Re-focus on the importance of HDL-C as a therapeutic target

A new analysis of data from the Framingham Offspring study is supportive of the hypothesis that raising levels of high-density lipoprotein (HDL) cholesterol is associated with reduction in cardiovascular risk across the spectrum of patients receiving lipid therapy. The data were discussed by HDL Forum Editor Professor Philip Barter, one of the authors of the paper.

 

Grover SA, Kaouache M, Joseph L, Barter P, Davignon J. Evaluating the incremental benefits of raising high-density lipoprotein cholesterol levels during lipid therapy after adjustment for the reductions in other blood lipid levels. Arch Intern Med 2009;169: 1-7. Published on-line 26 October 2009.

 

Evidence from population studies has conclusively demonstrated an inverse relationship between HDL cholesterol and cardiovascular risk (Figure 1) (1,2).

 

A meta-analysis of four large prospective studies showed that a 1 mg/dL increment in HDL cholesterol is associated with a 2-3% decrease in the risk of future cardiovascular events, independent of levels of low-density lipoprotein (LDL) cholesterol (Figure 2) (3).

 

Furthermore, evidence from the Treating to New Targets (TNT) study showed that this relationship was maintained even when the level of LDL cholesterol was reduced to less than 70 mg/dL by aggressive statin therapy (Figure 3) (4).

Despite this, evidence from clinical trials investigating the effects of therapeutic agents aimed at raising HDL cholesterol has been somewhat controversial, in contrast to the body of evidence supportive of LDL cholesterol lowering. Recent research efforts have focused on raising HDL cholesterol by inhibiting cholesteryl ester transfer protein (CETP), the enzyme which is involved in redistribution of cholesteryl esters from HDL, where they are formed, to other plasma lipoprotein fractions. However, results from trials investigating the first of the CETP inhibitors, torcetrapib, have been negative.  While treatment with torcetrapib at a dose of 60 mg per day increased HDL cholesterol levels by more than 60% in clinical trials, there was no apparent effect on atherosclerosis (5,6).  In fact, the outcomes study ILLUMNINATE (7) showed that treatment with torcetrapib (against a background of atorvastatin therapy) was associated with excess total mortality and an excess of major cardiovascular events, leading to early termination of the clinical development programme. Although subsequent data suggested that these findings may have been attributable to off-target adverse effects of torcetrapib (7), there has been much debate about the viability of the CETP inhibitors (8), and, indeed, HDL cholesterol as a therapeutic target (9).

 

The aim of this analysis was to determine whether increases in HDL cholesterol after starting lipid therapy were associated with a reduction in cardiovascular events. The analysis was based on data from individuals in the Framingham Offspring Study and covered the follow-up period 1975-2003. Adjustment was made for changes in LDL cholesterol, plasma triglycerides and pre-treatment blood lipid levels, as well as potential confounders (such as smoking, weight and the use of beta-blockers).  The analysis included 454 patients who started lipid therapy between the second and sixth examination cycles of the study. In 359 patients in whom lipid therapy was known, 96% were taking one drug only, and in the majority of cases (72%) this was a statin (Table 1).

 

Over an 8-year follow-up period, 79 patients experienced a cardiovascular event. The change in HDL cholesterol associated with taking lipid therapy was an independent predictor of cardiovascular events, with a 5 mg/dL increase in HDL cholesterol translating into a 21% decrease in cardiovascular risk (hazard ratio 0.79, 95% CI 0.67-0.93). This relationship was independent of changes in other lipid fractions and remained stable across a wide range of patient subgroups.

 

Of note, when the data were stratified by LDL cholesterol levels prior to treatment, there was evidence of a significant interaction. The lower the pre-treatment level of LDL cholesterol, the greater the impact of raising HDL cholesterol (Figure 4). 

 

This suggests that raising HDL cholesterol levels may be particularly beneficial in individuals with mixed dyslipidaemia, in contrast to those with isolated elevated LDL cholesterol levels, consistent with findings from the Scandinavian Simvastatin Survival Study (4S) (10).

 

While acknowledging limitations associated with this type of study, specifically relating to residual confounding, the authors concluded that these data provide some of the strongest evidence currently available to support the hypothesis that raising HDL cholesterol levels is associated with a reduction in cardiovascular risk. This effect appears to be independent of effects on other lipid measures. While the benefits of therapeutic agents aimed at raising HDL cholesterol levels have yet to be confirmed in prospective randomized clinical trials, the data presented in this report lend further support to the argument for considering HDL cholesterol as a therapeutic target.

 

References

1. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High- density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977; 62:707-14.

2. Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996;124 Suppl:S11-20.

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

4. Barter PJ, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357: 2109-22.

5. Vergeer M, Bots ML, van Leuven SI et al. Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity. A pooled analysis of the Rating Atherosclerotic Disease Change by Imaging with a New CETP inhibitor (RADIANCE) trials. Circulation 2008; 118:2515-22.

6. Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC, Nissen SE. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis. Insights from ILLUSTRATE (Investigation of Lipid Level Management using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 2008; 118:2506-14.

7. Barter P, Caulfield M, Eriksson M et al. Effects of Torcetrapib on Morbidity and Mortality in Patients at High Risk for Coronary Events. New Eng J Med 2007;357:2109-22.

8. Rader DJ. Illuminating HDL – is it still a viable therapeutic target? N Engl J Med 2007;357:2180-3.

9. Briel M, Ferreira-Gonzalez I, You JJ 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

10. Ballantyne CM, Olsson AG, Cook TJ et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001;104:3046-51.

 


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