Cardiology

High-density lipoprotein cholesterol (HDL-C) has long been recognized as an inverse predictor of atherosclerotic events, yet remains elusive as a therapeutic target in reducing vascular risk.^1,2 As coronary disease is a phenomenon of recent centuries, it seems improbable that HDL evolved as a function of its ability to slow atherosclerotic disease. More likely, the role of HDL in the body’s innate immune system has afforded a survival advantage, and its protective cardiovascular effects stem from a convenient but complex interplay between its numerous enzymatic and other protein substituents, its lipid composition, and its interaction with the arterial vessel wall and other lipoproteins. These characteristics of HDL, including its cholesterol content, change in the context of both acute and chronic inflammation.

Although the epidemiology of HDL-C and cardiovascular risk has been fairly consistent, clinical trials of pharmacologic interventions to raise HDL-C have yielded under-whelming results.^2,3 Furthermore, the functional characteristics of HDL are impaired in patients with atherosclerosis and inflammatory disorders.⁴ The lack of consensus concerning which aspects of HDL function are most important has contributed to controversy over whether HDL quantity or HDL quality is the most relevant target of treatment.

HDL Composition

HDL particles are surrounded by an outer amphipathic layer containing free cholesterol, phospholipid and apolipoproteins (in decreasing order, AI, AII, C, E, AIV, J, and D) on the surface, with a triglyceride- and cholesterol ester–rich hydrophobic core. Apolipoprotein AI (apo AI) is the principal protein of HDL. The “cargo” carried by HDL particles includes enzymes such as paraoxonase, platelet-activating factor acetylhydrolase (both anti-oxidants), lecithin cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP). HDL subtypes can be separated and quantified on the basis of ultracentrifugation, electrophoresis or nuclear magnetic resonance; these particle classes include HDL-2 and HDL-3. The differences in particle size primarily result from the number of apolipoprotein molecules and the volume of the cholesterol ester in the particle core.⁵

Functional Roles of HDL

HDL possesses multiple potentially atheroprotective characteristics, although the relative importance of these characteristics remains the subject of debate. Participation of HDL in reverse cholesterol transport (RCT), the process through which intracellular lipids are mobilized onto apo AI for hepatic elimination, is the most elucidated and least controversial atherosclerotic characteristic.

In RCT, cholesterol and other lipids in the macrophages (foam cells) of the arterial wall plaque are transported either to lipid-poor apo AI or immature forms of HDL through ATP-binding cassette transporter A1 (ABCA1), or to more mature HDL via ATP-binding cassette subfamily G, member 1, present on the cell membrane. LCAT present within HDL catalyzes the conversion of this cholesterol to cholesteryl ester (CE). CE is either passed to the liver via the scavenger receptor B1 on the hepatocyte surface or transferred to particles containing apolipoprotein B, predominantly very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), through the HDL-associated enzyme CETP.⁶ In type 2 diabetes and metabolic syndrome, CETP activity is relatively high, in association with the clinical phenotype of low HDL-C, elevated triglycerides, and small, dense cholesterol-rich LDL particles.⁷

Beyond RCT, HDL has other properties that appear to contribute to reduced vascular risk. Among these are anti-inflammatory capabilities, including reducing chemoattraction of monocytes to vascular endothelial cells by reducing the chemokine monocyte chemotaxis protein-1 (MCP-1), down-regulating cellular adhesion molecule expression on endothelial cell membranes (to which monocytes attach), and decreasing differentiation of subendothelial macrophages into foam cells within plaque.⁸

One of the major drivers of atherosclerosis and many associated inflammatory pathways is the oxidation of lipids within lipoproteins and plaque.⁹ Under normal circumstances, HDL reduces production of oxidized lipids within macrophages and LDL.¹⁰ This anti-oxidative capacity is anti-inflammatory in that HDL decreases the significant stimulus of monocyte attraction and foam-cell development.⁹ Even RCT may be considered anti-inflammatory, since it promotes efflux of lipids—many of which are oxidized and promote vascular inflammation—from within the artery wall. This may explain the observation that the ability of HDL to inhibit monocyte chemotaxis highly correlates with its capacity to promote cholesterol efflux.¹¹

The apolipoprotein content of HDL also seems to be related to the apparent clinical relevance of HDL in regulation of platelet aggregation.¹² HDL is believed to be protective against both arterial and venous thrombosis.¹³ In these ways, HDL could well mitigate the entire course of atherothrombosis, from fatty streak (its earliest stage) to acute coronary syndrome.

