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Published in:

01-09-2014 | Diabetes and Cardiovascular Disease (S Malik, Section Editor)

Role of HDL in Those with Diabetes

Authors: Carlos G. Santos-Gallego, Robert S. Rosenson

Published in: Current Cardiology Reports | Issue 9/2014

Abstract

Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with an increased risk of coronary heart disease in prospective population studies and clinical trials of high-risk patients treated with a low to moderate intensity statin. As a result, therapeutic targets were developed to increase concentrations of HDL-C. Subsequently, clinical trials of high-intensity statins have not supported this previously well-established association. In trials of high-intensity statin therapy, low HDL particle concentration (HDL-P) has been associated with an increased risk of future cardiovascular events. Therefore, strategies that increase HDL-C without expanding the pool of HDL-P with its rich proteome/lipidome do not seem to be an effective strategy. In this review, we discuss potential mechanisms of action for the anti-atherogenic effect of HDL and the impact of current and emerging therapies on the functional capacity of HDL-P. Finally, we discuss emerging therapies that increase the concentration and functional properties of HDL.

Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e21–181.PubMedCrossRef

Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78.PubMedCrossRef

Fruchart JC, Sacks FM, Hermans MP, Assmann G, Brown WV, Ceska R, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diabetes Vasc Dis Res. 2008;5:319–35.CrossRef

LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.PubMedCrossRef

Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–10.PubMedCrossRef

Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. 2010;376:333–9.PubMedCrossRef

7.••

Mora S, Glynn RJ, Ridker PM. High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy. Circulation. 2013;128:1189–97. Groundbreaking study proving that HDL-P concentration is a better marker of residual risk than HDL-C. In the setting of potent statin therapy (JUPITER trial), HDL-P predict CV events, while HDL-C or apo A-I do not. PubMedCrossRef

8.••

Rosenson RS, Brewer Jr HB, Ansell B, Barter P, Chapman MJ, Heinecke JW, et al. Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges. Circulation. 2013;128:1256–67. A thorough and up-to-date review on the “pleiotropic” effects of HDL. PubMed

9.••

Rosenson RS, Brewer Jr HB, Chapman MJ, Fazio S, Hussain MM, Kontush A, et al. HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem. 2011;57:392–410. A new standardized and homogenous classification of HDL is proposed. PubMedCrossRef

10.••

Rosenson RS, Brewer Jr HB, Davidson WS, Fayad ZA, Fuster V, Goldstein J, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125:1905–19. In-depth review of the concept of macrophage reverses cholesterol transport and the different methods to quantify it. PubMedCrossRef

11.

Santos-Gallego CG, Torres F, Badimon JJ. The beneficial effects of HDL-C on atherosclerosis: rationale and clinical results. Clin Lipidol. 2011;6:181–208.CrossRef

12.

Davidson WS, Silva RA, Chantepie S, Lagor WR, Chapman MJ, Kontush A. Proteomic analysis of defined HDL subpopulations reveals particle-specific protein clusters: relevance to antioxidative function. Arterioscler Thromb Vasc Biol. 2009;29:870–6.PubMedCentralPubMedCrossRef

13.

Santos-Gallego CG, Giannarelli C, Badimon JJ. Experimental models for the investigation of high-density lipoprotein-mediated cholesterol efflux. Curr Atheroscler Rep. 2011;13:266–76.PubMedCrossRef

14.

Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–35.PubMedCentralPubMedCrossRef

15.•

Li XM, Tang WH, Mosior MK, Huang Y, Wu Y, Matter W, et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol. 2013;33:1696–705. Increased ABCA1-mediated cholesterol efflux was associated to reduced risk of prevalent coronary atherosclerotic disease, but it was also paradoxically associated with an increase in the risk of myocardial infarction and cardiovascular death. PubMedCentralPubMedCrossRef

16.•

Camont L, Lhomme M, Rached F, Le Goff W, Negre-Salvayre A, Salvayre R, et al. Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and anti-apoptotic functionalities. Arterioscler Thromb Vasc Biol. 2013;33:2715–23. The composition of the HDL lipidome influences HDL functionality. An increase in phosphatidylserine (especially on HDL-S) improves the functionality of HDL-P. PubMedCrossRef

17.

Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, et al. Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med. 2007;13:340–7.PubMedCrossRef

18.

Vergeer M, Brunham LR, Koetsveld J, Kruit JK, Verchere CB, Kastelein JJ, et al. Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction. Diabetes Care. 2010;33:869–74.PubMedCentralPubMedCrossRef

19.•

Drew BG, Rye KA, Duffy SJ, Barter P, Kingwell BA. The emerging role of HDL in glucose metabolism. Nat Rev Endocrinol. 2012;8:237–45. Interesting review of the “pleiotropic” role of HDL in modulating glucose metabolism. PubMed

20.

Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, et al. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation. 2009;119:2103–11.PubMedCrossRef

21.

Han R, Lai R, Ding Q, Wang Z, Luo X, Zhang Y, et al. Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism. Diabetologia. 2007;50:1960–8.PubMedCrossRef

22.

Drew BG, Carey AL, Natoli AK, Formosa MF, Vizi D, Reddy-Luthmoodoo M, et al. Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus. J Lipid Res. 2011;52:572–81.PubMedCentralPubMedCrossRef

23.

Theilmeier G, Schmidt C, Herrmann J, Keul P, Schafers M, Herrgott I, et al. High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation. 2006;114:1403–9.PubMedCrossRef

24.

Calabresi L, Rossoni G, Gomaraschi M, Sisto F, Berti F, Franceschini G. High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion injury by reducing cardiac tumor necrosis factor-alpha content and enhancing prostaglandin release. Circ Res. 2003;92:330–7.PubMedCrossRef

25.

Rossoni G, Gomaraschi M, Berti F, Sirtori CR, Franceschini G, Calabresi L. Synthetic high-density lipoproteins exert cardioprotective effects in myocardial ischemia/reperfusion injury. J Pharmacol Exp Ther. 2004;308:79–84.PubMedCrossRef

26.

Marchesi M, Booth EA, Rossoni G, Garcia RA, Hill KR, Sirtori CR, et al. Apolipoprotein A-IMilano/POPC complex attenuates post-ischemic ventricular dysfunction in the isolated rabbit heart. Atherosclerosis. 2008;197:572–8.PubMedCrossRef

27.

Sattler KJ, Herrmann J, Yun S, Lehmann N, Wang Z, Heusch G, et al. High high-density lipoprotein-cholesterol reduces risk and extent of percutaneous coronary intervention-related myocardial infarction and improves long-term outcome in patients undergoing elective percutaneous coronary intervention. Eur Heart J. 2009;30:1894–902.PubMedCrossRef

28.

Van Lenten BJ, Hama SY, de Beer FC, Stafforini DM, McIntyre TM, Prescott SM, et al. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell co-cultures. J Clin Invest. 1995;96:2758–67.PubMedCentralPubMedCrossRef

29.

Van Lenten BJ, Wagner AC, Nayak DP, Hama S, Navab M, Fogelman AM. High-density lipoprotein loses its anti-inflammatory properties during acute Influenza A infection. Circulation. 2001;103:2283–8.PubMedCrossRef

30.

Morgantini C, Natali A, Boldrini B, Imaizumi S, Navab M, Fogelman AM, et al. Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes. 2011;60:2617–23.PubMedCentralPubMedCrossRef

31.

Zheng L, Nukuna B, Brennan ML, Sun M, Goormastic M, Settle M, et al. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest. 2004;114:529–41.PubMedCentralPubMedCrossRef

32.•

Huang Y, Didonato JA, Levison BS, Schmitt D, Li L, Wu Y, Buffa J, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med. 2014;20:193–203. Apo A-I is oxidized at the position Trp72 by MPO in atheroma lesions, which reduces HDL functionality. This Trp72-oxidized apo A-I can subsequently diffuse back into plasma, thus, giving a mechanistic explanation for HDL dysfunction.

33.

Hoang A, Murphy AJ, Coughlan MT, Thomas MC, Forbes JM, O'Brien R, et al. Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties. Diabetologia. 2007;50:1770–9.PubMedCrossRef

34.

Ansell BJ, Navab M, Hama S, Kamranpour N, Fonarow G, Hough G, et al. Inflammatory/anti-inflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation. 2003;108:2751–6.PubMedCrossRef

35.

Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest. 2011;121:2693–708.PubMedCentralPubMedCrossRef

36.•

Riwanto M, Rohrer L, Roschitzki B, Besler C, Mocharla P, Mueller M, et al. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation. 2013;127:891–904. The composition of the HDL proteome influences HDL functionality, especially regarding anti-apoptotic effects on endothelial cells. PubMedCrossRef

37.

Sorrentino SA, Besler C, Rohrer L, Meyer M, Heinrich K, Bahlmann FH, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. 2010;121:110–22.PubMedCrossRef

38.

Choudhury RP, Leyva F. C-Reactive protein, serum amyloid A protein, and coronary events. Circulation. 1999;100:e65–6.PubMedCrossRef

39.

Nobecourt E, Jacqueminet S, Hansel B, Chantepie S, Grimaldi A, Chapman MJ, et al. Defective antioxidative activity of small dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and hyperglycaemia. Diabetologia. 2005;48:529–38.PubMedCrossRef

40.

de Souza JA, Vindis C, Hansel B, Negre-Salvayre A, Therond P, Serrano Jr CV, et al. Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity. Atherosclerosis. 2008;197:84–94.PubMedCrossRef

41.

Zerrad-Saadi A, Therond P, Chantepie S, Couturier M, Rye KA, Chapman MJ, et al. HDL3-mediated inactivation of LDL-associated phospholipid hydroperoxides is determined by the redox status of apolipoprotein A-I and HDL particle surface lipid rigidity: relevance to inflammation and atherogenesis. Arterioscler Thromb Vasc Biol. 2009;29:2169–75.PubMedCrossRef

42.

Garvey WT, Kwon S, Zheng D, Shaughnessy S, Wallace P, Hutto A, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes. 2003;52:453–62.PubMedCrossRef

43.

Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15.PubMedCrossRef

44.

deGoma EM, Leeper NJ, Heidenreich PA. Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol. J Am Coll Cardiol. 2008;51:49–55.PubMedCrossRef

45.•

Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet. 2012;380:572–80. Genetic variation in the activity of endothelial lipase (which increases HDL-C levels) is not associated with risk of myocardial infarction. However, we must take into account that EL increases HDL-C without affecting the concentration of HDL-P. PubMedCentralPubMedCrossRef

46.•

Ray K, Wainwright NW, Visser L, Witteman J, Breteler M, Ambegaonkar B, et al. Changes in HDL cholesterol and cardiovascular outcomes after lipid modification therapy. Heart. 2012;98:780–5. In a subanalysis of 1148 participants in EPIC-Norfolk and Rotterdam studies, changes in HDL-C after lipid-modifying therapy did not predict CV risk. PubMedCentralPubMedCrossRef

47.

Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009;338:b92.PubMedCentralPubMedCrossRef

48.

Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.PubMedCrossRef

49.•

Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–99. In 15871 patients with a recent ACS, the CETP inhibitor dalcetrapib increased HDL-C levels but did not reduce the risk of recurrent cardiovascular events. PubMedCrossRef

50.

Ginsberg HN, Elam MB, Lovato LC, Crouse III JR, Leiter LA, Linz P, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.PubMedCrossRef

51.

Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol. 2002;90:22i–9.PubMedCrossRef

52.

Kuller LH, Grandits G, Cohen JD, Neaton JD, Prineas R. Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome. Atherosclerosis. 2007;195:122–8.PubMedCentralPubMedCrossRef

53.••

Mackey RH, Greenland P, Goff Jr DC, Lloyd-Jones D, Sibley CT, Mora S. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2012;60:508–16. In 5598 participants of the MESA trial, HDL-C did not predict carotid intima-media thickness (cIMT) of CVD events after adjusting by LDL-P. However, HDL-P (measured by NMR) predicted both cIMT and CV events, even after adjusting by LDL-P and HDL-C. PubMedCentralPubMedCrossRef

54.•

Akinkuolie AO, Paynter NP, Padmanabhan L, Mora S. High-density lipoprotein particle subclass heterogeneity and incident coronary heart disease. Circ Cardiovasc Qual Outcomes. 2014;7:55–63. Another proof that HDL-P (and not HDL-C) explains CVD risk. Twenty-six thousand, three hundred thirty-two women were followed-up for 17 years. Concentrations of HDL-P (specifically of HDL-S, HDL-M and HDL-L) were inversely associated with CVD risk, even after adjusting for HDL-C. PubMedCrossRef

55.

Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, McNamara JR, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006;113:1556–63.PubMedCrossRef

56.

Vergeer M, Boekholdt SM, Sandhu MS, Ricketts SL, Wareham NJ, Brown MJ, et al. Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility. Circulation. 2010;122:470–7.PubMedCrossRef

57.

Kraus WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB, McCartney JS, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med. 2002;347:1483–92.PubMedCrossRef

58.

Kodama S, Tanaka S, Saito K, Shu M, Sone Y, Onitake F, et al. Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis. Arch Intern Med. 2007;167:999–1008.PubMedCrossRef

59.

Roberts CK, Ng C, Hama S, Eliseo AJ, Barnard RJ. Effect of a short-term diet and exercise intervention on inflammatory/anti-inflammatory properties of HDL in overweight/obese men with cardiovascular risk factors. J Appl Physiol. 2006;101:1727–32.PubMedCrossRef

60.

Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med. 1991;325:461–6.PubMedCrossRef

61.

Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56:320–8.PubMed

62.

Schwartz RS, Brunzell JD. Increase of adipose tissue lipoprotein lipase activity with weight loss. J Clin Invest. 1981;67:1425–30.PubMedCentralPubMedCrossRef

63.

Weisweiler P. Plasma lipoproteins and lipase and lecithin:cholesterol acyltransferase activities in obese subjects before and after weight reduction. J Clin Endocrinol Metab. 1987;65:969–73.PubMedCrossRef

64.

Aron-Wisnewsky J, Julia Z, Poitou C, Bouillot JL, Basdevant A, Chapman MJ, et al. Effect of bariatric surgery-induced weight loss on SR-BI-, ABCG1-, and ABCA1-mediated cellular cholesterol efflux in obese women. J Clin Endocrinol Metab. 2011;96:1151–9.PubMedCrossRef

65.

Craig WY, Palomaki GE, Haddow JE. Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. BMJ. 1989;298:784–8.PubMedCentralPubMedCrossRef

66.

Richard F, Marecaux N, Dallongeville J, Devienne M, Tiem N, Fruchart JC, et al. Effect of smoking cessation on lipoprotein A-I and lipoprotein A-I:A-II levels. Metabolism. 1997;46:711–5.PubMedCrossRef

67.

Maeda K, Noguchi Y, Fukui T. The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis. Prev Med. 2003;37:283–90.PubMedCrossRef

68.

Valmadrid CT, Klein R, Moss SE, Klein BE, Cruickshanks KJ. Alcohol intake and the risk of coronary heart disease mortality in persons with older-onset diabetes mellitus. JAMA. 1999;282:239–46.PubMedCrossRef

69.

Mukamal KJ, Conigrave KM, Mittleman MA, Camargo Jr CA, Stampfer MJ, Willett WC, et al. Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med. 2003;348:109–18.PubMedCrossRef

70.

Costanzo S, Di Castelnuovo A, Donati MB, Iacoviello L, de Gaetano G. Alcohol consumption and mortality in patients with cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2010;55:1339–47.

71.••

Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–90. This randomized control trial convincingly proves that Mediterranean diet (with supplementation with olive oil and nuts) results in reduced mortality and lower cardiovascular risk in patients with cardiovascular disease. PubMedCrossRef

72.

Nicholls SJ, Lundman P, Harmer JA, Cutri B, Griffiths KA, Rye KA, et al. Consumption of saturated fat impairs the anti-inflammatory properties of high-density lipoproteins and endothelial function. J Am Coll Cardiol. 2006;48:715–20.PubMedCrossRef

73.

Frost G, Leeds AA, Dore CJ, Madeiros S, Brading S, Dornhorst A. Glycaemic index as a determinant of serum HDL-cholesterol concentration. Lancet. 1999;353:1045–8.PubMedCrossRef

74.

Ford ES, Liu S. Glycemic index and serum high-density lipoprotein cholesterol concentration among us adults. Arch Intern Med. 2001;161:572–6.PubMedCrossRef

75.

