The news broke pretty rapidly today. The
NY times is probably the most cited, but the scariest headline belongs to the Washington Post which might scare some patients stating "
Cholesterol Drug Zetia Doesn't Benefit Health." Essentially, Merck and Schering-Plough, the companies that make Zetia and Vytorin (a combination of Zetia and Zocor), released the results of a study they funded called ENHANCE which compared Vytorin to Zocor alone in 720 patients with an inherited type of high cholesterol, and showed no benefit in the progression of atherosclerosis after 2 years of treatment.
Bottom Line (for those who want a quick opinion): Prevention of heart attacks and strokes may be more about the cholesterol medicine you take then how much your cholesterol is actually lowered. Based on this study and others, patients at risk for heart disease that require medications to lower cholesterol should be on a statin (Crestor, Lipitor, Zocor) at the dose which gets their cholesterol down. Zetia should probably be reserved for patients who can not take a statin due to side effects, or who need additional cholesterol lowering after taking the highest dose of a statin. Patients on Vytorin should not stop taking it (study showed no additional benefit, not that Vytorin didn't work), but might want to discuss with their doctor about taking a different kind of statin.
Details (for those that are interested).
First, don't be scared by the headline. Zetia is a good drug and does work. The problem is the benefit of Vytorin (two drugs: Zocor or simvistatin +Zetia). You have seen the clever TV ads about the
two sources of cholesterol. Problem is that though cholesterol does come from two sources, there was never any proven benefit in treating those two sources over that standard approach which is using a statin alone.
When the drug reps initially promoted Vytorin, the pitch they would use implied that you could get the same results with a lower amount of statin, suggesting some safety benefit, since statins can and do cause side effects. (They had to back off of this approach when safety concerns with Zetia emerged, and the ENHANCE trial confirms there is really no safety differences).
The issue here has to due with outcomes, surrogate endpoints and surrogate markers. When you take a drug to prevent a heart attack or stroke, you want to know whether that drug actually resutls in decreases in heart attacks or strokes (outcomes). We have definitive evidence that taking statins lowers the risk for heart attacks and strokes. This is true even in high risk patients with normal cholesterol levels,
such as diabetics, (which already suggests it may be the statin and not the actual amount of cholesterol reduced). The problem is that doing these types of studies requires a lot of patients over a long period of time, which is difficult and costly.
The ENHANCE trial looked at plaque build up (thickness) in the carotid arteries (arteries that supply blood to the brain). Clogging of the arterties has been shown to correlate well with heart attacks and strokes, but this is not the same thing.
Most trials look at cholesterol lowering. Cholesterol (specifically the bad cholesterol or LDL) is what is known as a surrogate marker for heart attack and stroke. We know the higher your cholesterol, the greater the chance of getting a heart attack. We also know that statins and even Zetia can lower the cholesterol. But does that mean that if you lower the cholesterol (surrogate marker) with a statin, Zetia or a statin plus Zetia; that you decrease your risk of heart attack and stroke (outcomes)? The answer is "yes" for statins, and (now after ENHANCE) possibly not with Zetia and Zetia plus statin.
We have been burned by surrogate markers before. I have mentioned use of folate to lower homocysteine levels in my
previous post about Vitamin D. Lowering antioxidants with Vitamin E is another example (patients taking Vitamin E actually had more heart attacks).
In the ENHANCE study, the Vytorin did lower the cholesterol to a greater degree than the Zocor alone. However, this didn't show any differences in thickness of the carotid arteries. We know that when you lower LDL cholesterol with a statin, lower is better. The question is whether reaching your cholesterol goal with a statin (say 40mg of Zocor) has a difference in benefit with a combination of a lower dose of statin plus another drug (Zetia plus Zocor 20mg = Vytorin 10/20)? There has never been any evidence that treating those two sources of cholesterol showed any benefit. Safety (which was the intial promotional message) does not seem to be a reason. Additionally, Zocor is now generic (simvistatin) and Vytorin now costs more. Now with ENHANCE, there is evidence that by using a drug like Vytorin we may be denying a patient the dose of statin they need.
DB suggests that we consider using only high dose statins, and pay less attention to the LDL number, and there is plenty of evidence to back up this claim.
I would recommend using a potent statin (Crestor, Lipitor, and possibly higher doses of simvistatin) that acheives your LDL goal. If that goal can't be achieved by the highest dose of statin or you have side effects at the statin dose that achieves this goal, then I would add Zetia to the statin.