Proinflammatory HDL

In a variety of clinical circumstances that manifest features of either acute or systemic inflammation, composition and function of HDL can become impaired, resulting in a particle with less ability to reduce or with a paradoxical tendency to increase evidence of vascular inflammation.¹⁴ The latter, specifically HDL that promotes lipid oxidation, cellular adhesion molecule expression, and monocyte attraction to the vessel wall, has been isolated from patients with coronary disease and other forms of atherosclerosis;⁴ patients following a single ingestion of a meal predominantly consisting of saturated fat;¹⁵ and patients with type 2 diabetes,¹⁶ rheumatoid arthritis,¹⁷ systemic lupus, renal disease,¹⁸ and uremia.¹⁹

Other measures of HDL function have shown the same paradoxical reversal of HDL protective capacity in Crohn’s disease (impaired HDL protection against lipid oxidation)²⁰ and obstructive sleep apnea (paradoxically increased lipid oxidation),²¹ and after elective non-vascular surgery (increased HDL-mediated monocyte chemotaxis).²² In patients with rheumatoid arthritis, the degree of HDL dysfunction correlated with disease activity,²³ while in patients with metabolic syndrome and diabetes, the impairment in HDL activity was highly associated with the degree of hyperglycemia.¹⁶ In sepsis, HDL-C content is reduced as much as 50% as part of the acute phase response.²⁴ In addition, low levels of apo AI independently predict 30-day mortality and are highly correlated with the degree of HDL-mediated platelet activation in sepsis.¹²

This change in HDL is associated with a change in the structure and content of HDL particles. Concentrations of apo AI and the key antioxidant enzyme paraoxonase are reduced, while the levels are increased of other “acute phase proteins” such as serum amyloid A, apolipoprotein J and ceruloplasmin.²⁵ Moreover, the remaining apo AI is itself often oxidized due to the release of the enzyme myeloperoxidase (MPO) by phagocytic mononuclear cells.²⁶ This oxidation occurs at specific amino acid residues within apo AI, and is often followed by a chemical process known as nitrotyrosination, which impedes the ability of HDL to facilitate ABCA1-mediated lipid transport.²⁶

Another acute phase reactant, secretory phospholipase A2 (sPLA2), reduces HDL-C concentrations and particle size by hydrolyzing phospholipids, including those in HDL. Activity of sPLA2 releases from lipoproteins highly proinflammatory oxidized fatty acids that reduce HDL’s ability to promote cholesterol efflux and decrease macrophage expression of ABCA1 by accelerating its degradation.^27-29

Interpretation of Clinical Trials

Interpretation of published clinical trials on the relationship between modification of HDL-C and HDL itself has been challenging for a number of reasons. Therapeutic interventions (lifestyle or pharmacologic) that affect HDL-C also typically affect other lipoproteins and vascular risk factors (including blood pressure, fasting glucose levels, and inflammatory markers). The ability to modulate HDL-C levels has been modest relative to the ability to modulate other risk factors. Several promising therapies have failed to achieve clinical acceptance because of tolerability, toxicity, absence of cardiovascular benefits, and clear evidence of harm in some circumstances.

