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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
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).
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).
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).
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).
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).
Board, J. B. S. Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 100 Suppl. 2, ii1–ii67 (2014).
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).
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).
Hohenstein, B. Lipoprotein(a) in nephrological patients. Clin. Res. Cardiol. Suppl. 12, 27–30 (2017).
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).
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).
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).
Vanholder, R. et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol. Dial. Transplant. 20, 1048–1056 (2005).
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).
de Jager, D. J. et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 302, 1782–1789 (2009).
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).
Bottomley, M. J. & Harden, P. N. Update on the long-term complications of renal transplantation. Br. Med. Bull. 106, 117–134 (2013).
Neale, J. & Smith, A. C. Cardiovascular risk factors following renal transplant. World J. Transplant. 5, 183–195 (2015).
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).
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).
Hart, A., Weir, M. R. & Kasiske, B. L. Cardiovascular risk assessment in kidney transplantation. Kidney Int. 87, 527–534 (2015).
Pilmore, H., Dent, H., Chang, S., McDonald, S. P. & Chadban, S. J. Reduction in cardiovascular death after kidney transplantation. Transplantation 89, 851–857 (2010).
Hager, M. R., Narla, A. D. & Tannock, L. R. Dyslipidemia in patients with chronic kidney disease. Rev. Endocr. Metab. Disord. 18, 29–40 (2017).
Zheng-Lin, B. & Ortiz, A. Lipid management in chronic kidney disease: systematic review of PCSK9 targeting. Drugs 78, 215–229 (2018).
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).
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).
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).
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).
Mesquita, J., Varela, A. & Medina, J. L. Dyslipidemia in renal disease: causes, consequences and treatment. Endocrinol. Nutr. 57, 440–448 (2010).
Kaysen, G. A. New insights into lipid metabolism in chronic kidney disease. J. Ren Nutr. 21, 120–123 (2011).
Reiss, A. B., Voloshyna, I., De Leon, J., Miyawaki, N. & Mattana, J. Cholesterol metabolism in CKD. Am. J. Kidney Dis. 66, 1071–1082 (2015).
Vaziri, N. D. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am. J. Physiol. Renal Physiol. 290, F262–F272 (2006).
Kronenberg, F. HDL in CKD-the devil is in the detail. J. Am. Soc. Nephrol. 29, 1356–1371 (2018).
Annema, W. & von Eckardstein, A. Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy. Transl Res. 173, 30–57 (2016).
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).
Kaysen, G. A. Lipid and lipoprotein metabolism in chronic kidney disease. J. Ren Nutr. 19, 73–77 (2009).
Tsimihodimos, V., Mitrogianni, Z. & Elisaf, M. Dyslipidemia associated with chronic kidney disease. Open Cardiovasc. Med. J. 5, 41–48 (2011).
Gaudet, D., Drouin-Chartier, J. P. & Couture, P. Lipid metabolism and emerging targets for lipid-lowering therapy. Can. J. Cardiol. 33, 872–882 (2017).
Bermudez-Lopez, M. et al. New perspectives on CKD-induced dyslipidemia. Expert Opin. Ther. Targets 21, 967–976 (2017).
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).
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).
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).
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).
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).
Kwiterovich, P. O. Jr. Lipoprotein heterogeneity: diagnostic and therapeutic implications. Am. J. Cardiol. 90, 1i–10i (2002).
Gelissen, I. C. et al. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler. Thromb. Vasc. Biol. 26, 534–540 (2006).
Voloshyna, I. & Reiss, A. B. The ABC transporters in lipid flux and atherosclerosis. Prog. Lipid Res. 50, 213–224 (2011).
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).
Guarnieri, G. F. et al. Lecithin-cholesterol acyltransferase (LCAT) activity in chronic uremia. Kidney Int. Suppl. S26–S30 (1978).
Attman, P. O., Alaupovic, P. & Gustafson, A. Serum apolipoprotein profile of patients with chronic renal failure. Kidney Int. 32, 368–375 (1987).
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).
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).
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).
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).
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).
Navab, M. et al. Oxidized lipids as mediators of coronary heart disease. Curr. Opin. Lipidol. 13, 363–372 (2002).