Since this post has gotten way to lenghty, I won't even go into the scandal about the drug companies trying to delay and even change the way the ENHANCE data was presented so it didn't look as bad. This has been
documented elsewhere.
Bottom Line (for those who want a quick opinion): Prevention of heart attacks and strokes may be more about the cholesterol medicine you take then how much your cholesterol is actually lowered. Based on this study and others, patients at risk for heart disease that require medications to lower cholesterol should be on a statin (Crestor, Lipitor, Zocor) at the dose which gets their cholesterol down. Zetia should probably be reserved for patients who can not take a statin due to side effects, or who need additional cholesterol lowering after taking the highest dose of a statin. Patients on Vytorin should not stop taking it (study showed no additional benefit, not that Vytorin didn't work), but might want to discuss with their doctor about taking a different kind of statin.
Details (for those that are interested).
First, don't be scared by the headline. Zetia is a good drug and does work. The problem is the benefit of Vytorin (two drugs: Zocor or simvistatin +Zetia). You have seen the clever TV ads about the two sources of cholesterol. Problem is that though cholesterol does come from two sources, there was never any proven benefit in treating those two sources over that standard approach which is using a statin alone.
When the drug reps initially promoted Vytorin, the pitch they would use implied that you could get the same results with a lower amount of statin, suggesting some safety benefit, since statins can and do cause side effects. (They had to back off of this approach when safety concerns with Zetia emerged, and the ENHANCE trial confirms there is really no safety differences).
The issue here has to due with outcomes, surrogate endpoints and surrogate markers. When you take a drug to prevent a heart attack or stroke, you want to know whether that drug actually resutls in decreases in heart attacks or strokes (outcomes). We have definitive evidence that taking statins lowers the risk for heart attacks and strokes. This is true even in high risk patients with normal cholesterol levels, such as diabetics, (which already suggests it may be the statin and not the actual amount of cholesterol reduced). The problem is that doing these types of studies requires a lot of patients over a long period of time, which is difficult and costly.
The ENHANCE trial looked at plaque build up (thickness) in the carotid arteries (arteries that supply blood to the brain). Clogging of the arterties has been shown to correlate well with heart attacks and strokes, but this is not the same thing.
Most trials look at cholesterol lowering. Cholesterol (specifically the bad cholesterol or LDL) is what is known as a surrogate marker for heart attack and stroke. We know the higher your cholesterol, the greater the chance of getting a heart attack. We also know that statins and even Zetia can lower the cholesterol. But does that mean that if you lower the cholesterol (surrogate marker) with a statin, Zetia or a statin plus Zetia; that you decrease your risk of heart attack and stroke (outcomes)? The answer is "yes" for statins, and (now after ENHANCE) possibly not with Zetia and Zetia plus statin.
We have been burned by surrogate markers before. I have mentioned use of folate to lower homocysteine levels in my previous post about Vitamin D. Lowering antioxidants with Vitamin E is another example (patients taking Vitamin E actually had more heart attacks).
In the ENHANCE study, the Vytorin did lower the cholesterol to a greater degree than the Zocor alone. However, this didn't show any differences in thickness of the carotid arteries. We know that when you lower LDL cholesterol with a statin, lower is better. The question is whether reaching your cholesterol goal with a statin (say 40mg of Zocor) has a difference in benefit with a combination of a lower dose of statin plus another drug (Zetia plus Zocor 20mg = Vytorin 10/20)? There has never been any evidence that treating those two sources of cholesterol showed any benefit. Safety (which was the intial promotional message) does not seem to be a reason. Additionally, Zocor is now generic (simvistatin) and Vytorin now costs more. Now with ENHANCE, there is evidence that by using a drug like Vytorin we may be denying a patient the dose of statin they need. DB suggests that we consider using only high dose statins, and pay less attention to the LDL number, and there is plenty of evidence to back up this claim.
I would recommend using a potent statin (Crestor, Lipitor, and possibly higher doses of simvistatin) that acheives your LDL goal. If that goal can't be achieved by the highest dose of statin or you have side effects at the statin dose that achieves this goal, then I would add Zetia to the statin.
Since this post has gotten way to lenghty, I won't even go into the scandal about the drug companies trying to delay and even change the way the ENHANCE data was presented so it didn't look as bad. This has been documented elsewhere.