Statins have only a modest (4%–10%) ability to raise HDL-C³⁰ but appear to more substantially improve the anti-inflammatory functions of HDL. In patients with coronary disease or risk equivalents, treatment with simvastatin resulted in partial reversion of pro-inflammatory HDL to a more neutral phenotype, in contrast to HDL isolated from patients receiving a placebo.⁴ In patients with active rheumatoid arthritis but no known vascular disease, high-dose atorvastatin resulted in a 15% reduction of HDL-associated lipid oxidation in a cell-free assay in significant contrast to placebo, which had no effect.³¹ Increases in HDL-C have correlated with statin-induced regression of plaque measurements as determined using intravascular ultrasonography (IVUS), so the relatively slight increase of HDL-C with statins may be relevant.³²

Clinically, fibrates are typically used as a means to reduce levels of VLDL-C, chiefly triglycerides. However, the modest effects of fibrates in elevating HDL-C may be more relevant to cardiovascular disease prevention.³³ The Helsinki Heart Study showed a 34% reduction in coronary events in dyslipidemic men treated with gemfibrozil, but subjects in the lowest baseline HDL-C tertile experienced the largest benefit from the drug.³⁴ Changes in plasma triglycerides did not correlate with outcome, but increases in HDL-C (+14% overall) and decreases in LDL-C (–15% overall) were each associated with significant coronary event reduction with gemfibrozil compared with placebo.³⁵ In the Veterans Affairs HDL Intervention Trial (VA-HIT), use of gemfibrozil to treat male patients who have coronary heart disease (CHD) with low HDL-C levels resulted in a 22% reduction in coronary events. Multivariate analysis revealed that the changes in LDL-C or triglyceride levels were not related to this outcome.³³ Rather, for each 5 mg/dL rise in HDL-C, a significant 11% reduction in coronary events occurred.³³ The small (6%) rise in HDL-C only partially accounted for the benefit of drug treatment in VA-HIT. Notably, similar findings have not been demonstrated to date with fenofibrate.

Niacin and HDL-C

Niacin has long been the staple of pharmacologic efforts to raise HDL-C, a construct bolstered by the results of the Coronary Drug Project, which showed a significant but small reduction in recurrent coronary events after 6 years and an 11% relative risk reduction in total mortality after 15-year follow-up in survivors of myocardial infarction who were receiving niacin monotherapy. A smaller angio-graphic trial indicated 70% to 90% reduction in a composite of cardiovascular events in CHD patients with low HDL-C who received high-dose nicotinic acid in combination with low-dose simvastatin treatment versus placebo.^35,36 However, neither study was designed or subsequently analyzed in a manner that could attribute the clinical benefits observed to any change in HDL-C distinct from reduction in LDL-C or VLDL-C.

More widespread use of niacin has been limited in no small part due to intolerable side effects. For this reason, extended-release niacin (ER-niacin) is the most widely used formulation in practice. Recently, the National Heart, Lung, and Blood Institute’s (NHLBI) AIM-HIGH study was prematurely terminated after its data safety monitoring board projected futility of detecting any cardiovascular benefits of ER-niacin versus placebo in CHD patients with low HDL-C and aggressively treated LDL-C levels.³ The study organizers and NHLBI have noted that an unexpected increase in stroke rate was also seen in the ER-niacin group.³ The results of AIM-HIGH challenge the treatment role of niacin in the context of contemporary LDL-C targets.

The results of the Heart Protection Study 2-THRIVE (HPS2- THRIVE) are expected in several years. The study is assessing whether the addition of ER-niacin with the flush-blocking agent laropiprant will affect the rate of cardiovascular disease relative to placebo in 20,000 patients with symptomatic atherosclerotic disease who are simultaneously receiving simvastatin.³⁷

CETP Inhibitors

A group of investigational agents that inhibit CETP have generated great interest because this mechanism raises HDL-C significantly, lowers LDL-C in some cases, and shows promise in animal models of atherosclerosis.³⁸ The development of one CETP inhibitor, torcetrapib, was abruptly halted due to evidence of a significant 58% relative increase in the risk of all-cause mortality associated with its use in a large placebo-controlled trial of patients at high-risk for cardiovascular disease who were also receiving atorvastatin.³⁹ Torcetrapib treatment was associated with an additional 25% reduction in LDL-C and 72% increase in HDL-C compared with atorvastatin treatment alone, but also with a median increase in blood pressure of 5.4 mm Hg.⁴⁰

