Why we need new therapeutic strategies for raising high-density lipoprotein (HDL) cholesterol?

HDL Forum Editor Professor John Chapman reviews what interventions are currently available for raising high-density lipoprotein (HDL) cholesterol and why new treatments are essential. This discussion is based on a recent paper he authored in Pharmacology and Therapeutics.

Chapman MJ. Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease. Pharmacol Ther 2006;111:893-908

Epidemiological and observational studies1,2 have conclusively established low HDLC as a strong, independent predictor of coronary heart disease (CHD). Conversely, subjects with high levels of HDL cholesterol have a reduced CHD risk. In the Framingham study1, subjects with high HDL cholesterol levels (in the 80th percentile) had a 50% lower risk of cardiovascular events during follow-up compared with subjects with low HDL cholesterol levels (20th percentile). Similarly, data from the Prospective Cardiovascular Münster (PROCAM) study showed a 4-fold lower risk of CHD among subjects with HDL cholesterol levels ≥35 mg/dL compared with those with levels <35 mg/dL.2

Although current treatment guidelines recommend that HDL cholesterol levels should be >40 mg/dL3 (and >50 mg/dL in women4) in subjects at high cardiovascular risk, there is evidence of a continuum of benefit. The cross-sectional Atherosclerosis Risk in Communities (ARIC) study showed that there was a strong and continuous association between HDL cholesterol levels and CHD risk, which extended up to levels of 80 mg/dL or more.5 Individuals at high cardiovascular risk with subnormal HDL cholesterol levels, on the basis of population data, should therefore benefit from interventions that raise HDL cholesterol. Recent evidence from the Honolulu Heart Program indicates that we should be aiming to raise HDL cholesterol levels to at least 60 mg/dL6, by either lifestyle or pharmacological intervention, to significantly impact on cardiovascular risk in the context of primary and secondary prevention.

To achieve this clinically, we need therapeutic tools capable of raising HDL cholesterol levels by at least 50%, especially in individuals with levels ≤ 40 mg/dL. Yet the agents that are currently available for raising HDL cholesterol fall short of this requirement. Nicotinic acid (niacin), which is the most potent treatment available to clinicians, raises HDL cholesterol levels by about 25% on average (at a dose of 1-2 g/day)7; remarkably, when used in association with a statin, nicotinic acid provides clinical benefit in terms of plaque regression, as shown by the HDL-Atherosclerosis Treatment Study.8 However, even with the combination of nicotinic acid and a statin, the increase in HDL cholesterol is generally less than 50%.9

The renewed focus on HDL cholesterol as a target for therapeutic intervention has prompted the development of novel therapeutic approaches capable of raising HDL-C by at least 50%.

Suggested potential options include cholesteryl ester transfer protein (CETP) inhibitors such as torcetrapib and JTT704, as well as recombinant forms of apolipoprotein A-I (apoA-I) and reconstituted HDL. CETP facilitates transfer of cholesteryl ester from HDL to very low-density lipoproteins and LDL with hetero-transfer of triglyceride from the latter particles to HDL, in the process of reverse cholesterol transport.

Interestingly, a substantial body of information concerning both genetic deficiency10 and genetic variants11 of CETP that lead to lower CETP concentrations in plasma, showed an association with elevated HDL cholesterol levels and potentially with protection against premature CHD and longevity. These findings prompted evaluation of the therapeutic potential of the CETP inhibitors. However, the safety of the CETP inhibitors 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. 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.

Encouraging preliminary clinical data suggest that recombinant apoA-IMilano may prove useful. This agent differs from the wild type by substitution of cysteine for arginine at position 173, resulting in a more efficient cholesterol acceptor. In a small study using intravascular ultrasound imaging, infusion of recombinant apoAIMilano/phospholipid complexes for 5 weeks in patients with acute coronary syndromes significantly decreased atheroma volume, relative to placebo.12 This study is particularly important as it provides proof of concept that apoA-I and potentially small, poorly lipidated HDL particles are able to stop atherosclerosis by potentiating cholesterol efflux from the plaque and ultimately possibly initiating regression. These agents are still at a somewhat early stage of development, and their potential clinical benefit has yet to be established in larger controlled clinical trials.

With the ageing of society, low HDL cholesterol is likely to become an increasingly important cardiovascular risk factor warranting clinical intervention. Given that there is a continuum of clinical benefit associated with HDL cholesterol raising, we should be aiming to increase levels by at least 50%, potentially to at least 60 mg/dL in high risk subjects, well above current targets. It is clear that we need new therapeutic agents to achieve this and await with interest ongoing developments.

References

1. Gordon DJ, Probstfield JL, Garrison RJ et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15.

2. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the PROCAM Study. Circulation 2002;105:310-5.

3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.

4. Mosca L, Appel LJ, Benjamin EJ et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004;109:672-93.

5. Sharret AR, Ballantyne CM, Coady SA et al. Coronary heart disease protection from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108-13.

6. Curb JD, Abbott RD, Rodriguez Bl et al. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res 2004;45:948-53.

7. Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med 2005;258:94-114.

8. Brown BG, Zhao XQ, Chait A et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.

9. Chapman MJ, Assmann G, Fruchart J-C 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.

10. Nagano M, Yamashita S, Hirano K et al. Molecular mechanisms of cholesteryl ester transfer protein deficiency in Japanese. J Atheroscler Thromb 2004;11:110-21.

11. Barzilai N, Atzmon G, Schechter EJ et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 2003;290:2030-40.

12. 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.

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