Impaired high-density lipoprotein (HDL) in diabetic dyslipidaemia: new therapeutic horizons

HDL Forum Editor Professor John Chapman discusses evidence that impaired high-density lipoprotein (HDL) quality and function may be at least as important as low HDL cholesterol concentrations in contributing to accelerated formation of atherosclerotic plaque in type 2 diabetes. These data were reviewed recently in Pharmacological Reviews.

Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidaemia, inflammation, and atherosclerosis. Pharmacol Rev 2006;58:342-74.

Cardiovascular disease (CVD) is the most common cause of mortality, responsible for about one-third of all deaths globally, according to recent estimates from the World Health Organization.1 Notably, subjects with type 2 diabetes are at substantially increased cardiovascular risk, with mortality rates 2-4-fold higher than in normoglycaemic subjects.2,3 A clustering of cardiovascular risk factors in type 2 diabetes contributes to accelerated micro- and macrovascular disease. In particular, a dyslipidaemic profile characterised by low plasma levels of HDL cholesterol, elevated triglycerides (TG) and an increase in small, dense low-density lipoprotein (LDL) particles is intimately associated with the development of premature atherosclerosis in insulin-resistant states. Epidemiological studies such as the Strong Heart Study have clearly established an independent, inverse relationship between HDL-C levels and the risk of coronary artery disease in both non-diabetic and diabetic subjects.4

Normally, HDL exert a range of potent biological activities that provide protection against atherosclerosis. These actions include a key role in mediating cholesterol efflux from plaque macrophages and foam cells, and from peripheral tissues, with transport to the liver for excretion via the process of reverse cholesterol transport; equally, anti-oxidant, anti-inflammatory, anti-apoptotic, antithrombotic, anti-infectious and vasodilatory properties are central features of HDL-mediated atheroprotection.5 HDL particles are highly heterogeneous in terms of their physico-chemical characteristics, structure, intravascular metabolism and biological activity. Among the heterogeneous spectrum of circulating HDL particles, small, dense lipid-poor HDL (HDL3) have potent cholesterol efflux capacity, protect LDL against oxidative stress, and attenuate inflammation.5,6

In subjects with type 2 diabetes in whom atherosclerosis typically develops prematurely, it is critical that the atheroprotective activities of HDL are fully expressed and exerted at the arterial wall. Perturbations of HDL metabolism in both moderate and marked hypertriglyceridaemia characteristic of insulin-resistant states, results in defective capacities of HDL to facilitate cellular cholesterol efflux, as well as protect LDL against oxidative modification.5-8 Such defects in the atheroprotective actions of diabetic HDL result from a number of factors which include protein and lipid oxidation and protein glycation especially in patients with poorly controlled glycaemia. In addition, elevated cholesteryl ester transfer protein (CETP) activity drives TG enrichment of HDL, leading to enhanced phospholipid and TG lipolysis by hepatic lipase. As a consequence, HDL particle size is reduced and thus diabetic HDL particles are associated with reduced plasma residence time, hypercatabolism via the renal megalin-cubulin pathway, and attenuated anti-atherogenic activities.5-8 Acting together, these factors contribute to subnormal HDL particle numbers and HDL-C levels, and thus the defective function of HDL in type 2 diabetes.

Clearly, therefore, therapeutic approaches to reduce cardiovascular risk in type 2 diabetes should aim to raise HDL-C levels and equally to normalise the metabolism, chemical composition and structure of HDL. Strategies including upregulation of apoA-I synthesis in the liver, enhanced lipidation of apolipoprotein A-I (apoA-I), accelerated efflux of cholesterol and phospholipid from peripheral cells mediated by enhanced ABCA1 transporter protein activity, as well as decreased CETP activity, may prove useful. To date, current investigation of these potential targets has focused on small molecules with known potent HDL-C-raising capacity, such as nicotinic acid and, more recently CETP inhibitors. In addition, reconstituted HDL and apoA-I mimetics are also attracting considerable attention as agents to enhance both cellular cholesterol efflux and reverse cholesterol transport.

Nicotinic acid
Nicotinic acid mainly acts by suppressing lipolysis of triacylglycerol in adipose tissue via inhibition of the hormone-sensitive TG lipase9, leading to reduction in circulating levels of non-esterified fatty acid, the main substrate for TG synthesis in the liver. As a result, there is a decrease in plasma levels of VLDL-TG, small, dense LDL and apolipoprotein(a). As TG levels are strongly inversely related to HDL-C levels10, nicotinic acid-mediated reduction in TG levels favours retention of cholesteryl ester (CE) in HDL, an increase in HDL particle size and prolongation of HDL and apoA-I residence time, resulting in marked raising of plasma HDL-C levels. There is also evidence that nicotinic acid stimulates cholesterol efflux via an ABCA1-mediated mechanism11 and decreases HDL uptake by the liver12, which contribute to the HDL-C raising effect.

Furthermore, nicotinic acid favourably modifies HDL composition, increasing apoA-I in the form of large, CE-rich HDL particles.12 Thus, by normalising HDL structure and composition, and increasing HDL particle numbers and levels, nicotinic acid may normalise functionally defective HDL.