Whether this increase in blood pressure (later shown to correlate with a compound-specific rise in serum aldosterone levels and decrease in potassium levels) is adequate explanation for the increased mortality in the trial remains controversial. A post hoc analysis suggested that the subgroup of the trial that experienced the greatest rise in HDL-C showed the lowest mortality rate.⁴⁰ However, approximately half of the excess total mortality observed in the trial was related to incident cancer and serious infections, which could suggest abnormal immune function of the HDL produced in association with torcetrapib. A separate study indicated no advantage of the use of torcetrapib versus placebo in addition to atorvastatin treatment, as assessed by carotid intima-media thickness measurement.⁴¹

The effects on hypertension and aldosterone levels seen with torcetrapib have not been seen with two other investigational CETP inhibitors, anacetrapib and dalcetrapib.⁴² Although direct comparisons have not been studied, the former appears to raise HDL-C levels more than the latter. In addition to increasing HDL-C levels by 140%, in comparison to placebo anacetrapib 100 mg daily was associated with a 40% reduction in LDL-C.⁴³ Serious safety concerns were not evident in 1,623 patients treated with anacetrapib 100 mg daily for 76 weeks.⁴³ Several smaller studies have also shown no increased blood pressure or cardiovascular toxicity with dalcetrapib.^44,45 With the exception of minor gastrointestinal complaints, tolerance of both compounds has been similar to that for placebo.⁴²

Dalcetrapib treatment in patients with CHD or at high risk for developing CHD did not result in any difference (in comparison with placebo) in arterial plaque measurement by MRI and FDG-positron emission tomography.⁴⁶ The dal-OUTCOMES trial is comparing the effect of initiating dalcetrapib and placebo treatment in >15,000 patients following recent acute coronary events on the risk of recurrent cardiovascular events.⁴⁷ The study has no predefined HDL-C enrollment criteria.⁴⁷

The REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) study is currently enrolling an anticipated 30,000 subjects with clinical vascular disease to evaluate the effects of anacetrapib 100 mg daily on cardiovascular outcomes and lipid parameters.⁴⁸ Results are not expected until 2017 at the earliest.

Other Approaches

Other therapeutic approaches have not targeted HDL-C per se, but rather attempted to increase the amount of circulating functional HDL, or HDL-like particles. Two areas of investigation (infusion therapy and apo AI mimetics) have been scaled back following disappointing clinical trial results.

Infusion Therapy

Six weekly infusions of recombinant apo AI Milano to survivors of myocardial infarction was associated with reduction in atheroma volume as measured by IVUS, but the treatment proved to be impractical for commercial development, in part because of hypotension related to difficulty with the purification process for the recombinant apo AI.⁴⁹ Reconstituted HDL using wild-type apo AI and soybean-derived phospholipid showed an insignificant trend toward angio-graphic plaque regression in coronary disease patients.⁵⁰

Apo AI Mimetics

Animal models of small peptide apo AI “mimetics” indicated that oral ingestion or infusion of these synthetic compounds, similar in amino acid structure to apo AI, improved anti-inflammatory and antioxidative functionality of HDL.⁵¹ However, oral administration of D-4F to humans with cardiovascular disease resulted in highly variable plasma concentrations of the peptide and insignificant changes in HDL function overall. Subsequently, neither intravenous nor subcutaneous treatment of patients with cardiovascular disease with L-4F, a related mimetic, resulted in meaningful changes in assays of HDL function.⁵²