Mosdol A, Witte DR, Frost G, Marmot MG, Brunner EJ. Dietary glycemic index and glycemic load are associated with high-density-lipoprotein cholesterol at baseline but not with increased risk of diabetes in the Whitehall II study. Am J Clin Nutr. 2007;86:988–94.PubMed

76.

Rosenson RS, Otvos JD, Hsia J. Effects of rosuvastatin and atorvastatin on LDL and HDL particle concentrations in patients with metabolic syndrome: a randomized, double-blind, controlled study. Diabetes Care. 2009;32:1087–91.PubMedCentralPubMedCrossRef

77.

Schaefer JR, Schweer H, Ikewaki K, Stracke H, Seyberth HJ, Kaffarnik H, et al. Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease. Atherosclerosis. 1999;144:177–84.PubMedCrossRef

78.

Chapman MJ, Le Goff W, Guerin M, Kontush A. Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J. 2010;31:149–64.PubMedCentralPubMedCrossRef

79.

Guerin M, Egger P, Soudant C, Le Goff W, van Tol A, Dupuis R, et al. Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux. Atherosclerosis. 2002;163:287–96.PubMedCrossRef

80.•

Niesor EJ, Schwartz GG, Suchankova G, Benghozi R, Abt M, Kallend D. Statin decrease in transporter ABC A1 expression via miR33 induction may counteract cholesterol efflux by high-density lipoproteins raised with the cholesteryl ester transfer protein modulator dalcetrapib. Atherosclerosis. 2014; [In press]. In vitro models of cell culture show that statin treatment result in a reduction of ABCA1 expression via a statin-induced increase in miR33. This result seems to be confirmed because statin treatment reduces the effect of HDL on ABCA1-mediated cholesterol efflux. This finding might explain the lack of effect of HDL-raising therapies in patients already on statins.

81.

Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98:2088–93.PubMedCrossRef

82.

Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, 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. 1987;317:1237–45.PubMedCrossRef

83.

Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992;85:37–45.PubMedCrossRef

84.

Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, 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. 1999;341:410–8.PubMedCrossRef

85.

Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000;102:21–7.

86.

Scott R, O'Brien R, Fulcher G, Pardy C, D'Emden M, Tse D, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care. 2009;32:493–8.PubMedCentralPubMedCrossRef

87.

Ginsberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, Linz P, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.

88.

Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875–84.PubMedCrossRef

89.

Airan-Javia SL, Wolf RL, Wolfe ML, Tadesse M, Mohler E, Reilly MP. Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared with low- and high-dose simvastatin monotherapy. Am Heart J. 2009;157:687. e681–8. PubMedCentralPubMedCrossRef

90.

Yvan-Charvet L, Kling J, Pagler T, Li H, Hubbard B, Fisher T, et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30:1430–8.PubMedCentralPubMedCrossRef

91.•

Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol. 2013;62:1909–10. The addition of niacin to statin therapy led to favorable changes in patients’ lipid profiles without a demonstrable effect on HDL functionality, thus, providing 1 potential mechanistic hypothesis for the disappointing results in recent clinical trials. PubMedCrossRef

92.

Wu BJ, Yan L, Charlton F, Witting P, Barter PJ, Rye KA. Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. Arterioscler Thromb Vasc Biol. 2010;30:968–75.PubMedCrossRef

93.

Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990;323:1234–8.PubMedCrossRef

94.

Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004;350:1505–15.PubMedCrossRef

95.

Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–22.PubMedCrossRef

96.

Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356:1304–16.PubMedCrossRef

97.

Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomized, double-blind trial. Lancet. 2007;370:153–60.PubMedCrossRef

98.

Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356:1620–30.PubMedCrossRef

99.

Yvan-Charvet L, Matsuura F, Wang N, Bamberger MJ, Nguyen T, Rinninger F, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27:1132–8.PubMedCrossRef

100.

Bellanger N, Julia Z, Villard EF, El Khoury P, Duchene E, Chapman MJ, et al. Functionality of postprandial larger HDL2 particles is enhanced following CETP inhibition therapy. Atherosclerosis. 2012;221:160–8.PubMedCrossRef

101.

de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002;105:2159–65.PubMedCrossRef

102.

Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378:1547–59.

103.

