Monday, January 14, 2008

Vytorin and Zetia: What to do now?

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.


Anonymous said...

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.
But if Zetia doesn't provide any benefit why prescribe it at all? Why take a drug that reduces the number when reduction the number by this method doesn't provide any benefit? Shouldn't there be some evidence that Zetia actually reduces heart attacks before you prescribe it? Are there any studies that Zetia is better than placebo in reducing heart attacks not in merely reducing LDL number? If statins primary benefit is in reducing inflammation and not in reducing cholesterol and Zetia doesn't reduce inflammation, why take it?

OK, so it lowers cholesterol. In a trial it lowered cholesterol more than statin did. It didn't result in any additional benefit. In fact, the endpoints were worse than with statin alone even though cholesterol was better. So maybe just reducing LDL more without any addition action that statins provide isn't that important?

Dr. Matthew Mintz said...

Even though Zetia plus Zocor showed no benefit over Zocor alone, this does not necessarily mean that Zetia has no benefit at all. All evidence shows that lowering the ldl prevents heart attacks and strokes. The ENHANCE study is is the first and only study to suggest that there may be something more than just the ldl. In addition, this was not an outcome study. Though it would be surprising if the people on the Zetia and Zocor combination had the fewer heart attacks then the people on Zocor alone, given that there was really no difference in artery clogging; we don't know since the study wasn't designed to show this.
Finally, what it missing is a Zetia vs. Placebo study looking at plaque buildup. Since the statin is so much better, its effect may make Zetia's effect statistically negligible. However, when compared to nothing, Zetia may actually have some benefit. Again, unclear because there is not study to tell us.
I agree that until there are good outcomes studies, especially given the ENHANCE study's findings, we should use Zetia sparingly. However, to withold Zetia from a patient at high risk heart attack and stroke who needs cholesterol lowering but is unable to take a statin due to side effects would be ill advised. There may still be some benefit from Zetia, it is unlikely to be harmful, and there are not really any alternatives.

Anonymous said...

Eureka! Have you ever considered that maybe it is not about cholesterol, or the statin dosage? Zetia has been proven to lower LDL cholesterol in clinical studies involving thousands of patients. Yet Zetia has never been shown to prevent heart disease or heart attacks. Could the cholesterol theory of heart disease be based on shoddy science and greedy pharmaceutical companies who are simply motivated by economic profits?

Dr. Matthew Mintz said...

Your skepticism is appreciated. There is definitely a connection between LDL lowering with statins. The graph from the 2004 NIH update (link below-you can argue that some of the authors themselves have industry connections, but this is the most unbiased source I have)shows a linear relationship bewtween ldl reduction and heart disease risk. According to the NIH "for every 30-mg/dL change in LDL-C, the relative risk for CHD is changed in proportion by about 30%."
The issue is that all this data was with statins and not Zetia. Since Zetia did lower the ldl, there is more to the story than just the ldl, and why I was not shocked when the ENHANCE study came out.
One theory considers "plaque stabalization," which means that high dose statins prevent heart clogging buildup from breaking off and causing a heart attack or stroke. Others are looking into CRP, which (like ldl) is another bio-marker that correlates well with heart disease risk. CRP is also a marker of inflammation. We do know that Statins lower CRP, so perhaps they are anti-inflammatory? Our institution is part of a study looking at high dose statins in patients with normal cholesterol but high CRP's to see if they will reduce heart attacks.
There is clearly a lot more to the story than just ldl. And even though statins work, they do not prevent all or even most heart attacks, so there is a long way to go.

Anonymous said...

VytorinGate's Smoking Gun????

Did Schering employees leak ENHANCE results last spring just prior to Carrie Cox’s $28 Million Dollar Stock Dump? Read the Cafe Pharma posts from that time period and decide for yourself.

Anonymous said...

Wrong: "The graph from the 2004 NIH update (link below-you can argue that some of the authors themselves have industry connections, but this is the most unbiased source I have)shows a linear relationship bewtween ldl reduction and heart disease risk. According to the NIH "for every 30-mg/dL change in LDL-C, the relative risk for CHD is changed in proportion by about 30%."
That`s a LOG scale,.. says right there in the margin of the NCEP graph. The LDL Mafia has done a 'job' on us all. research NNT, Number Needed to Treat. Statins will liely NEVER reach an NNT < 20,.. currently NO statin alone reached an NNT < 27,.. the range is 27 to 100. However, 6 NIH [goverment funded] studies beat thise numbers 'soundly; 3 to 11. ALL of them had one common denominator; niacin.

