Apr. 29, 2003 DALLAS, April 29 – Combining a new drug that impairs cholesterol absorption in the gut with a drug that impedes cholesterol production in the liver may deliver a one-two punch to lower bad cholesterol, researchers report in today's rapid access issue of Circulation: Journal of the American Heart Association.
Combining the cholesterol absorption-blocking drug ezetimibe and the cholesterol-lowering drug atorvastatin was significantly more effective at reducing concentrations of low-density lipoprotein (LDL) cholesterol levels, the so-called "bad" cholesterol, than either drug alone in a short-term multicenter study.
The 2001 National Cholesterol Education Program (NCEP) guidelines put optimal LDL at less than 100 milligrams per deciliter (mg/dL) in high-risk people. This means millions of Americans with diabetes, coronary heart disease or multiple risk factors are now recommended to reach this more aggressive target. "With the guidelines getting more and more aggressive, it is getting harder and harder to reach desirable levels," says lead investigator Christie M. Ballantyne, M.D., director of the Center for Cardiovascular Prevention at Methodist DeBakey Heart Center and Baylor College of Medicine in Houston. "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."
The most potent and widely used class of cholesterol-lowering agents, statins, block cholesterol production in the liver. This study examined one drug in the statin class known as atorvastatin. Even at maximum dose, atorvastatin may fail to lower cholesterol to target levels in more than 25 percent of patients with high cholesterol. It can also be toxic to the liver at high doses.
In this study, researchers added the cholesterol absorption-blocker to examine whether this mechanism may complement a statin. Researchers studied 628 adults with high cholesterol. Their LDL cholesterol at the beginning of the 12-week study ranged from 145-250 mg/dL and their triglyceride levels were 350 mg/dL or less.
After a washout phase during which previous cholesterol-lowering agents were eliminated from their bodies, participants were randomly assigned to one of 10 treatment groups. On a daily basis, they received either a placebo or atorvastatin alone (10 mg, 20 mg, 40 mg or 80 mg), or ezetimibe alone (10 mg), or ezetimibe (10 mg) plus atorvastatin (10 mg, 20 mg, 40 mg or 80 mg) for 12 weeks.
Researchers report that ezetimibe plus atorvastatin lowered LDL cholesterol levels an additional 12 percent on average beyond what atorvastatin alone could provide. Any dose of atorvastatin plus ezetimibe reduced LDL 50 percent to 60 percent depending on the atorvastatin dose.
Combination therapy also was superior to statins alone in raising high-density lipoprotein (HDL) cholesterol – the so-called "good cholesterol," and in reducing levels of triglycerides and C-reactive protein (CRP). Adding ezetimibe did not increase side effects when compared with those of patients on atorvastatin, Ballantyne says. All drug regimens were well tolerated.
"Getting patients to the recommended targets has been a problem that physicians have been facing," he notes. "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 says increasing the dose of a statin isn't always effective. In the current study, he says, "the starting dose of atorvastatin (10 mg) plus ezetimibe gives you as much LDL cholesterol and triglyceride reduction as the maximum dose of atorvastatin (80 mg)."
Co-investigators are John Houri, M.D.; Alberto Notarbartolo, M.D.; Lorenzo Melani, M.D.; Leslie J. Lipka, M.D., Ph.D.; Ramachandran Suresh, Ph.D.; Steven Sun, Ph.D.; Alexandre P. LeBeaut, M.D.; Philip T. Sager, M.D.; and Enrico Veltri, M.D., for the Ezetimibe Study Group.
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