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Combination Therapy Lowers LDL Cholesterol Levels

Am Fam Physician. 2003 Apr 15;67(8):1809-1811.

Lowering elevated low-density lipoprotein (LDL) cholesterol levels is a primary strategy in reducing coronary artery disease (CAD) events. This can be done by lifestyle changes, lipid-lowering drugs, or surgery, with varying degrees of success for each method. LDL cholesterol transports most of the cholesterol from the hepatocytes to macrophages that then transfer this cholesterol to subendothelial tissue of the coronary arteries. This initiates and increases the development of atherosclerosis and CAD events. McKenney reviewed the use of combination therapy for the management of elevated LDL cholesterol levels.

Aggressive lowering of LDL cholesterol levels slows atherosclerosis progression and may even cause lesion regression. Studies demonstrate that there is minimal risk for CAD events if LDL cholesterol is reduced to at least 98 mg per dL (2.55 mmol per L). The value of further reduction is being studied. Even with maximal use of potent statins under ideal research conditions, only 72 percent of patients achieved LDL cholesterol goals. One of the reasons that many patients cannot achieve LDL cholesterol goals is the failure to use combination therapy.

The National Cholesterol Education Program Adult Treatment Panel III guidelines set the optimal LDL cholesterol level at less than 100 mg per dL (2.60 mmol per L) in patients with CAD or CAD risk equivalent (noncoronary atherosclerosis, diabetes, and a 10-year CAD risk of 20 percent or more based on a global risk assessment); an LDL cholesterol level of less than 130 mg per dL (3.35 mmol per L) is acceptable in patients without CAD or CAD risk equivalent who have at least two risk factors for CAD events.

Statins can be combined with other lipid-lowering agents to further lower LDL cholesterol levels. One of these agents is a bile acid sequestrant. Bile acid enterohepatic circulation is disrupted when bile acids are bound to a sequestrant, resulting in increased cholesterol metabolism into bile acids. This removes LDL cholesterol from the systemic circulation and increases cholesterol biosynthesis. A newer bile acid sequestrant, colesevelam, works more efficiently than the older preparations, allowing lower dosing and decreased adverse effects, although the tablets are relatively large and swallowing two tablets three times daily can be difficult. The addition of colesevelam to a statin regimen can provide an 8 to 18 percent additional reduction in LDL cholesterol levels, depending on the dosage used, and it has been documented to reduce CAD events.

Adding niacin to a statin regimen can lower LDL cholesterol and triglyceride levels while increasing high-density lipoprotein (HDL) cholesterol levels. Niacin functions by decreasing mobilization of free fatty acids from adipose tissue, reducing triglyceride and very-low-density lipoprotein (VLDL) cholesterol synthesis. Production of LDL cholesterol also is reduced. The immediate-release, short-acting formulations often are difficult to take because of adverse effects, notably cutaneous flushing. However, flushing can be reduced by premedicating with aspirin before the first niacin dose of the day, taking niacin with a snack, or taking once-daily niacin doses at bedtime. Extended-release niacin efficacy in lowering LDL cholesterol levels is linear, increasing to around 22 percent at doses of 3,000 mg. Dosages of 1 g daily provide near maximal response in triglycerides and HDL cholesterol levels (25 percent). The addition of niacin to statin therapy can decrease LDL cholesterol by an additional 8 to 23 percent. A combination product, Advicor, combines extended-release niacin at varying doses with 20 mg of lovastatin.

Incidences of muscle toxicity, including myopathy and rhabdomyolysis, are more common when the simvastatinniacin combination is used, and special precautions should be observed. Combination therapy with niacin and a statin has been documented to decrease CAD events.

Ezetimibe, a cholesterol-absorption inhibitor, reduces LDL cholesterol levels with minimal systemic effects by action in the intestines. It is available in a once-daily dosage and results in diminished cholesterol transport from the gut to the liver, resulting in enhanced uptake of LDL particles from the systemic circulation. In combination with statins, ezetimibe can lower LDL cholesterol levels by an additional 12 to 21 percent. There are no reports of increased liver function abnormalities or muscle toxicity with this combination.

The author concludes that when lifestyle changes do not adequately lower LDL cholesterol levels, statins are a good starting treatment because they are well tolerated, safe, and effective. However, when statins alone do not lower LDL cholesterol to a satisfactory level, combination therapy with a statin and cole-sevelam, extended-release niacin, or ezetimibe can lower LDL cholesterol levels an additional 10 to 20 percent.

McKenney J. Combination therapy for elevated low-density lipoprotein cholesterol: the key to coronary artery disease risk reduction. Am J Cardiol. November 20, 2002;90suppl:8K–20K.


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