When it comes to cholesterol, LDL might as well stand for “Lower, Darn it, Lower” - at least for some of us. The results of several recent clinical trials have shown that patients who are at high risk for heart attack and death from cardiovascular disease can substantially lower their risk by reducing levels of LDL (“bad”) cholesterol well below previously recommended targets. In response to these findings, a National Cholesterol Education Program (NCEP) panel issued a statement in July, 2005 calling for more aggressive lowering of LDL cholesterol in people at high risk. According to the revised guidelines, a reasonable therapeutic option for people at “very high” risk (such as those who have experienced a heart attack) is to push LDL cholesterol levels below 70 mg/dL -30 points below the prior target level of 100 mg/dL for this group. Several types of cholesterol medicine are used to treat high cholesterol levels.

The new recommendations also give doctors the option of prescribing cholesterol medicine therapy to people at “moderately” high risk who have LDL cholesterol levels higher than 100 mg/dL. Moderately high risk is defined as having multiple risk factors, including older age (45 or older for men, 55 or older for women), smoking, and high blood pressure, which confer a 10% to 20% chance of having a heart attack within 10 years. Previously, drug therapy was only advised for such patients if their LDL cholesterol levels were 130 mg/dL or higher. In addition, the guidelines now say that for people at high or moderately high risk for a heart attack, drug therapy should aim to decrease LDL cholesterol levels by at least 30% to 40%. Achieving these new, lower LDL cholesterol goals, however, can pose a challenge.

Although statin drugs, which inhibit the synthesis of cholesterol, are effective at reducing LDL levels, researchers estimate that only about half of high-risk patients currently on statins have even reached the LDL cholesterol target of less than 100 mg/dL. For patients with very high initial LDL cholesterol levels, even maximal doses of statins aren’t able to bring levels below the new threshold. Other patients who require high statin doses to attain LDL cholesterol levels below 70 mg/dL are unable to tolerate the drugs because of side effects. People in these circumstances should first focus on their lifestyle habits: The new guidelines stress that eating a healthy diet, low in saturated fat and cholesterol, and exercising regularly can be important in lowering blood cholesterol. In addition, another option can be very effective - combining a statin medicine with a second cholesterol-lowering medicine. Your doctor can decide which type of cholesterol medicine is right for you. He or she may prescribe more than 1 of these medicines at a time because combinations of these cholesterol medicines can be more effective.

First, combination therapy significantly enhances the likelihood of meeting LDL cholesterol goals, especially in high-risk patients with coronary heart disease. Second, cholesterol-lowering drugs that work by different mechanisms may have distinct, and potentially additive, beneficial effects on the fatty deposits in the coronary arteries (atherosclerosis).

Statins, for example, reduce inflammation associated with atherosclerosis and help stabilize the lipid-rich plaques lining the arteries. Adding prescription-level doses of niacin to statin therapy can substantially increase HDL (“good”) cholesterol levels as well as lower LDL cholesterol and triglyceride levels. Niacin also appears to enhance reverse cholesterol transport, a process by which HDL particles ferry cholesterol from peripheral cells and arterial plaques to the liver for breakdown, and thus may help thwart the progression of atherosclerosis. Another possible benefit of combination therapy is that it may help avert potentially serious side effects. When a statin is given at its maximal dose, there is a slight but significant increase in the risk of liver enzyme abnormalities and muscle toxicity. Giving a statin in lower doses together with another cholesterol-lowering drug could produce the same, or an even greater, degree of LDL lowering as the highest statin dose while minimizing the risk of serious side effects. Combination Options The drugs most often added to statin therapy are niacin; ezetimibe (Zetia), a drug that inhibits cholesterol absorption; or a bile-acid sequestrant such as colesevelam (WelChol). Drugs that join one of these cholesterol fighters with a statin in a single pill have recently become available: The drug Advicor combines lovastatin with extendedrelease niacin, while Vytorin puts together simvastatin (Zocor) and ezetimibe.

Niacin-statin. Niacin has a beneficial effect on the overall lipid profile, lowering LDL and triglyceride levels while raising HDL cholesterol. “Niacin is primarily given in combination with a statin to patients who have low HDL levels,”says Roger S. Blumenthal, M.D., Director of the Johns Hopkins Ciccarone Preventive Cardiology Center. In a controlled study conducted in patients with known coronary heart disease and published in The New England Journal of Medicine in 2001, the combination of simvastatin and niacin reduced LDL cholesterol levels by 42%, increased HDL cholesterol by 26%, and caused regression of fatty plaques in the coronary arteries. After 3 years, the incidence of major cardiovascular events was about 90% lower in patients treated with the simvastatin-niacin combination compared with the placebo group.

Muscle toxicity is a possible problem with the niacin-statin combination, but it is not as common as when a statin is combined with a fibrate, a drug that is mainly used to lower triglyceride levels,” notes Dr. Blumenthal. Some patients are unable to tolerate niacin because it produces flushing of the skin, but an extended-release form (Niaspan), which is available by prescription, causes less frequent and less severe flushing symptoms. Other side effects of niacin include liver toxicity, sstomach ulcers, and gout.

Ezetimibe-statin. Combining a statin, which inhibits cholesterol production, with ezetimibe, a drug that blocks the intestinal absorption of cholesterol, can lower LDL cholesterol more than a statin alone. “I think at this stage, most of us would prefer to reach the LDL cholesterol target with only a statin,” says Dr. Blumenthal, “but if someone can only tolerate a lower dose of a statin and cannot reach their LDL cholesterol goal with this dose, then we would certainly add ezetimibe.” Patients can take separate pills for each medication or choose the new drug Vytorin, which combines 10 mg of ezetimibe with different dosages of simvastatin.

Colesevelam-statin. Bile acid sequestrants partially prevent bile acid absorption from the intestine and cause the liver to convert more cholesterol into bile acids, thereby removing more LDL cholesterol from the circulation. Older drugs in this category were difficult to take and caused many gastrointestinal side effects. A newer bile acid sequestrant, colesevelam, works more efficiently and thus can be administered in lower doses with fewer side effects. In a randomized controlled trial published in Atherosclerosis in 2001, patients given 10 mg/day of atorvastatin (Lipitor) alone experienced 38% decrease in their LDL cholesterol, while the addition of colesevelam to atorvastatin produced a 48% drop in LDL cholesterol without any increase in adverse effects.

If your LDL cholesterol still exceeds the recommended target despite optimal statin therapy, or if you are unable to tolerate higher doses of statins because of side effects, ask your doctor if cholesterol medicine combination therapy would be an appropriate option. Similarly, if your HDL cholesterol level is too low or your triglycerides too high, ask about adding niacin or a fibrate to your regimen. “Many doctors now try to push LDL cholesterol way down in high-risk asymptomatic patients,” says Dr. Blumenthal, “especially if tests have established they have a lot of plaque in their heart. At Hopkins, we are very aggressive about lowering LDL cholesterol levels and would add ezetimibe if necessary. And if a patient’s HDL cholesterol or triglycerides are still suboptimal after treatment, we would probably add another drug to improve these levels.”