012).

    PubMed  Google Scholar 

  358. 358.

    Chang, T. I., Desai, M., Solomon, D. H. & Winkelmayer, W. C. Kidney function and long-term medication adherence after myocardial infarction in the elderly. Clin. J. Am. Soc. Nephrol. 6, 864–869 (2011).

    PubMed  PubMed Central  Google Scholar 

  359. 359.

    Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).

    CAS  PubMed  Google Scholar 

  360. 360.

    Boekholdt, S. M. et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J. Am. Coll. Cardiol. 64, 485–494 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  361. 361.

    Marma, A. K., Berry, J. D., Ning, H., Persell, S. D. & Lloyd-Jones, D. M. Distribution of 10-year and lifetime predicted risks for cardiovascular disease in US adults: findings from the National Health and Nutrition Examination Survey 2003 to 2006. Circ. Cardiovasc. Qual. Outcomes 3, 8–14 (2010).

    PubMed  Google Scholar 

  362. 362.

    Zha, Y. & Qian, Q. Protein nutrition and malnutrition in CKD and ESRD. Nutrients 9, E208 (2017).

    PubMed  Google Scholar 

  363. 363.

    Schlackow, I. et al. A policy model of cardiovascular disease in moderate-to-advanced chronic kidney disease. Heart 103, 1880–1890 (2017).

    PubMed  PubMed Central  Google Scholar 

  364. 364.

    Epstein, M. & Vaziri, N. D. Statins in the management of dyslipidemia associated with chronic kidney disease. Nat. Rev. Nephrol. 8, 214–223 (2012).

    CAS  PubMed  Google Scholar 

  365. 365.

    Vaziri, N. D. & Norris, K. C. Reasons for the lack of salutary effects of cholesterol-lowering interventions in end-stage renal disease populations. Blood Purif. 35, 31–36 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  366. 366.

    Massy, Z. A. et al. Importance of geranylgeranyl pyrophosphate for mesangial cell DNA synthesis. Kidney Int. Suppl. 71, S80–83 (1999).

    CAS  PubMed  Google Scholar 

  367. 367.

    Beltowski, J., Wojcicka, G. & Jamroz-Wisniewska, A. Adverse effects of statins - mechanisms and consequences. Curr. Drug Saf. 4, 209–228 (2009).

    CAS  PubMed  Google Scholar 

  368. 368.

    Ezekowitz, J. et al. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J. Am. Coll. Cardiol. 44, 1587–1592 (2004).

    PubMed  Google Scholar 

  369. 369.

    Meyers, C. D. et al. Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis. 14, 8 (2015).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This Review was planned as part of the activity of the European Renal and Cardiovascular Medicine working (EURECAm) group and all authors are EURECAm members. A.O.’s work was supported by Spanish Government ISCIII FEDER funds (PI16/02057, ISCIII-RETIC REDinREN RD16/0009) and Community of Madrid (B2017/BMD-3686 CIFRA2-CM). P.R.’s work is supported by a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program FIGHT-HF (reference: ANR-15-RHU-0004) and by the French PIA project “Lorraine Université d’Excellence”, reference ANR-15-IDEX-04-LUE.”

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Nature Reviews Nephrology thanks N. Vaziri and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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C.J.F., P.B.M., M.K., R.V., C.Z. and A.O. researched the data and wrote the article. All authors made substantial contributions to discussions of the content and reviewed or edited the manuscript before submission.

Corresponding author

Correspondence to Charles J. Ferro.

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Competing interests

A.O. is a consultant for Sanofi Genzyme and has received speaker fees from Amgen. Z.A.M. has received grants for CKD REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka and the French government, as well as fees and grants to charities from Amgen and Daichii. P.R. has consulted for Novartis, Relypsa, AstraZeneca, Grünenthal, Stealth Peptides, Fresenius, Idorsia, Vifor Fresenius Medical Care Renal Pharma, Vifor and CTMA, has received lecture fees from Bayer and CVRx and is a cofounder of CardioRenal. The other authors declare no competing interests.

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Glossary

Hypertriglyceridaemia

Normally defined as a fasting plasma triglyceride level ≥2.3 mmol/l (200 mg/dl).

LDL subfractions

Subfractions of LDL particles are defined based on their size and density; small dense LDL particles are generally associated with high cardiovascular risk.

Atheroma

An abnormal mass of fatty or lipid material with a fibrous covering that exists as a discrete, raised plaque within the intima of an artery.

Chylomicron

A lipoprotein with a core of triglycerides surrounded by cholesterol, phospholipids and apolipoproteins that transports dietary fats from the small intestine to tissues after a meal.

Fibrinolysis

The process of enzymatic breakdown of fibrin, mainly by plasmin, that is the usual mechanism for the removal of fibrin clots.

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Ferro, C.J., Mark, P.B., Kanbay, M. et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol 14, 727–749 (2018). https://doi.org/10.1038/s41581-018-0072-9

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