You are probably as tired as I am of the relentless onslaught of television ads for Vytorin, a cholesterol-lowering agent that's a combination of ezetimibe (Zetia) and simvastatin (Zocor).
Since the drug's approval by the FDA in 2004, Schering-Plough and Merck have spent more than $155 million a year to get patients to badger their doctors into prescribing this drug to lower cholesterol levels.
The ads point out that Vytorin lowers cholesterol in two ways: simvastatin fights elevated cholesterol due to family genetics; ezetimibe reduces intestinal absorption of cholesterol from the diet.
But annoying as they may be, the ads are at least correct: Studies have shown that adding Zetia to a statin lowers the total and LDL cholesterol levels more than does doubling the dose of a single statin like simvastatin.
On January 14, 2008, however, the two companies released a sketchy press report on the results of a randomized trial called ENHANCE, a study that compared the effects of simvastatin by itself with those of Vytorin in 716 subjects — all of whom had inherited a genetic defect that interferes with the body's ability to remove LDL cholesterol from the blood.
Vytorin did lower LDL cholesterol more than simvastatin alone — 58 percent compared with 42 percent over a two-year period. But — there was no significant difference between the two drugs in their ability to reduce atherosclerotic plaque, the major underlying cause of heart attacks and strokes. And the drug companies waited almost two years before releasing these results of the ENHANCE study.
Other studies have generally shown that the further the level of LDL cholesterol is brought down by a statin, the greater is the decrease in atherosclerosis.
These results raise medical and ethical issues. Why wasn't the greater lowering of LDL cholesterol by Vytorin associated with a greater reduction (called regression) of the atherosclerosis?
One possible explanation is that statins have benefits that are not connected with lowering LDL cholesterol. For example, they appear to decrease inflammation and improve the function of the endothelial cells lining the walls of arteries. As a result, one would expect that using a more potent statin, such as atorvastatin (Lipitor) or rosuvastatin (Crestor), would result in more regression than was achieved with the same lowering of LDL cholesterol obtained by using Vytorin.
The ethical issue relates to the continued advertising of Vytorin during the long delay before the results of the ENHANCE study were made public. Michigan Representatives John Dingall and Bart Stupak have opened an investigation into this issue.
The fact that the drug companies continued advertising Vytorin (2 more full-page spreads appeared this week in my local newspaper) in the face of these disappointing results has raised an academic and political furor.
But, to give Vytorin the benefit of the doubt, the failure to show that it was superior to simvastatin alone may be due to the known fact that it is especially difficult to lower LDL cholesterol in people who are genetically predisposed to high cholesterol levels. Neither Vytorin nor simvastatin lowered LDL cholesterol to the recommended levels.
The actions of these drug companies are deplorable, but don't throw away your Zetia or Vytorin pills. Zetia is safe and effective in lowering LDL cholesterol, and the trial did not show adverse effects of Vytorin.
A longer trial that looks at cardiovascular events — heart attacks and strokes — in a larger number of participants may still show that Vytorin provides more benefits than a comparable dose of simvastatin alone. And the benefits may be even greater if ezetimibe is added to the more powerful statins, atorvastatin or rosuvastatin.
