Patients with low high-density lipoprotein (HDL) levels (men <40 mg/dL, women <50 mg/dL) are at increased risk for cardiovascular disease.  HDL is involved in reverse cholesterol transport; it helps to remove cholesterol from peripheral tissues and transports it to the liver for metabolism.  This is accomplished through 2 different pathways.  In the direct pathway, HDL delivers cholesterol esters directly to the liver via a scavenger receptor (SCARB1) on the hepatocyte cell membrane.  In the indirect pathway, the cholesterol in HDL is transferred to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) by the cholesteryl ester transfer protein.

Nonpharmacologic measures such as exercise, weight loss, and smoking cessation help to raise HDL levels and have significant cardiovascular benefits.  In contrast, use of medications to raise HDL levels does not improve cardiovascular outcomes.  Pharmacologic treatment of patients with low HDL levels should focus on lowering LDL cholesterol with HMG-CoA reductase inhibitors (statins), as these are the most effective lipid-lowering drugs for preventing cardiovascular events.  Statins are indicated for secondary prevention in all patients with known atherosclerotic cardiovascular disease, regardless of baseline lipid levels.

(Choice A)  Ezetimibe inhibits cholesterol absorption from the gastrointestinal tract, but evidence for reduction in cardiovascular events is mixed, and benefits over statin monotherapy are likely minimal.  It may be considered for patients who cannot take statins due to significant hepatotoxicity or myopathy, or who have very high LDL levels despite statin therapy.

(Choice B)  Cationic exchange resins (eg, cholestyramine) decrease LDL cholesterol by interfering with the enterohepatic circulation of bile acids.  Bile acid binding resins can significantly increase triglyceride levels in patients with pre-existing hypertriglyceridemia.  In addition, cationic exchange resins have not been proven to prevent cardiac events.

(Choice D)  Omega-3 essential fatty acids are sometimes used for hyperlipidemia treatment.  They cause a decrease in serum triglycerides and a slight increase in HDL concentration but do not appear to significantly reduce cardiovascular events.

(Choice E)  Niacin (vitamin B₃) given in pharmacologic doses is the most effective agent for raising HDL levels, but does not reduce the risk of cardiovascular events and is associated with adverse effects (eg, flushing, hyperglycemia).  It is primarily used for patients who have failed other lipid-lowering drugs.

(Choice F)  Fibrates activate peroxisomal proliferator-activated receptor alpha, a transcription factor that increases lipoprotein lipase activity.  Fibrates decrease triglyceride levels and raise HDL levels.  However, fibrates are inferior to statins for reducing cardiovascular events and are primarily used to prevent pancreatitis in patients with very high triglyceride levels.

Educational objective:
Although low HDL concentration is associated with increased cardiovascular risk, the use of medications to raise HDL levels does not improve cardiovascular outcomes.  HMG-CoA reductase inhibitors (statins) lower total cholesterol and LDL levels.  Statins are the most effective lipid-lowering drugs for primary and secondary prevention of cardiovascular events, regardless of baseline lipid levels.