Merck & Co remains confident in Zetia and Vytorin, despite studying questioning the drugs

USA-based Merck & Co, now the world's number two drugmaker following its acquisition of Schering-Plough, says it remains confident about the safety and efficacy of its leading cholesterol-lowering drugs, despite the results of a much-anticipated head-to-head study which calls into question the level of effectiveness of Zetia (ezetimibe) and Vytorin. (ezetimibe and simvastatin).

In combination with statins, adding a medication that raises high-density lipoprotein cholesterol was more effective in reversing artery wall plaque buildup and in reducing heart disease risk than adding a drug that lowers low-density lipoprotein cholesterol, researchers reported yesterday at the American Heart Association Scientific Sessions 2009, held in Orlando, Florida.

In the study, titled The Effect of Extended-release Niacin or Ezetimibe Added to Chronic Statin Therapy On Carotid Intima Media Thickness (ARBITER 6-HALTS), it was found that:

' Adding the cholesterol drug niacin (Abbott Laboratories' Niaspan) to a statin improved high density lipoprotein HDL ('good') cholesterol levels and significantly reduced arterial plaque buildup within eight months, with further improvement seen at the end of the study (14 months);
' A second approach, adding ezetimibe to a statin, lowered low density lipoprotein  ('bad') cholesterol to a greater extent, but did not raise HDL. With it, there was no overall effect on arterial build up in the neck arteries;
' With ezetimibe, greater reductions in LDL cholesterol paradoxically were associated with more arterial buildup, a result opposite to that expected; and
' The incidence of major cardiovascular events such as fatal and non-fatal heart attack was higher in the ezetimibe group as compared to the niacin group (5% versus 1%).

"The results of the small ARBITER 6 study do not, in any way, change our view of Zetia and Vytorin as effective medicines for fighting high LDL cholesterol," said Peter Kim, president, Merck Research Laboratories. "Nothing from this study, which a New England Journal of Medicine editorial says has 'several limitations,' changes the well-established understanding that lowering LDL cholesterol is the primary target of therapy according to the guidelines. Zetia and Vytorin, when used as a supplement to a healthy diet, are effective in reducing LDL cholesterol," said Dr Kim

The results of ARBITER 6 were widely predicted because the study design favored niacin as the patient population selected had well-controlled LDL cholesterol and relatively low HDL cholesterol, Merck noted. Also, it is important to remember that ARBITER 6 is not an outcomes study, and does not have the rigor or size to provide meaningful insight into the effect of either niacin or ezetimibe on clinical outcomes. Merck said it has reviewed the data from 43 completed shorter-term clinical trials involving approximately 2,400 patients who received ezetimibe alone and 13,600 patients who received ezetimibe with statins, as well as two longer-term studies, and is confident that the data support the safety profiles of Zetia and Vytorin as described in their labels.

"Any suggestion that the results of ARBITER 6 can definitively answer the question of the impact of ezetimibe on cardiovascular outcomes or that its results have implications for clinical use should be met with skepticism," said Dr Kim.

"The ARBITER 6 - HALTS study is the first study showing that HDL-raising with Abbott's Niaspan on top of statin regresses atherosclerosis compared to an LDL-lowering strategy," said Eugene Sun, vice president, Global Pharmaceutical Development, at Abbott. "These data reinforce the importance of looking beyond LDL treatment targets to address other lipid parameters," he noted.

Revenue drop likely?

Revenue for Zetia and Vytorin could fall 2%, or $800 million, with a negative finding, said Seamus Fernandez, a Leerink Swann & Co. analyst in a note to investors last week, reported by Bloomberg. Sales for the two drugs have dropped 14% this year to about $3 billion.