June 30, 2003


News this month
New weapon in war against cholesterol

While more Americans with coronary heart disease (CHD) are receiving treatment for high cholesterol, almost 60 percent of those treated still are not reaching the recommended cholesterol levels established by the National Institutes of Health (NIH).

Almost 60 percent of those treated still are not reaching the recommended cholesterol levels.

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The cholesterol treatment gap is quickly shifting from a problem of no treatment to one of under-treatment. This is particularly important since the NIH made its cholesterol guidelines even more aggressive in 2001, substantially expanding the number of Americans who are candidates for drug therapy and calling for lower cholesterol goals for many patients.

Those 60 percent of the estimated 13 million patients taking statins who continue to have LDL “bad” cholesterol higher than recommended levels now have a new option. The FDA recently approved the first in a new class of cholesterol-lowering drugs that has been shown to work well in combination with statin drugs, considered the gold standard for cholesterol treatment.

Ezetimibe works in a unique way
This drug, ezetimibe, marketed as Zetia®, is the first breakthrough to treat cholesterol since statins were introduced 15 years ago. It has been approved for use either by itself or together with statins in patients with high cholesterol to reduce LDL cholesterol and total cholesterol.

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Ezetimibe is the first breakthrough to treat cholesterol since statins were introduced 15 years ago.

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Ezetimibe works in a different but complementary way to the statins in reducing cholesterol. Cholesterol in the blood is controlled primarily by the liver, which produces cholesterol and bile acids, and the intestine, which absorbs cholesterol both from food and from the bile made by the liver. Ezetimibe inhibits cholesterol absorption in the intestine, which makes it  complementary to the statin drugs, which work in the liver, so patients who take both can achieve additional reductions in LDL and total cholesterol.

Combination therapy yields a 25% additional benefit
Patients who had not reached their recommended LDL goal using statins alone achieved a 25 percent (36 mg/dL) additional reduction in LDL cholesterol when ezetimibe was added to their ongoing statin therapy versus 4 percent (6 mg/dL) with the addition of placebo, according to research findings in the American Journal of Cardiology.

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Seventy-two percent…who were not able to reach goal on their statin dose reached goal when ezetimibe was added.

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The same study also found that 72 percent of these patients who were not able to reach goal on their statin dose reached goal when ezetimibe was added, compared to 19 percent of patients with the addition of a placebo.

The randomized, double-blind, multicenter study included 769 patients who had primary  hypercholesterolemia and were not at goal. They had been on statin drugs for a minimum of six weeks prior to inception of this study. Most of the response in LDL cholesterol reduction was seen within two weeks of adding ezetimibe. The benefit was generally consistent no matter which statin drug patients were currently taking.

The combination therapy also significantly improved both HDL "good" cholesterol and triglyceride profiles. HDL cholesterol improved by 2.7 percent with the addition of ezetimibe vs. 1 percent with placebo, and  triglyerides decreased 14 percent when ezetimibe was added vs. 2.9 percent with placebo.

Excellent safety profile
Ezetimibe has been evaluated for safety in more than 4,700 patients in clinical trials, and it has been generally well tolerated with the overall incidence of adverse events similar to that reported with placebo.

New drug offers physicians more treatment options

Physicians have been treating patients who have high cholesterol with combination therapy since the 1970s when clinical trials indicated niacin and cholestyramine used together were more effective than either therapy alone.

The downside of combination therapy
Clinicians became more cautious about combination therapy, however, after treating patients with one of the statin drugs, Baycol^®, along with gemfibrozil, another drug with cholesterol-lowering properties. This combination resulted in some toxic reactions; renal failure and, in some rare instances, death. (See Baycol withdrawn because of fatal side effects.)

Both the statins and gemfibrozil work in the liver and the combination of Baycol and gemfibrozil resulted in toxic buildups in some patients. Unlike gemfibrozil and statin drugs, ezetimibe inhibits cholesterol absorption in the intestine.

Before statin drugs were introduced in the 1990s, combination therapy was the only effective way to reduce cholesterol. With the advent of statin drugs, monotherapy became the standard of practice because these drugs are very effective by themselves. However, in the last few years as we have learned more about the relationship between heart disease and high cholesterol, our goals for lowering cholesterol have become more aggressive. As we work with our patients to lower cholesterol even more, combination therapy is again becoming an appealing option, if we can do so safely.

Need to do more for patients
Most patients experience a 20 to 40 percent reduction in cholesterol when placed on a statin drug, which often isn't enough to get them to their goal level. We need additional treatment options.

Increasing the doses of statin drugs is often not the best approach. If we double the dose, we can expect an additional 7 percent decrease in cholesterol, but as the dosage increases, so do the side effects.

Ezetimibe is the first of a new class of medications that selectively blocks cholesterol uptake in the small intestine, preventing it from being reabsorbed into the bloodstream. When we use it without other cholesterol-lowering medications, patients experience a 15 to 20 percent reduction. When we use it in combination with a minimum dose (10 mg. ) of a statin, we often achieve the same results as using a high statin dose, with fewer side effects.

Ezetimibe is a very safe therapy with no significant side effects reported in repeated clinical trials. Our practice was involved in the multicenter trials of the drug before its FDA approval, and we had no patients who dropped out of the trial due to adverse effects. We also found that ezetimibe is particularly effective in the treatment of a certain group of patients that includes some diabetics who tend to be super absorbers of cholesterol.

Cholesterol still major health risk
Cholesterol is a major risk factor in the development of heart disease. And — as the incidence of obesity continues to climb in this country along with diabetes and high LDL cholesterol— we have a combination that presents a significant public health problem. Effective treatment of these patients is critically important.

”Ezetimibe makes it possible to get patients closer to goal without using higher doses of statins.”

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We find that physicians are aware of this and are increasingly treating their patients with high cholesterol aggressively. Many, however, are reluctant to increase the dose of statin drugs because of side effect risks. Ezetimibe makes it possible to get patients closer to goal without using higher doses of statins.

There are some other drugs that can be safely used in combination therapy — the bile acid resins, for example, can reduce cholesterol an additional 10 to 12 percent. The side effects can be very uncomfortable for patients who may experience abdominal bloating, constipation and diarrhea. Resin type treatments also need to be given several times a day, which makes it inconvenient for many patients to follow.

Niacin has been used since the 1960s. It has a very good safety profile and works well for patients who have low HDL “good”cholesterol and high triglycerides. High doses of niacin are needed to significantly lower LDL cholesterol, however, and high doses are accompanied by side effects such as intense flushing and gastrointestinal upsets.

Role of lifestyle changes
Diet and exercise do make a significant difference in cholesterol levels, and some patients can achieve as much as a 20 percent decrease in LDL and a smaller increase in HDL levels by eating a healthful diet and exercising more, but this  is often not enough to get patients to our current goal levels.

Fully one-third of our patients have a familial type of hypercholesterolemia that is less responsive to changes in diet. Clearly we need to approach cholesterol management in various ways, supporting patients in making lifestyle changes, providing monotherapy for appropriate patients and combination therapy for others. The more effective options we have, the better.

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Dr. Gerber is a partner with Cardiology Associates of New Haven. He is director of quality improvement at the Yale-New Haven Heart Center, an attending physician at Yale-New Haven Hospital and an assistant clinical professor of medicine and cardiology at the Yale University School of Medicine.