The following is a guest post by Marilyn Mann.
On November 2, 2011, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review Merck’s application for using two cholesterol-lowering drugs to lower the cardiovascular risk in chronic kidney disease patients. The drugs are generic simvastatin and ezetimibe, which is sold alone as Zetia and as part of Vytorin, a combination pill. Simvastatin, a statin, inhibits synthesis of cholesterol in the liver. Ezetimibe is a cholesterol absorption inhibitor that works in the intestine.
Ezetimibe was approved in 2002 on the basis that it lowers LDL the “bad” cholesterol and Vytorin was approved in 2004 on the basis that the addition of ezetimibe to various doses of simvastatin lowers LDL an additional 8-17%. Currently, Zetia and Vytorin have indications for treatment of various forms of high cholesterol. Ezetimibe has never been shown to prevent heart attacks or other clinical events, either alone or when added to a statin (the ongoing IMPROVE-IT trial is testing the addition of ezetimibe to simvastatin as compared to simvastatin alone but the results will not be available for a couple of more years).
The new indication would be for lowering the risk of cardiovascular events in patients with chronic kidney disease and is based on the SHARP trial. SHARP was a trial comparing simvastatin/ezetimibe with placebo in patients with chronic kidney disease, some of whom were on dialysis, and showed a 16% reduction in major cardiovascular events. This new indication would be beneficial to Merck, since it would allow them to market the drug combination for reducing heart attacks, strokes and other cardiovascular events instead of just for lowering cholesterol.
The FDA approves combination drugs based on evidence that the two drugs have additive effects. For example, in 2003 the FDA approved the combination of aspirin and pravastatin (a statin drug) for secondary prevention of cardiovascular disease based on clinical trials showing that the combination of the two drugs prevented more cardiovascular events than either drug alone.
Unfortunately, the SHARP trial did not have an arm in which the patients received simvastatin alone. The 16% reduction in cardiovascular events could have come entirely from the effect of simvastatin. The briefing materials will not be posted until shortly before the meeting. It will be interesting to see what they contain. Based on what has been shown to date, Merck will be hard pressed to show that ezetimibe contributed to the result in SHARP. Unless it can, the new indication should not be approved.
For more information see: Charles H. Hennekins. Fixed-Dose Combination Therapy with Statins. American Journal of Cardiovascular Drugs 2008; 8 (3):155-160; and Baigent, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. The Lancet 2011; 377 (9784):218-2192.
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