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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 (See Baycol withdrawn because of fatal side effects.)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.

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.