Dr. Matthew Mintz said...

I recognize the graph is uses a log scale, which certainly makes the numbers look more convincing. Also, you may be correct that statins will not get NNT's lower than 20. However, sometimes a NNT of 100 is acceptable and sometimes a NNT is unacceptable, depending on the severity of what you are treating (heart attacks are pretty bad) and the side effects of what you are using (statins are pretty well tolerated, though if you consider cost of preventing heart attacks there is a compelling arguement to be made).
You are correct that niacin can help statins improve outcomes (though please let me know which 6 you are referring to). The HATS study did show benefit. However, the only niacin alone study to show decreased heart attacks and/or mortality was the Coronary Drug Project which was started in 1966. However, this prevented second heart attacks. In 2008, not giving a patient with a heart attack a statin would likely be considered malpractice. All other niacin studies were combined with another agent (statin or colestopol) and were progression/regression studies (like ENHANCE). In addition, niacin causes a significant degree of flushing, can raise sugar, and can cause gout. I am not saying that niacin has no role, but statins are the best agent we have.

Ralph Taite said...

The best agent we have for what? Clearly, niacin is the ONLY drug which lowers Lipoprotein A (LpA) and it may be a bigger marker for heart attacks than LDL. Also, niacin eliminates VLDL -- which is considered to be the most dangerous form of cholesterol and raises the level of HDL.

Niacin plus zocor actually REDUCED plaque buildup. Niacin is known to reduce the likelihood of another heart attack by 26%.

As for flushing, take an aspirin with your niacin and drink a full glass of water and the flushing is usually minimal.

Anyway, just wanted to say that statins don't work well for all. They make me ache everywhere. So I'm not sure how you can call it the "best" we have.

Dr. Matthew Mintz said...

Statins do not work well for all, and if you can't take them there are several alternatives which have advantages and disadvatanges, including Niacin. Statins cause muscle aches in about 3% of patients, these are usually mild and usually go away. But if a patient gets muscle aches from taking a statin that is not mild and/or does not go away, the they should lower the statin dose or stop the statin altogether.

I am not sure which study you are referring to when you state that "niacin is known to reduce the likelihood of another heart attack by 26%," but I bet it was done in combination with a statin. In my experience, when I have prescribed Niacin, patients complained about severe flushing even with taking an aspirin. One of the drug companies is working on a product that can be taken with Niacin to eliminate the flushing. Hope it will be out soon.

Anonymous said...

I take Zetia alone and have had good results: LDL 87,
HDL60 and total 196. I am concerned about the study conducted in regards to the drug Vytorin possibly causing cancer. Since Vytorin contains Zetia I am unsure whether I should continue to take it.

I live a healthy lifestyle and I am wondering if Zetia is making the difference in keeping my cholesterol in check and is it worth the risk?

Sometimes I am torn between feeling that the cholesterol numbers are constantly being lowered to sell more prescriptions or listening to my Doctor and continue to take the medication.

Dr. Matthew Mintz said...

From my most recent blog post, you can see that I really don't think there is any reason to use Vytorin. However, as mentioned in another recent post it doesn't seem like the cancer link is real, despite the fact that others are using medical reports for media hype and political attention.
The question you should ask your doctor is "do I need my cholesterol lowered with a medication." This decision is based on your baseline cholesterol numbers and risk for a heart attack or stroke. If your doctor states thats you do need medication, then you should start a statin medication. If for some reason you have side effects from a statin, other alternatives include niacin and Zetia which you are already on.
Again, though I don't believe cancer concerns would be a good reason to stop Zetia, if you really need a pill, you should use one that is proven to prevent heart attacks and strokes.

Anonymous said...

Doctor took me off zetia after Monday's reports. But, not off Crestor to lower tricylcerides.
Is Crestor being a statin next for attack, maybe it causing liver cancer or inflammation, or fatty liver? Overall Cholesterol was
120, seems low for my age of 57, yet tricylcerides remained high, LDL went up. Is lowering overall cholesterol really the answer, how much lower do we settle for?