The FDA has just released their review of the ENHANCE trial involving Vytorin. I have blogged about Vytorin, a combination of a statin medication (simvastatin) and another cholesterol lowering medication that blocks cholesterol absorption from the gut called ezetimibe (Zetia), and the ENHANCE trial many times (here, here, here, here, here, and here)
The FDA's analysis concluded that after 2 years of treatment with either Vytorin or simvastatin alone, carotid artery thickness (a marker of risk for cardiovascular disease) increased by 0.011 mm in the Vytorin group and by 0.006 mm in the simvastatin group, which was not statistically significantly different. However, the levels of LDL (bad) cholesterol decreased by 56% in the Vytorin group and by 39% in the simvastatin group, which was statistically significantly different.
Here's what the FDA concluded:
The results from ENHANCE do not change FDA’s position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease. Based on current available data, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about Vytorin, Zetia, or the ENHANCE trial.
First, the FDA is stating that despite the fact that LDL lowering did not correlate with improvement in atherosclerosis, LDL is still a reliable surrogate marker for cardiovascular disease and thus a good target of therapy.
As I have mentioned previously, when you take a drug to prevent a heart attack or stroke, you want to know whether that drug actually decreases heart attacks or strokes (outcomes). The problem is that doing outcomes studies requires a large number of patients to be studied over a long period of time, which is difficult and costly. Therefore, many of the studies we use to make medical decisions rely on markers or proxies for disease called "surrogates." Cholesterol (specifically the bad cholesterol or LDL) is a known surrogate marker for heart attack and stroke, as is carotid artery thickness, the endpoint in ENHANCE. Though both surrogates correlate well with the outcome of heart attacks and stroke, in the ENHANCE study lowering the LDL did not cause a decrease in carotid artery thickness. Despite this, the FDA still believes that LDL is a good surrogate.
Second, the FDA states that because LDL is still a good surrogate and because Vytorin lowered LDL, depsite that fact that it failed to do any good in the ENHANCE study, the FDA recommends that patients NOT stop Vytorin. This one is more problematic.
I agree that LDL is a good surrogate, but we have been burned by surrogates before. High levels of homocysteine are linked to heart attacks, and folic acid lowers homocysteine, but when we looked at whether folic acid reduced heart attacks (outcomes), it actually caused MORE heart attacks, and is no longer recommended.
We know the lowering the LDL with a statin reduces heart attacks, and this relationship is in fact linear (the lower the LDL with a statin the lower the risk of heart attacks-see figure from 2004 NIH guideline update). The questions is whether lowering the LDL with something other than a statin, i.e. ezetimibe (Zetia) will reduce the risk of heart attacks and strokes. It may very well, but we have no evidence to date. Though ENHANCE may not have been the perfect trial to look at this, it is the only study we have using Vytorin/Zetia looking at something other than LDL, and this study was negative. Finally, it may be more about the statin than the LDL. The JUPITER study (which I have also blogged about) showed that lowering the CRP with a statin (Crestor)decreased heart attacks. LDL's were also lowered, but where CRP was elevated at the beginning of the study, LDL was relatively normal and would not have normally required a statin.
Thus, though the FDA suggests to not to stop taking Vytorin because it does lower LDL (and also does not appear to have a major safety issue), the question is whether or not you should be on Vytorin (statin plus zetia) or just a statin? Based on the figure above, by using a combination (Vytorin) instead of a statin alone to achieve LDL lowering, are you denying yourself the maximum amount of statin that you need to acheive outcomes? We don't have the studies to answer this question, but in my opinion it would be better to lower your LDL with a stronger statin like Lipitor and Crestor, then to use a weaker statin (like simvastatin) plus Zetia, i.e. Vytorin. The highest dose of Vytorin lowers cholesterol just a little bit more than the highest dose of Lipitor and Crestor, but not by much. In addition, adding Zetia to any statin will lower your LDL an additional 25%. Thus, based on the available data, it would be better to use the dose of a statin needed to lower your LDL. If the maxium dose of a statin failed to achieve the LDL to goal, or one could not tolerate the maxium dose of a statin, the adding Zetia seems a reasonable option.
1. LDL is still a good surrogate market and target for therapy.
2. The best way to lower LDL is with a statin, and lower appears to be better.
3. If you are on Vytorin, I wouldn't stop it, but would discuss with your doctor about of switching to something like Crestor or Lipitor.
4. If you are unable to reach your LDL goal on the highest tolerable dose of Crestor or Lipitor, than adding Zetia seems reasonable.