A Low HDL Level Is as Bad as a High LDL Level ....

Summarized by Robert W. Griffith, MD
October 11, 2007

Summary

High-density lipoprotein cholesterol (HDL) levels can predict major cardiovascular events such as heart attack, stroke, and cardiac death. Analysis of a large study shows that both low HDL levels and raised low-density cholesterol (LDL) levels are independently predictive of such events.

Introduction

Studies have shown, quite consistently, that blood levels of high-density lipoprotein cholesterol (HDL) - the "good" cholesterol - are strong predictors of cardiovascular disease. HDL levels below 40 mg/mL are linked to an increased risk of major cardiovascular events such as heart attack, stroke, and cardiac death. Each increase of 1 mg/dL is linked to a 2-3% decrease in the risk of future heart disease.

Although the role of HDL has long been known, for the last 40-odd years attention has been focused on the "bad" cholesterol - low-density lipoprotein cholesterol, or LDL. The availability of the statin drugs has allowed significant reductions in LDL to be achieved (sometimes accompanied by smaller increases in HDL). Each 40 mg/dL decrease in LDL has been shown to be linked with 24% fewer major cardiovascular events.

Not surprisingly the question arises, which should one should strive for - a low LDL or a high HDL? Both would be best, of course. But if one can produce a very low LDL level, is it still important to achieve a higher HDL to avoid cardiovascular problems? A new study, published in the New England Journal of Medicine, has answered this question.

What was done

The Treating to New Targets (TNT) trial was an international multicenter study that gave patients with coronary heart disease a statin drug (atorvastatin, or Lipitor®) at two dose levels. There were 256 study sites in 14 countries. The aim was to explore the possible benefits of very low LDL levels; the target set was an LDL below 70 mg/dL. The selected patients had to have an LDL below 130 mg/dL after a run-in period of 8 weeks at an atorvastatin daily dose of 10 mg, to show they responded to the drug. They were then allocated to take either 10 mg or 80 mg of the statin.

The patients' HDL levels after 3 months were used to classify them into 5 roughly equal groups, or quintiles: below 38 mg/dL, 38-43, 43-48, 48-55, and over 55 mg/dL. The differences in the average time to a major cardiovascular event for each quintile were analyzed to determine the importance of HDL levels in patients with low LDL levels.

What was found

Among the 9,770 subjects in the trial, those with higher HDL levels were older, more likely to be female, and leaner than those with lower HDLs. Diabetes was twice as common in the lowest quintile of HDL. The average LDL levels ranged between 96.7 and 98.4 mg/dL; there was no association between LDL and HDL levels. (Note that these results were based on the whole collective, which included both the low and high dose levels of the statin; the HDL levels for just those subjects who took 80 mg atorvastatin daily averaged 77 mg/dL, and they had 22% fewer cardiovascular events - see first link below.)

The risk of having a major cardiovascular event during the 5 years following the start of the statin ranged between 6.5% and 10%. Adjustment was made for factors that might influence the likelihood of such an event, e.g. sex, age, smoking, body mass index, blood pressure, blood sugar, LDL level, and triglyceride level measured at month 3 of the trial, and a history of diabetes, heart attack, high blood pressure, and cardiac disease. Analyses of the changes in risk were done both for the total collective and for those patients whose LDL had been brought below 70 mg/dL - the 'very low LDL' subjects. The lowest HDL quintile (less than 38 mg/dL) was used as the reference, and given a value of 1. The Hazard Ratio (or level of risk) for each quintile is given in the table:

HDL Quintile	Hazard Ratio - all patients	Hazard Ratio - low LDL pts.
Below 38 mg/dL	1.00 (reference)	1.00 (reference)
38 - 43 mg/dL	1.00	0.85
43 - 48 mg/dL	0.80	0.57
48 - 55 mg/dL	0.92	0.55
Above 55 mg/dL	0.75	0.61

It can be seen that, for all the subjects, the HDL level was predicative for a risk of a major cardiovascular event within 5 years. Although the numbers of subjects (and hence events) were smaller in the next analysis, it was clear that higher HDL levels are linked with fewer cardiovascular events in those whose LDL has been lowered to 70 mg/dl or below.

Not surprisingly, the ratio of individual LDL to HDL levels at month 3 of the trial was also highly predictive of cardiovascular events. Using the same quintile method, the likelihood of an event in those with the lowest ratio (below 1.33) was less than half that of those in the highest ratio quintile (over 2.41); the risks were 5.8% and 13.5%, respectively.

Conclusions

This analysis of a large study in which coronary artery disease patients were taking a statin (and thereby lowering their LDL) shows that HDH levels were predictive of major cardiovascular events such as heart attack, stroke, and cardiac death. When those with very low LDL levels (below 70 mg/dL) were analyzed, the benefits of higher HDL levels were still evident.

It has previously been argued that, if LDL levels were reduced sufficiently, the HDL level might be irrelevant. This is clearly not the case, as this study shows. Statin drugs are effective in lowering LDL levels, are well-tolerated, and are widely used; indeed, their use has spread to other conditions where there may not be a raised LDL. Now that it's been shown that HDL and LDL are both independently predictive of cardiovascular events, greater attention should be paid to ensuring that HDL levels in patients are brought above the accepted threshold. Statins are only achieve modest increases in HDL. Better results are obtained with extended release niacin. A specific HDL-raising drug, torcetrapib, has shown spectacular results (boosting HDL by 50% to 100%), but unfortunately it appears to increase cardiovascular mortality - not the desired effect!

Source

• HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. P. Barter, AM.  Gotto, JC. LaRosa,  et al. , N Engl J Med , 2007, vol. 357, pp. 1301--1310

Related Links
TNT Study Results
Improving Niacin for Lipid Lowering
HDL-Cholesterol's Role in Coronary Artery Disease

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