Patients with risk factors for coronary heart disease (CHD) should be targeted for aggressive prevention. Elevated serum high-density lipoprotein (HDL) cholesterol levels are thought to be cardioprotective, while a low level is a potent predictor of premature CHD. Currently, most efforts are directed at lowering the low-density lipoprotein (LDL) cholesterol levels and do not concentrate on the HDL levels.

An isolated low HDL level is defined as an HDL cholesterol level of 35 mg per dL (0.90 mmol per L) or less, an LDL cholesterol level of less than 160 mg per dL (4.15 mmol per L) and a triglyceride level of less than 250 mg per dL (2.83 mmol per L). Therapy for patients with low HDL cholesterol levels has been controversial for three reasons: (1) a lack of randomized studies demonstrating the benefit of raising HDL cholesterol levels, (2) uncertainty about how the HDL cholesterol level imparts its cardioprotective effect and (3) the absence of an easy risk assessment tool for physicians to stratify patients with isolated low HDL cholesterol levels.

Recent advances in understanding make it necessary to reconsider aggressive management of patients with isolated low HDL levels. Epidemiologic studies provide increasing evidence of the relationship between increasing HDL cholesterol levels and decreased CHD risk. The Helsinki Heart Study, a primary prevention study using gemfibrizol in men at high risk for CHD, demonstrated that for every increase of 1 mg per dL in the HDL cholesterol level, a 2 to 3 percent decrease in CHD risk may occur, independent of changes in the LDL cholesterol level. Studies assessing statin drugs and risk reductions demonstrate similar statistics.

The cardioprotective effect of the HDL cholesterol level has been attributed to its role in reverse cholesterol transport, in which cholesterol is moved from peripheral tissue to the liver. Evidence also demonstrates an antioxidant effect and an ability to prolong the half-life of prostacyclin. Physicians now have tools to assess patient risk for CHD and determine when to begin aggressive therapy. Most of these guidelines are based on LDL cholesterol levels, and a significant number of patients with low HDL cholesterol levels have “normal” LDL cholesterol levels. The National Cholesterol Education Program (NCEP II) guidelines recommend that in patients with isolated low HDL cholesterol levels and other nonlipid CHD risk factors (age, blood pressure, smoking, diabetes, premature family history of CHD) therapy should be directed at further lowering the LDL cholesterol level. The Framingham Risk Prediction Chart may be more useful in determining management in primary prevention of a patient with isolated low HDL cholesterol levels by correlating risk factors with lipoprotein levels, including LDL and HDL cholesterol levels. Based on international European guidelines, more aggressive treatment (including pharmacotherapy) should be considered if the 10-year Framingham risk score exceeds 20 percent. In the primary prevention setting, pharmacotherapy is advocated in a patient with low cholesterol if the 10-year Framingham risk score exceeds 20 percent or if the patient has a significant family history of premature CHD.

Pharmacotherapy in patients with isolated low HDL cholesterol levels involves three classes of drugs: (1) statins, (2) fibrates and (3) niacin. Given the long-term safety and total mortality benefit associated with statins, it appears best to initially choose a statin for the treatment of patients with CHD and LDL cholesterol levels of 100 mg per dL (2.5 mmol per L) or higher, or primary prevention in patients with LDL cholesterol levels of more than 130 mg per dL (3.35 mmol per L). The treatment of patients with low HDL cholesterol levels and low LDL cholesterol levels is less clear. Niacin actually appears to be most efficacious in raising the HDL cholesterol level. Evidence with fibrates is mixed, and they should probably be considered a second-line alternative to statins or niacin. Further comparative trials are needed.

The authors conclude that an isolated low HDL cholesterol level is a relatively common clinical problem. A biologically plausible mechanism has been suggested to explain how the HDL cholesterol level exerts its antiatherogenic effect. Clinical trial evidence in primary and secondary prevention now supports treating patients with isolated low HDL cholesterol levels. Until additional evidence from clinical trials becomes available, targeting patients with isolated low HDL cholesterol levels in the primary prevention setting whose absolute risk of CHD is highest seems to be a rational approach.