Yamamoto, S. et al. Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. J. Am. Coll. Cardiol. 60, 2372–2379 (2012).
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).
Thompson, M. et al. Kidney function as a determinant of HDL and triglyceride concentrations in the Australian population. J. Clin. Med. 5, E35 (2016).
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).
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).
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).
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).
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).
Liang, K. & Vaziri, N. D. Acquired VLDL receptor deficiency in experimental nephrosis. Kidney Int. 51, 1761–1765 (1997).
Vaziri, N. D. & Liang, K. Down-regulation of VLDL receptor expression in chronic experimental renal failure. Kidney Int. 51, 913–919 (1997).
Li, P. K. et al. Randomized, controlled trial of glucose-sparing peritoneal dialysis in diabetic patients. J. Am. Soc. Nephrol. 24, 1889–1900 (2013).
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).
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).
Nordestgaard, B. G. & Varbo, A. Triglycerides and cardiovascular disease. Lancet 384, 626–635 (2014).
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).
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).
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).
Lamprea-Montealegre, J. A. et al. Coronary heart disease risk associated with the dyslipidaemia of chronic kidney disease. Heart 104, 1455–1460 (2018).
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).
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).
Berg, K. A. New serum type system in man — the Lp system. Acta Pathol. Microbiol. Scand. 59, 369–382 (1963).
Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).
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).
Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013).
Langsted, A., Kamstrup, P. R. & Nordestgaard, B. G. Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis 234, 95–101 (2014).
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).
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).
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).
Catapano, A. L. et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur. Heart J. 37, 2999–3058 (2016).
Agrawal, S., Zaritsky, J. J., Fornoni, A. & Smoyer, W. E. Dyslipidaemia in nephrotic syndrome: mechanisms and treatment. Nat. Rev. Nephrol. 14, 57–70 (2018).
Vaziri, N. D. Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences. Kidney Int. 90, 41–52 (2016).
Dounousi, E. et al. Oxidative stress is progressively enhanced with advancing stages of CKD. Am. J. Kidney Dis. 48, 752–760 (2006).
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).
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).
Uchida, K. Role of reactive aldehyde in cardiovascular diseases. Free Radic. Biol. Med. 28, 1685–1696 (2000).
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).
Levitan, I., Volkov, S. & Subbaiah, P. V. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid. Redox Signal. 13, 39–75 (2010).
Drozdz, D. et al. Oxidative stress biomarkers and left ventricular hypertrophy in children with chronic kidney disease. Oxid. Med. Cell. Longev. 2016, 7520231 (2016).
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).
Massy, Z. A. & de Zeeuw, D. LDL cholesterol in CKD — to treat or not to treat? Kidney Int. 84, 451–456 (2013).
Speer, T. et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38, 754–768 (2013).
Vaziri, N. D. HDL abnormalities in nephrotic syndrome and chronic kidney disease. Nat. Rev. Nephrol. 12, 37–47 (2016).
Haas, M. E. et al. The role of proprotein convertase Subtilisin/Kexin type 9 in nephrotic syndrome-associated hypercholesterolemia. Circulation 134, 61–72 (2016).
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).
Agarwal, A. & Prasad, G. V. Post-transplant dyslipidemia: mechanisms, diagnosis and management. World J. Transplant 6, 125–134 (2016).
de Groen, P. C. Cyclosporine, low-density lipoprotein, and cholesterol. Mayo Clin. Proc. 63, 1012–1021 (1988).
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).
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).
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).
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).
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).
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).
Kasiske, B. L. et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am. J. Transplant. 8, 1384–1392 (2008).
Emerging Risk Factors Collaboration et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009).
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).
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).
Baigent, C., Burbury, K. & Wheeler, D. Premature cardiovascular disease in chronic renal failure. Lancet 356, 147–152 (2000).
Zoccali, C. Cardiovascular risk in uraemic patients-is it fully explained by classical risk factors? Nephrol. Dial. Transplant. 15, 454–457 (2000).
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).
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).
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).
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).
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).
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).
Mall, G., Huther, W., Schneider, J., Lundin, P. & Ritz, E. Diffuse intermyocardiocytic fibrosis in uraemic patients. Nephrol. Dial. Transplant. 5, 39–44 (1990).