CETP inhibitors
CETP inhibitors, such as torcetrapib and JTT-705, markedly decrease plasma CETP activity, thereby raising HDL-C levels and concomitantly decreasing LDL-C and apoB levels. CETP inhibition also reduces the TG content and increases the CE content of HDL particles, which in turn may improve HDL functionality.13 These effects may be particularly relevant for HDL antioxidative activity, which is strongly dependent on the ratio of CE to TG in HDL particles. Beneficial effects on HDL metabolism associated with CETP inhibition may be attributable to normalisation of apoA-I lipidation and conformation, resulting from normalisation of the CE/TG core lipid ratio. These data suggest that the CETP inhibitors may prove particularly useful in the treatment of hypertriglyceridaemic metabolic disorders, notably insulin-resistant states such as prediabetes, metabolic syndrome and type 2 diabetes.

However, this approach to HDL-C raising has been called into question, following the recent termination of the ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial involving the CETP inhibitor torcetrapib. ILLUMINATE was designed to test whether combination treatment with torcetrapib plus atorvastatin reduced cardiovascular events compared with atorvastatin alone in subjects with or at high risk of CHD. Unexpectedly, the study showed an excess of deaths among patients treated with torcetrapib combination therapy, resulting in study termination. The reasons for this finding and whether this was specific to torcetrapib or a class effect, remains the subject of ongoing analyses.

Reconstituted HDL and apoA-I mimetics
Although less advanced in development, administration of reconstituted HDL or apoA-I mimetics may provide promising strategies for the treatment of insulin-resistant metabolic disorders, particularly in an acute therapeutic context in individuals with established atherosclerotic disease.

Intravenous injection of reconstituted HDL results in a rapid rise in the availability of primary cholesterol acceptors at the arterial wall and in peripheral tissues to facilitate reverse cholesterol transport. Preliminary clinical evidence for apoA-IMilano, which has potent cholesterol efflux capacity, has shown that 5-weekly infusions in patients with acute coronary syndromes induced significant reduction in atheroma volume, as assessed by intravascular ultrasound imaging.14 ApoA-I and apoA-IMilano are preferentially metabolised to small HDL particles, which are potentially cardioprotective.

ApoA-I mimetics have been shown to possess a range of atheroprotective effects, as a result of their beneficial impact on HDL metabolism. These investigational agents promote the formation of pre-beta HDL, improved HDL-mediated cholesterol efflux as well as improvements in the anti-inflammatory properties of HDL.15

In conclusion, evidence suggests that, in addition to raising low HDL-C levels, normalising of the antiatherogenic function of defective HDL represents a promising therapeutic strategy for the treatment of insulin-resistant metabolic diseases such as type 2 diabetes and metabolic syndrome. Further data relating to innovative agents, specifically CETP inhibitors and apoA-I mimetics, are awaited with interest.

References

1. World Health Organization. The atlas of heart disease and stroke. World Health Organization; Geneva, Switzerland: 2004.

2. Kannel WB. Lipids, diabetes and coronary heart disease: insights from the Framingham Study. Am Heart J 1985;110:1100-7

3. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44

4. Lee ET, Howard BV, Wang W et al. Prediction of coronary heart disease in a population with high prevalence of diabetes and albuminuria: the Strong Heart Study. Circulation 2006;113:2897-905.

5. Assmann G, Nofer JR. Atheroprotective effects of high-density lipoproteins. Ann Rev Med 2003;54:321-341.

6. Kontush A, Chantepie S, Chapman MJ. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress. Arterioscler Thromb Vasc Biol 2003;23:1881-8.

7. Nobecourt E, Jacqueminet S, Hansel B et al. Defective antioxidative activity of small, dense HDL particles in type 2 diabetes: relationship to oxidative stress and hyperglycaemia. Diabetologia 2005;48:529-38.

8. Kontush A, de Faria EC, Chantepie S et al. A normotriglyceridemic, low HDL-cholesterol phenotype is characterised by elevated oxidative stress and HDL particles with attenuated antioxidative activity. Atherosclerosis 2005;182:277-85.

9. Rosenson RS. Antiatherothrombotic effects of nicotinic acid. Atherosclerosis 2003;171:87-96.

10. Chapman MJ, Assmann G, Fruchart JC et al. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid – a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004;20:1253-68.

11. Rubic T, Trottmann M, Lorenz RL. Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-blinding cassette A1 in monocytoid cells by niacin. Biochem Pharmacol 2004;67:411-9.

12 Sakai T, Kamanna VS, Kashyap ML. Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol. Arterioscler Thromb Vasc Biol 2001;21:73-9.

13. Le Goff W, Guerin M, Chapman MJ. Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyslipidemia. Pharmacol Ther 2004;101:17-38.

14. Nissen SE, Tsunoda T, Tuzeu EM 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.

15. Navab M, Anantharamaiah GM, Reddy ST et al. Apolipoprotein A-I mimetic peptides. Arterioscler Thromb Vasc Biol 2005;25:1335-41.


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