There is some debate about whether the risk of cardiovascular events associated with low high-density lipoprotein (HDL) cholesterol levels is attenuated by very low low-density lipoprotein (LDL) cholesterol levels (< 60 mg/dL), which can be obtained with statins and combination therapy. Therefore, we conducted a study to determine the clinical significance of HDL cholesterol in subjects with low LDL cholesterol levels.

Subjects and methods

Subjects with fasting LDL cholesterol levels < 60 mg/dL were included in the study. The combined endpoint was defined as myocardial injury (troponin I > 0.07 ng/mL) or hospitalization with a primary diagnosis of coronary artery disease after 1 year. Subjects were categorized into quartiles according to their HDL cholesterol levels.

We used multivariate logistic regression analysis to determine the odds ratios for the outcomes. The odds ratios were adjusted for race, sex, age, and a history of diabetes, hypertension, coronary artery disease, heart failure, stroke, peripheral arterial disease, malignancy, alcohol use, chronic obstructive pulmonary disease, and liver disease. They were also adjusted for use of statins, fibrates, β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, as well as levels of LDL cholesterol, triglycerides, troponin I > 0.07 ng/mL, creatinine > 2 mg/dL, hemoglobin < 10 g/dL, aspartate amino-transferase > 500 IU/L, and glycosylated hemoglobin > 7%.

Results

The Table outlines the characteristics of the subjects. The mean HDL cholesterol values were 28, 36, 43, and 63 mg/dL for quartiles 1, 2, 3, and 4, respectively. The mean LDL cholesterol values of the lowest HDL cholesterol quartile, Q1, were 47, 49, 50, and 50 mg/dL for quartiles 1, 2, 3, and 4, respectively. An inverse association between HDL cholesterol and the combined primary endpoint of myocardial injury or hospitalization for coronary artery disease after 1 year (17.0%, 12.7%, 13.1%, and 10.9% for quartiles 1, 2, 3, and 4, respectively; P = .001) was shown on univariate analysis. As shown in the Figure, there was an inverse relationship between HDL cholesterol quartiles and the odds ratios for myocardial injury or hospitalization for coronary artery disease at 1 year after multivariate-adjusted analysis. A 10% increase (95% confidence interval, 3%-17%) in the combined primary endpoint of myocardial injury or hospitalization for coronary artery disease was observed for every decrease in HDL cholesterol of 10 mg/dL after analysis of HDL cholesterol as a continuous variable. The findings among subgroups were the same as for the primary analysis.

Table 1. Subject characteristics by HDL cholesterol quartile.

HDL indicates high-density lipoprotein cholesterol; Q, quartile; LDL, low-density lipoprotein cholesterol. *Laboratory abnormalities were recorded within 12 months before the index LDL cholesterol date. Numbers indicate percent of subjects tested for the following: creatinine, n = 4,074; hemoglobin, n = 3,667; aspartate aminotransferase, n = 4,019; and glycosylated hemoglobin, n = 2,358. (Adapted with permission from deGoma EM, Leeper NJ, Heidenreich PA. Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol. J Am Coll Cardiol. 2008;51[1]:49-55.)

Discussion

A low HDL cholesterol level is an important risk factor for coronary artery disease and one of the main criteria in the Framingham Risk Score, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines.¹ Among men with premature coronary artery disease, an isolated low HDL cholesterol level was shown to be the most common dyslipidemia.² HDL cholesterol levels < 40 mg/dL have been shown in a quarter of men aged 20 years and older, based on the 2007 American Heart Association heart disease statistics.³

Figure. Adjusted odds ratios for the combined endpoint of myocardial injury or coronary artery disease (CAD) hospital admission at 1 year following the index low-density lipoprotein cholesterol date. P values for myocardial injury or CAD admission: .04 high-density lipoprotein (HDL) categorical, .007 HDL continuous. Q indicates quartile. (Adapted with permission from deGoma EM,Leeper NJ, Heidenreich PA. Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol. J Am Coll Cardiol. 2008;51[1]:49-55.)

In patients with normal or increased LDL cholesterol levels, an inverse association between coronary risk and HDL cholesterol levels has been shown.^4,5 After a mean of 4 years of follow-up, the risk of death from coronary artery disease or myocardial infarction (MI) decreased by 25% for each 10-mg/dL increase in HDL cholesterol level among patients aged 50 to 80 years, according to data from the Framingham Heart Study.⁶ After a mean follow-up period of 5 years, a 10-mg/dL increase in HDL cholesterol level correlated with a 29% decrease in the combined endpoint of death from coronary artery disease, nonfatal MI, or coronary revascularization among Pravastatin Pooling Project patients who were not taking a statin and had an LDL cholesterol level < 125 mg/dL.

The risk of cardiovascular events may be decreased by increasing HDL cholesterol levels, according to several randomized controlled studies that evaluated lipid-lowering treatments. Based on the 5-year VA HDL Intervention Trial results, the 6% increase in HDL cholesterol level observed among patients with an HDL cholesterol level < 40 mg/dL due to gemfibrozil (Lopid) therapy was shown to result in a 22% decreased risk of nonfatal MI and death from coronary artery disease. According to data from the HDL Atherosclerosis Treatment Study, patients with coronary artery disease and low HDL cholesterol levels showed increased HDL cholesterol levels of 26% with niacin plus simvastatin (Zocor) compared with placebo, and a 60% to 90% decrease in mortality, MI, stroke, or revascularization.¹⁰ Studies that evaluated treatment with statins alone showed a decrease of only 24% to 34% in these clinical endpoints and did not reverse atheroma development, although disease progression was slowed.¹¹

The results of our study demonstrate the clinical significance of HDL cholesterol levels among patients with low LDL cholesterol (< 60 mg/dL). Findings also validate the high prevalence of the at-risk HDL cholesterol profile. After 1 year, a 10% increase in the occurrence of the combined end-point was shown for every 10-mg/dL increase in HDL cholesterol.

Conclusion

Increased HDL cholesterol levels and improved outcomes have been shown to result from modifications in lifestyle, such as dietary changes, weight loss, and exercise.¹² For high-risk patients who have persistently low HDL cholesterol levels despite lifestyle changes, niacin or fibrates may be considered in the absence of any contraindications.¹ Definitive conclusions regarding the efficacy of pharmacotherapy above and beyond curent aggressive medical treatment await the results of ongoing clinical trials.

References