The combination of ezetimibe, a new drug that decreases cholesterol absorption from the gut, and atorvastatin, which blocks cholesterol synthesis in the liver, is more effective in reducing low-density lipoprotein cholesterol than either drug alone, according to an article in the April 29th rapid access issue of Circulation.

Christie M. Ballantyne, MD, lead investigator for the study, placed the findings in the context of the 2001 National Cholesterol Education Program guidelines, which state that optimal low-density lipoprotein cholesterol should be less than 100 milligrams per deciliter (mg/dL) in high-risk people: “With the guidelines getting more and more aggressive, it is getting harder and harder to reach desirable levels It is very hard to do that with a single drug. That is why it is great to have another option. This is the first new class of drugs in 15 years ? since the introduction of statins ? to effectively lower cholesterol.”

In the current study, atorvastatin was the agent representing the statin group of drugs, the most potent and widely used class of cholesterol-lowering agents. Even at maximum dose, atorvastatin may fail to lower cholesterol to target levels in more than 25 percent of patients with high cholesterol. Liver toxicity is also possible at high doses.

Researchers added ezetimibe, which works through a different mechanism of action, to examine the efficacy of the combination in 628 adults with hypercholesterolemia (baseline low-density lipoprotein levels 145 to 250 mg/dL, triglyceride levels 350 mg/dL or less).

After a washout phase to eliminate previous cholesterol-lowering agents, participants were randomized to 1 of 10 treatment groups for the 12-week trial: Daily use of placebo, atorvastatin alone (at 10 mg, 20 mg, 40 mg, or 80 mg), ezetimibe alone (10 mg), or ezetimibe (10 mg) plus atorvastatin (10 mg, 20 mg, 40 mg or 80 mg).

The combination of the two drugs lowered low-density lipoprotein cholesterol levels an additional 12 percent on average beyond the reductions seen with atorvastatin alone. Any dose of atorvastatin plus ezetimibe reduced low-density lipoprotein cholesterol levels 50 percent to 60 percent dependent on atorvastatin dose.

Combination therapy also was superior to the statin alone in raising high-density lipoprotein cholesterol and in reducing levels of triglycerides and C-reactive protein.

Ballantyne said that the addition of ezetimibe did not increase side effects when compared with those of patients on atorvastatin alone. All drug regimens were well tolerated.

“Getting patients to the recommended targets has been a problem that physicians have been facing,” he commented. “Using the most aggressive treatment available doesn’t always work. “Atorvastatin helps; it just is not sufficient to get everyone to target by itself.”

Ballantyne added that increasing the dose of a statin isn’t always effective. In the current study, he said, “the starting dose of atorvastatin (10 mg) plus ezetimibe gives you as much low-density lipoprotein cholesterol and triglyceride reduction as the maximum dose of atorvastatin (80 mg).”