Conclusion

To be effective in mitigating cardiovascular risk, the ideal HDL-directed therapy would increase the amount of functional HDL available to antagonize lipid deposition, oxidation, inflammation and potential for thrombosis in the arterial wall. Reversing the epidemiology of low HDL-C has proven inadequate to ensure coronary risk reduction. Improving measures of HDL function in human subjects has not been as practical or demonstrable as in animal models, although statin therapy is a notable exception. The role of niacin in management of patients with low HDL-C is under reconsideration in light of recent evidence. Evaluation of dalcetrapib and anacetrapib is now ongoing, and the case in favor of their use is somewhat bolstered by the absence of aldosterone-like effects that coincided with the demise of torcetrapib. Demonstrating the effect of HDL interventions on clinically relevant outcomes will be necessary to earn CETP inhibitors a place in patient management. In the meantime, we must consider the possibility that raising HDL-C is neither sufficient, nor perhaps even necessary, to reduce HDL-mediated cardiovascular risk.

References

1. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986;256(20):2835-2838.
2. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target: a systematic review. JAMA. 2007;298(7):786-798.
3. Dolgin E. Trial puts niacin—and cholesterol dogma—in the line of fire. Nat Med. 2011;17(7):756.
4. Ansell BJ, Navab M, Hama S, Naeimeh Kamranpour N, Fonarow G, Hough G, et al. Inflammatory/antiinflammatory 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(22):2751-2756.
5. Syvanne M, Ahola M, Lahdenperä S, Kahri J, Kuusi T, Virtanen KS, Taskinen MR. High density lipoprotein subfractions in non-insulin-dependent diabetes mellitus and coronary artery disease. J Lipid Res. 1995;36(3):573-582.
6. Rader DJ. Regulation of reverse cholesterol transport and clinical implications. Am J Cardiol. 2003;92(4A):42J-49J.
7. Dullaart RP, Dallinga-Thie GM, Wolffenbuttel BH, van Tol A. CETP inhibition in cardiovascular risk management: a critical appraisal. Eur J Clin Invest. 2007;37(2):90-98.
8. Ansell BJ, Watson KE, Fogelman AM, Navab M, Fonarow GC. High-density lipoprotein function: recent advances. J Am Coll Cardiol. 2005;46(10):1792-1798.
9. Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Fonarow GC, et al. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res. 2004;45(6):993-1007.
10. Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD, et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res. 2000;41(9):1495-1508.
11. Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Hama S, et al. The double jeopardy of HDL. Ann Med. 2005;37:1-6.
12. Barlage S, Gnewuch C, Liebisch G, Wolf Z, Audebert FX, Glück T, et al. Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation. Intensive Care Med. 2009;35(11):1877-1885.
13. Ruberg FL, Loscalzo J. Prothrombotic determinants of coronary atherothrombosis. Vasc Med. 2002;7(4):289-299.
14. Dodani S, Grice DG, Joshi S. Is HDL function as important as HDL quantity in the coronary artery disease risk assessment? J Clin Lipidol. 2009;3(2):70-77.
15. 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(4):715-720.
16. 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(10):2617-2623.
17. Hahn BH, Grossman J, Ansell BJ, Skaggs BJ, McMahon M. Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):213.
18. Kalantar-Zadeh K, Kopple JD, Kamranpour N, Fogelman AM, Navab M. HDL-inflammatory index correlates with poor outcome in hemodialysis patients. Kidney Int. 2007;72(9):1149-1156.
19. Holzer M, Birner-Gruenberger R, Stojakovic T, El-Gamal D, Binder V, Wadsack C, et al. Uremia alters HDL composition and function. J Am Soc Nephrol. 2011;22(9):1631-1641.
20. van Leuven SI, Hezemans R, Levels JH, Snoek S, Stokkers PC, Hovingh GK. Enhanced atherogenesis and altered high density lipoprotein in patients with Crohn's disease. J Lipid Res. 2007;48(12):2640-2646.
21. Tan KC, Chow WS, Lam JC, Lam B, Wong WK, Tam S, Ip MS. HDL dysfunction in obstructive sleep apnea. Atherosclerosis. 2006;184(2):377-382.