Aoki, J. et al. Clinical and pathologic characteristics of dilated cardiomyopathy in hemodialysis patients. Kidney Int. 67, 333–340 (2005).
Storey, B. C. et al. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney Int. 93, 1000–1007 (2018).
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).
Liu, Y. et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 291, 451–459 (2004).
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).
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).
Castelli, W. P. et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 256, 2835–2838 (1986).
Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).
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).
Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).
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).
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).
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).
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).
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).
Silbernagel, G. et al. HDL cholesterol, apolipoproteins, and cardiovascular risk in hemodialysis patients. J. Am. Soc. Nephrol. 26, 484–492 (2015).
Moradi, H. et al. Elevated high-density lipoprotein cholesterol and cardiovascular mortality in maintenance hemodialysis patients. Nephrol. Dial. Transplant. 29, 1554–1562 (2014).
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).
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).
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).
Levy, R. I. & Glueck, C. J. Hypertriglyceridemia, diabetes mellitus, and coronary vessel disease. Arch. Intern. Med. 123, 220–228 (1969).
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).
Vaziri, N. D. Causes of dysregulation of lipid metabolism in chronic renal failure. Semin. Dial. 22, 644–651 (2009).
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).
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).
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).
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).
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).
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).
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).
Collins, R. et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 388, 2532–2561 (2016).
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).
Shepherd, J. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med. 333, 1301–1307 (1995).
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).
Tonelli, M. et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 110, 1557–1563 (2004).
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).
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).
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).
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).
Fellstrom, B. C. et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N. Engl. J. Med. 360, 1395–1407 (2009).
Wanner, C. et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 353, 238–248 (2005).
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).
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).
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).
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).
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).
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).
Haynes, R. et al. Effects of lowering LDL cholesterol on progression of kidney disease. J. Am. Soc. Nephrol. 25, 1825–1833 (2014).
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).
Krumholz, H. M. Statins evidence: when answers also raise questions. BMJ 354, i4963 (2016).
Tonelli, M. et al. Association between LDL-C and risk of myocardial infarction in CKD. J. Am. Soc. Nephrol. 24, 979–986 (2013).
Tsimikas, S. A. Test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol. 69, 692–711 (2017).
Hopewell, J. C., Haynes, R. & Baigent, C. The role of lipoprotein(a) in chronic kidney disease. J. Lipid Res. 59, 577–585 (2018).
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).
Palmer, S. C. et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst. Rev. CD004289 (2013).
Palmer, S. C. et al. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst. Rev. 1, CD005019 (2014).
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).
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).
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).
Libby, P. Inflammation in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 32, 2045–2051 (2012).
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).
Handelman, G. J. et al. Elevated plasma F2-isoprostanes in patients on long-term hemodialysis. Kidney Int. 59, 1960–1966 (2001).
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).
Akchurin, O. M. & Kaskel, F. Update on inflammation in chronic kidney disease. Blood Purif. 39, 84–92 (2015).
Amdur, R. L. et al. Inflammation and progression of CKD: The CRIC Study. Clin. J. Am. Soc. Nephrol. 11, 1546–1556 (2016).
Oesterle, A., Laufs, U. & Liao, J. K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res. 120, 229–243 (2017).
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).
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).
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).
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).
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).
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).
Lipscombe, J., Lewis, G. F., Cattran, D. & Bargman, J. M. Deterioration in renal function associated with fibrate therapy. Clin. Nephrol. 55, 39–44 (2001).
Lipscombe, J. & Bargman, J. M. Fibrate-induced increase in blood urea and creatinine. Nephrol. Dial. Transplant. 16, 1515 (2001).
Sica, D. A. Fibrate therapy and renal function. Curr. Atheroscler. Rep. 11, 338–342 (2009).
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).
Insull, W. Jr. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med. J. 99, 257–273 (2006).
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).
Couture, P. & Lamarche, B. Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond. Curr. Opin. Lipidol. 24, 227–232 (2013).
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).
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).
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).
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).
Harper, C. R. & Jacobson, T. A. Managing dyslipidemia in chronic kidney disease. J. Am. Coll. Cardiol. 51, 2375–2384 (2008).
