Cardiovascular Risk Increases with Low LDL When HDL is Low

Among patients treated with statins, including those who achieved very low levels of cholesterol with high-dose statin therapy, HDL-cholesterol levels are still predictive of major cardiovascular events.

"In this post hoc analysis from the Treating to New Targets (TNT trial), HDL cholesterol was a significant predictor of major cardiovascular events across the entire study cohort, even after all other baseline risk factors, including baseline LDL-cholesterol level, had been taken into account," writes Dr Philip Barter (Heart Research Institute, Sydney, Australia)
Discussing the rationale of the study, the authors note that while low levels of HDL cholesterol are known to be a strong predictor of increased cardiovascular risk, it is unknown whether low HDL cholesterol remained a significant risk factor in subjects treated to very low LDL-cholesterol levels. Some have argued, Barter and colleagues point out, that if LDL levels were reduced sufficiently, "the level of HDL cholesterol might be irrelevant."

The TNT trial was one of several studies that made the "lower-is-better" case for lowering LDL cholesterol beyond the then-current recommended guidelines. TNT, first presented at the American College of Cardiology (ACC) 2005 Scientific Sessions and published in the New England Journal of Medicine, showed that lowering LDL-cholesterol levels in stable coronary heart disease (CHD) patients substantially below the current targets resulted in better clinical outcomes.

Intensive lipid lowering with atorvastatin (Lipitor, Pfizer) 80 mg daily provided greater protection from major cardiovascular events compared with low-dose atorvastatin in stable CHD patients. High-dose atorvastatin reduced the primary composite end point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke 22% compared with patients treated with atorvastatin 10 mg.

In this newest post hoc analysis, the investigators assessed the predictive value of HDL cholesterol in 9770 patients, with the primary outcome measure being the time to a first major cardiovascular event. All subjects were stratified into quintiles based on their HDL-cholesterol levels determined at month 3 of the double-blind treatment phase.

In the determination of the five-year risk of major cardiovascular events across the different quintiles, univariate analysis showed the event rate to be reduced by 40% in the highest quintile when compared with subjects with the lowest HDL-cholesterol levels. After adjustment for covariates, HDL cholesterol remained a significant predictor of cardiovascular events; there was a 25% reduction in risk when those in the highest quintile were compared with those in the lowest. When the analysis was stratified according to LDL-cholesterol levels in patients receiving statins, the relationship between HDL-cholesterol levels and major cardiovascular events was of borderline significance (p=0.05).

The TNT investigators also report that when they examined subjects who achieved very low levels of cholesterol, less than 70 mg/dL, those with HDL-cholesterol levels 55 mg/dL or greater were still at significantly less risk for a major cardiovascular events than those in the lowest quintile.

Dr Monty Krieger (Massachusetts Institute of Technology, Cambridge, MA), commenting on the results of the study said that this is yet another study showing that HDL cholesterol is protective, this time at various LDL levels, and will reinforce the concept that doing something to treat low levels of HDL cholesterol may be beneficial, regardless of the LDL-cholesterol numbers.

New England Journal of Medicine, Sept 27, 2007: Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357:1301-10.

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