22. 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 cocultures. J Clin Invest. 1995;96(6):2758-2767.
23. Charles-Schoeman C, Watanabe J, Lee YY, Furst DE, Amjadi S, Elashoff D, et al. Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis. Arthritis Rheum. 2009;60(10):2870-2879.
24. van Leeuwen HJ, Heezius EC, Dallinga GM, van Strijp JA, Verhoef J, van Kessel KP. Lipoprotein metabolism in patients with severe sepsis. Crit Care Med. 2003;31(5):1359-1366.
25. Navab M, Hama-Levy S, Van Lenten BJ, Fonarow GC, Cardinez CJ, Castellani LW, et al. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest. 1997;99(8):2005-2019.
26. 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(4):529-541.
27. Rohrer L, Hersberger M, von Eckardstein A. High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease. Curr Opin Lipidol. 2004;15(3):269-278.
28. Ishimoto Y, Yamada K, Yamamoto S, Ono T, Notoya M, Hanasaki K. Group V and X secretory phospholipase A(2)s-induced modification of high-density lipoprotein linked to the reduction of its antiatherogenic functions. Biochim Biophys Acta. 2003;1642(3):129-138.
29. Wang Y, Oram JF. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase Cdelta pathway. J Lipid Res. 2007;48(5):1062-1068.
30. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152-160.
31. Charles-Schoeman C, Khanna D, Furst DE, McMahon M, Reddy ST, Fogelman AM, et al. Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J Rheumatol. 2007;34(7):1459-1464.
32. Nicholls SJ. Relationship between LDL, HDL, blood pressure and atheroma progression in the coronaries. Curr Opin Lipidol. 2009;20(6):491-496.
33. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. 2001;285(12):1585-1591.
34. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study. Am J Cardiol.1989;63(16):42H-47H.
35. Manttari M, Huttunen JK, Koskinen P, Manninen V, Tenkanen L, OP Heinonen, et al. Lipoproteins and coronary heart disease in the Helsinki Heart Study. Eur Heart J. 1990;11(suppl H):26-31.
36. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. New Engl J Med. 2001;345(22):1583-1592.
37. HPS2-THRIVE Design. http://clinicaltrials.gov/ct2/show/NCT00461630?term=hps-2+thrive&rank=1. Accessed October 31, 2011.
38. Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(2):160-167.
39. 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. New Engl J Med. 2007;357(21):2109-2122.
40. Barter P. Lessons learned from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial. Am J Cardiol. 2009;104(10 suppl):10E-15E.
41. Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. New Engl J Med. 2007;356(16):1620-1630.
42. Miyares MA. Anacetrapib and dalcetrapib: two novel cholesteryl ester transfer protein inhibitors. Ann Pharmacother. 2011;45(1):84-94.
43. 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. New Engl J Med. 2010;363(25):2406-2415.
44. Stein EA, Roth EM, Rhyne JM, Burgess T, Kallend D, Robinson JG. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J. 2010;31(4):480-488.
45. Stalenhoef AF, Davidson MH, Robinson JG, Burgess T, Duttlinger-Maddux R, Kallend D, et al. Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk. Diabetes Obes Metab. 2011;
46. 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(9802):1547-59.
47. Schwartz GG, Olsson AG, Ballantyne CM, Barter PJ, Holme IM, Kallend D, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158(6):896-901e3.
48. REVEAL Study Design. http://clinicaltrials.gov/ct2/show/NCT01252953 Accessed October 31, 2011.
49. 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(17):2292-2300.
50. Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM, et al. Effects of reconstituted high-density lipoproteini on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297(15):1675-1682.
51. Navab M, Shechter I, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Fogelman AM. Structure and function of HDL mimetics. Arterioscler Thromb Vasc Biol. 2010;30(2):164-168.
52. Watson CE, Weissbach N, Kjems L, Ayalasomayajula S, Zhang Y, Chang I, et al. Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function. J Lipid Res. 2011;52(2): 361-373.