Friedman, A. & Moe, S. Review of the effects of omega-3 supplementation in dialysis patients. Clin. J. Am. Soc. Nephrol. 1, 182–192 (2006).
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).
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).
Weintraub, H. S. Overview of prescription omega-3 fatty acid products for hypertriglyceridemia. Postgrad. Med. 126, 7–18 (2014).
Wu, L. & Parhofer, K. G. Diabetic dyslipidemia. Metabolism 63, 1469–1479 (2014).
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).
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).
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).
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).
Harris, W. S. & Bulchandani, D. Why do omega-3 fatty acids lower serum triglycerides? Curr. Opin. Lipidol. 17, 387–393 (2006).
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).
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).
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).
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).
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).
Barter, P. J. & Rye, K. A. New era of lipid-lowering drugs. Pharmacol. Rev. 68, 458–475 (2016).
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).
Lambert, G., Sjouke, B., Choque, B., Kastelein, J. J. & Hovingh, G. K. The PCSK9 decade. J. Lipid Res. 53, 2515–2524 (2012).
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).
Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).
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).
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).
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).
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).
Lepor, N. E. & Kereiakes, D. J. The PCSK9 inhibitors: a novel therapeutic target enters clinical practice. Am. Health Drug Benefits 8, 483–489 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Stein, E. A. & Raal, F. Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9. Annu. Rev. Med. 65, 417–431 (2014).
Robinson, J. G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).
Toth, P. P. et al. Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease. Kidney Int. 93, 1397–1408 (2018).
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).
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).
Fitzgerald, G. & Kiernan, T. PCSK9 inhibitors and LDL reduction: pharmacology, clinical implications, and future perspectives. Expert Rev. Cardiovasc. Ther. 16, 567–578 (2018).
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).
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).
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).
Blom, D. J. et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med. 370, 1809–1819 (2014).
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).
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).
Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).
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).
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).
Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).
Khvorova, A. Oligonucleotide therapeutics - a new class of cholesterol-lowering drugs. N. Engl. J. Med. 376, 4–7 (2017).
Fitzgerald, K. et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376, 41–51 (2017).
Ray, K. K. et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376, 1430–1440 (2017).
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).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03060577?term=NCT03060577&rank=1 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02963311?term=NCT02963311&rank=1 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03399370?term=NCT03399370&rank=1 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03400800?term=NCT03400800&rank=1(2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03159416?term=NCT03159416&rank=1 (2018).
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).
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).
Lincoff, A. M. et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N. Engl. J. Med. 376, 1933–1942 (2017).
Tall, A. R. & Rader, D. J. The trials and tribulations of CETP inhibitors. Circ. Res. 122, 106–112 (2018).
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).
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).
HPS3/TIMI55–REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med. 377, 1217–1227 (2017).
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).
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).
Moradi, H. & Vaziri, N. D. Molecular mechanisms of disorders of lipid metabolism in chronic kidney disease. Front. Biosci. (Landmark Ed) 23, 146–161 (2018).
Feinberg, M. W. No small task: therapeutic targeting of Lp(a) for cardiovascular disease. Lancet 388, 2211–2212 (2016).
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).
Tsimikas, S. et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–1483 (2015).
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).
Hussain, M. M., Rava, P., Walsh, M., Rana, M. & Iqbal, J. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.) 9, 14 (2012).
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).
Yamamoto, T., Wada, F. & Harada-Shiba, M. Development of antisense drugs for dyslipidemia. J. Atheroscler. Thromb. 23, 1011–1025 (2016).
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).
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).
Hussain, M. M. & Bakillah, A. New approaches to target microsomal triglyceride transfer protein. Curr. Opin. Lipidol. 19, 572–578 (2008).
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).
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).
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).
Ajufo, E. & Rader, D. J. New therapeutic approaches for familial hypercholesterolemia. Annu. Rev. Med. 69, 113–131 (2018).
Gordts, P. L. et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J. Clin. Invest. 126, 2855–2866 (2016).
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).
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).
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).
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).
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).
Dewey, F. E. et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377, 211–221 (2017).
Graham, M. J. et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 377, 222–232 (2017).
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).
