Low high-density lipoprotein (HDL) cholesterol: new data from TNT study

  • A low level of HDL cholesterol remains a predictor of cardiovascular events even when LDL cholesterol is reduced to very low levels by statins

HDL Forum Editor and lead author Professor Philip Barter highlights new data from the Treating to New Targets (TNT) study, published on-line in the September 27, 2007 issue of the New England Journal of Medicine.

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. Published on-line September 27.

A low level of HDL cholesterol remains predictive of major cardiovascular events even in statin-treated patients who achieved LDL cholesterol levels < 70 mg/dL (1.8 mmol/L) (Figure 1).This finding is expected to impact on treatment guidelines.

Figure 1. Relationship between major cardiovascular events and HDL cholesterol concentration assessed at different levels of LDL cholesterol in the TNT trial.

HDL Cholesterol and cardiovascular risk

Population studies have clearly established that HDL cholesterol levels are a strong, independent, inverse predictor of cardiovascular heart disease.1-5 For example, in the Framingham Heart Study, the HDL cholesterol level was more potent as a risk factor for coronary heart disease (CHD) than the level of LDL cholesterol (Figure 2).4

Figure 2. HDL cholesterol is a potent risk factor for CHD at all levels of LDL cholesterol

An analysis of data from four large studies concluded that each 1 mg/dL (0.026 mmol/L) increase in HDL cholesterol is associated with a 2% to 3% decrease in the risk of future CHD (Figure 3).6

Figure 3. Predictive value of HDL cholesterol

Statins, LDL cholesterol and residual risk

Intervention trials using statins to lower LDL cholesterol have consistently shown substantial reductions in major cardiovascular events in the treated groups. However, in all of these trials there is a persisting substantial residual risk in statin-treated patients (Figure 4).7

Figure 4. Statin-treated patients remain at high residual risk of cardiovascular events

A possible explanation for this may be the presence of a low baseline level of HDL cholesterol, which has been shown to remain predictive of major cardiovascular events even during treatment with statins.8,9 In a meta-analysis including 90,056 subjects in 14 prospective randomized statin trials, low HDL cholesterol at baseline was shown to be a contributor to this risk.10

Figure 5. Low HDL cholesterol increases cardiovascular risk in statin-treated patients

These findings have added support to the proposition that HDL cholesterol should be considered as a therapeutic target, independent of LDL cholesterol lowering.

Lowering LDL cholesterol levels beyond targets – the TNT study

However, it has also been argued that if the LDL cholesterol is reduced to very low levels, a low level of HDL cholesterol may no longer be relevant. This proposition has now been tested in a new analysis of data from the TNT study.

The TNT study was designed to investigate the effect on cardiovascular risk of lowering LDL cholesterol levels to <70 mg/dL (<1.8 mmol/L). The study included 10,001 patients with stable CHD, who were randomized to either atorvastatin 80 mg/day or 10 mg/day. Patients were followed-up for a median of 4.9 years. The primary study endpoint was major cardiovascular events, defined as CHD death, non-fatal, non-procedural myocardial infarction, resuscitation after cardiac arrest or fatal or nonfatal stroke.

The TNT study demonstrated the cardiovascular benefits of lowering LDL cholesterol lo very low levels, with a 22% relative reduction in cardiovascular risk (p<0.001).12

TNT study HDL cholesterol analysis

The TNT study has also made it possible to test the proposition that a low level of HDL cholesterol remains predictive of cardiovascular risk even when the LDL cholesterol is reduced to very low levels.1

This analysis showed that the HDL cholesterol level in patients receiving statins was predictive of major cardiovascular events. After adjusting for covariates, an increase of 1 mg/dL (0.026 mmol/L) in HDL cholesterol levels at 3 months could be expected to reduce the risk of major cardiovascular events by 1.1% (p=0.003).

Notably, 2,661 of the patients in the TNT study achieved on-statin LDL cholesterol concentrations <70 mg/dL (<1.8 mmol/L). The predictive power of a low HDL cholesterol in people with very low levels of LDL cholesterol remained significant even after adjusting for age and gender, smoking, hypertension, body mass index, fasting glucose, presence of diabetes, prior cardiovascular disease, on-treatment triglyceride concentration and baseline level of LDL cholesterol (p=0.03).1

Patients with HDL cholesterol levels > 55 mg/dL (>1.42 mmol/L) had a 39% lower risk of major cardiovascular events than those with levels < 37 mg/dL (<0.96 mmol/L) (Figure 6).

Figure 6. High HDL cholesterol decreases cardiovascular risk in statin-treated patients with low LDL cholesterol levels (<70 mg/dL) – data from the TNT study

Therapeutic implications

This analysis of the TNT study has major therapeutic implications and should substantially affect future therapeutic guidelines to include HDL cholesterol as an important therapeutic target. It will also stimulate further research into the development of new HDL-raising therapies.

References

1. 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.

2. 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.

3. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction 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.

4. 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.

5. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316:823-8.

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

7. Libby PJ, et al. The forgotten majority: unfinished business in cardiovascular risk reduction.J Am Coll Cardiol 2005;46:1225-8.

8. Barter P, Kastelein J, Nunn A, Hobbs R. High density lipoproteins (HDLs) and atherosclerosis; the unanswered questions. Atherosclerosis 2003; 168:195-211.

9. Sacks FM, Tonkin AM, Shepherd J, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation 2000; 102:1893-900.

10. Baigent C, Keech A, Kearney PM, 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.

11. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:1425-35.

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