New Goals, More Drugs

Statins remain the mainstay of therapy for most lipid disorders, as they lower LDL-C and triglycerides and raise HDL-C. They also have other benefits, including plaque stabilization, and antiinflammatory and antithrombogenic characteristics. Fibric acids have been shown to specifically lower triglycerides and increase HDL-C. Bile acid sequestrants lower LDL-C and raise HDL-C. Nicotinic acids lower LDL-C and triglycerides and raise HDL-C.

Several new products have been developed, which are generally used in conjunction with existing classes.

Intestinal Absorption Inhibitors:

Ezetimibe (Zetia) selectively inhibits cholesterol absorption and works in the brush border membrane of intestinal epithelial cells. It has minimal systemic exposure, no clinically significant pharmacokinetic drug interactions, and does not require safety monitoring when used alone. Therapy with ezetimibe produces a modest lowering of LDL-C and triglycerides, as well as a raising of HDL-C levels. Because of its modest effect, it is marketed at 10 mg as an add-on to statin therapy in patients who are not at goal. A combination formulation—ezetimibe/simvastatin (Vytorin)—is available.

Omega-3 Fatty Acids:

Omega-3 polyunsaturated fatty acids (mainly eicosapentaenoic and docosahexaenoic acids) are essential human nutrients found in fatty fish, such as salmon. They have been shown to lower plasma triglycerides and may have other benefits in persons with known CHD. They are generally well tolerated and have no major side effects. Prescription preparations are available in 1-g capsules, and the daily dosage is 1 to 4 g. Omega-3 fatty acids may be used alone or in conjunction with other agents.

Extended-Release Nicotinic Acid

: Niacin is a B vitamin. Its exact lipid-lowering mechanism is not completely understood, but it reduces hepatic synthesis of very low LDL (substrate for LDL) and triglycerides. Niacin also blocks hepatic uptake of apolipoprotein A-I, a major component of HDL, thereby increasing HDL-C levels. A major drawback has been flushing, which is reduced with the extended-release (ER) preparations.

An investigational drug (MK-0524; Merck) is in phase 3 testing that combines ER niacin with a DP-1 receptor antagonist and significantly reduces flushing. ER niacin is now also available in a combination pill with lovastatin (Advicor).

Cholesterol Ester Transfer Protein Inhibition: Torcetrapib, the first in what appeared to be a promising new drug class, was abruptly withdrawn by Pfizer during the phase 3 clinical trials. The drug targeted the cholesterol ester transfer protein, which is secreted by the liver, and its inhibition elevates HDL-C. Initial studies showed blood pressure elevations in some patients taking the drug, but interim results from a large trial showed increased deaths and heart problems in patients randomized to torcetrapib.