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).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03473223?term=NCT03473223&rank=1 (2018).
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).
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).
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).
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).
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).
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).
Chypre, M., Zaidi, N. & Smans, K. ATP-citrate lyase: a mini-review. Biochem. Biophys. Res. Commun. 422, 1–4 (2012).
Burke, A. C. & Huff, M. W. ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia. Curr. Opin. Lipidol. 28, 193–200 (2017).
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).
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).
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).
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).
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).
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).
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).
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).
Thompson, P. D. et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J. Clin. Lipidol. 9, 295–304 (2015).
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).
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).
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).
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).
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).
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).
Mistry, H. et al. Cost-effectiveness of a European preventive cardiology programme in primary care: a Markov modelling approach. BMJ Open 2, e001029 (2012).
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).
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).
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).
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).
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).
National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. NICE https://www.nice.org.uk/guidance/ta394 (2016).
Villa, G. et al. Cost-effectiveness of evolocumab in patients with high cardiovascular risk in Spain. Clin. Ther. 39, 771–786.e3 (2017).
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).
Pratt, C. M. & Moye, L. A. The cardiac arrhythmia suppression trial. Casting suppression in a different light. Circulation 91, 245–247 (1995).
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).
Carlberg, B., Samuelsson, O. & Lindholm, L. H. Atenolol in hypertension: is it a wise choice? Lancet 364, 1684–1689 (2004).
Singh, A. K. et al. Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 355, 2085–2098 (2006).
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).
ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N. Engl. J. Med. 361, 1953–1962 (2009).
Barrett, A., Roques, T., Small, M. & Smith, R. D. How much will Herceptin really cost? Bmj 333, 1118–1120 (2006).
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).
Joseph, P. D., Craig, J. C. & Caldwell, P. H. Clinical trials in children. Br. J. Clin. Pharmacol. 79, 357–369 (2015).
Liu, K. A. & Mager, N. A. Women’s involvement in clinical trials: historical perspective and future implications. Pharm. Pract. (Granada) 14, 708 (2016).
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).
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).
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).
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).
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).
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).
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).
Eddy, D. M. et al. Individualized guidelines: the potential for increasing quality and reducing costs. Ann. Intern. Med. 154, 627–634 (2011).
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).
Glasziou, P. P. et al. Monitoring cholesterol levels: measurement error or true change? Ann. Intern. Med. 148, 656–661 (2008).
Takahashi, O. et al. Lipid re-screening: what is the best measure and interval? Heart 96, 448–452 (2010).
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).
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).
Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).
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).
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).
Zha, Y. & Qian, Q. Protein nutrition and malnutrition in CKD and ESRD. Nutrients 9, E208 (2017).
Schlackow, I. et al. A policy model of cardiovascular disease in moderate-to-advanced chronic kidney disease. Heart 103, 1880–1890 (2017).
Epstein, M. & Vaziri, N. D. Statins in the management of dyslipidemia associated with chronic kidney disease. Nat. Rev. Nephrol. 8, 214–223 (2012).
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).
Massy, Z. A. et al. Importance of geranylgeranyl pyrophosphate for mesangial cell DNA synthesis. Kidney Int. Suppl. 71, S80–83 (1999).
Beltowski, J., Wojcicka, G. & Jamroz-Wisniewska, A. Adverse effects of statins - mechanisms and consequences. Curr. Drug Saf. 4, 209–228 (2009).
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).
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).
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.”
Nature Reviews Nephrology thanks N. Vaziri and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
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.
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.
The process of enzymatic breakdown of fibrin, mainly by plasmin, that is the usual mechanism for the removal of fibrin clots.
About this article
Cite this article
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
Nature Reviews Nephrology (2021)
Relationship between serum lipid concentrations and impaired renal function in patients with chronic kidney disease: the Fukuoka Kidney Disease Registry Study
Clinical and Experimental Nephrology (2021)
BMC Nephrology (2020)
Functional training added to intradialytic cycling lowers low-density lipoprotein cholesterol and improves dialysis adequacy: a randomized controlled trial
BMC Nephrology (2020)
Association of lipid profiles with severity and outcome of acute ischemic stroke in patients with and without chronic kidney disease
Neurological Sciences (2020)