Luscher TF, Taddei S, Kaski JC, Jukema JW, Kallend D, Munzel T, et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J. 2012;33:857–65.PubMedCentralPubMedCrossRef

104.

Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406–15.

105.

Franceschini G, Sirtori CR, Capurso II A, Weisgraber KH, Mahley RW. A-‘IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest. 1980;66:892–900.PubMedCentralPubMedCrossRef

106.

Sirtori CR, Calabresi L, Franceschini G, Baldassarre D, Amato M, Johansson J, et al. Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. Circulation. 2001;103:1949–54.PubMedCrossRef

107.

Shah PK, Nilsson J, Kaul S, Fishbein MC, Ageland H, Hamsten A, et al. Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation. 1998;97:780–5.PubMedCrossRef

108.

Ibanez B, Vilahur G, Cimmino G, Speidl WS, Pinero A, Choi BG, et al. Rapid change in plaque size, composition, and molecular footprint after recombinant apolipoprotein A-I Milano (ETC-216) administration: magnetic resonance imaging study in an experimental model of atherosclerosis. J Am Coll Cardiol. 2008;51:1104–9.PubMedCrossRef

109.

Kaul S, Rukshin V, Santos R, Azarbal B, Bisgaier CL, Johansson J, et al. Intramural delivery of recombinant apolipoprotein A-IMilano/phospholipid complex (ETC-216) inhibits in-stent stenosis in porcine coronary arteries. Circulation. 2003;107:2551–4.PubMedCrossRef

110.

Li D, Weng S, Yang B, Zander DS, Saldeen T, Nichols WW, et al. Inhibition of arterial thrombus formation by ApoA1 Milano. Arterioscler Thromb Vasc Biol. 1999;19:378–83.PubMedCrossRef

111.

Kaul S, Coin B, Hedayiti A, Yano J, Cercek B, Chyu KY, et al. Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-I(Milano)-phospholipid complex. J Am Coll Cardiol. 2004;44:1311–9.PubMedCrossRef

112.

Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292–300.PubMedCrossRef

113.

Nicholls SJ, Tuzcu EM, Sipahi I, Schoenhagen P, Crowe T, Kapadia S, et al. Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-I Milano. J Am Coll Cardiol. 2006;47:992–7.PubMedCrossRef

114.

Eriksson M, Carlson LA, Miettinen TA, Angelin B. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans. Circulation. 1999;100:594–8.PubMedCrossRef

115.

Tardif JC, Gregoire J, L'Allier PL, Ibrahim R, Lesperance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297:1675–82.PubMedCrossRef

116.

Waksman R, Torguson R, Kent KM, Pichard AD, Suddath WO, Satler LF, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol. 2010;55:2727–35.PubMedCrossRef

117.

Bailey D, Jahagirdar R, Gordon A, Hafiane A, Campbell S, Chatur S, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55:2580–9.PubMedCrossRef

118.

Nicholls SJ, Gordon A, Johansson J, Wolski K, Ballantyne CM, Kastelein JJ, et al. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J Am Coll Cardiol. 2011;57:1111–9.PubMedCrossRef

119.

http://www.resverlogix.com/media/press-release.html?id=494#.UxdhBvldWQc. Press release on November 4, 2013.

120.

Garber DW, Datta G, Chaddha M, Palgunachari MN, Hama SY, Navab M, et al. A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis. J Lipid Res. 2001;42:545–52.PubMed

121.

Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, et al. Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 2002;105:290–2.PubMedCrossRef

122.

Bloedon LT, Dunbar R, Duffy D, Pinell-Salles P, Norris R, DeGroot BJ, et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res. 2008;49:1344–52.PubMedCentralPubMedCrossRef

123.

Chattopadhyay A, Navab M, Hough G, Gao F, Meriwether D, Grijalva V, et al. A novel approach to oral apoA-I mimetic therapy. J Lipid Res. 2013;54:995–1010.PubMedCentralPubMedCrossRef

Title: Role of HDL in Those with Diabetes
Authors: Carlos G. Santos-Gallego
Robert S. Rosenson
Publication date: 01-09-2014
Publisher: Springer US
Published in: Current Cardiology Reports / Issue 9/2014
Print ISSN: 1523-3782
Electronic ISSN: 1534-3170
DOI: https://doi.org/10.1007/s11886-014-0512-5

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