Tuesday, April 8, 2008

Zetia In, Vytorin Out

As I said in my post last week, the now published ENHANCE study does not mean that Zetia is a bad drug, but that combining this drug with a statin (which is what Vytorin is) should not be used as first line therapy and adding to a statin when LDL goals are not met, may be beneficial.
Now, we have some evidence that this is in fact the case.
The SANDS study, reported in today's Journal of the American Medical Association shows that starting with a statin, and then adding Zetia improved atherosclerosis in diabetic patients treated to more aggressive LDL goals.
Bottom Line: If you have high cholesterol, your doctor says it needs to be lower, and diet and exercise won't get it down; first take a statin. If you can't take a statin or if a high dose statin can't get you to goal, then taking or adding Zetia is appropriate. If you get side effects with higher doses of statins, take the highest dose you can tolerate, then add Zetia if needed.
There is now really no good reason to ever start taking Vytorin. Though if you are on Vytorin, you should talk with your doctor before stopping.

For those who want more info:
The SANDS study looked at more aggressive goals for LDL (bad) cholesterol and blood pressure in patients with diabetes who are at very high risk for heart attacks and strokes. The took about 500 diabetic patients and half were treated to standard targets (LDL <100) and a systolic blood pressure (top number, SBP) of 130 mm Hg or lower. The other half was treated more aggressively to an LDL of 70 or lower and SBP of 115 mm Hg or lower. To look at progression of atherosclerosis (plaque build up), they measured by common carotid artery intimal medial thickness (IMT). The study showed that standard care group and progressive thickening of their arteries, but the aggressively treated group actually had regression or improvement. Unfortunately, there were no differences in deaths or heart attacks, but the rate of both were much lower than expected in the "normal" group, and it is possible that following these patients for a longer period of time will eventually show a difference.
The relation to Vytorin/Zetia is that in order to achive these more agressive blood pressure and cholesterol goals, more drugs were needed, including Zetia. More patients in the aggressive group got Zetia added to their statin medication, which was used first in both groups.

The ENHANCE trial also looked at the same outcome as SANDS, the CIMT.
In ENHANCE there was no improvement in CIMT when patients with very high cholesterol were given Zocor (simvistatin) 40mg or Zocor 40mg plus Zetia (Vytorin), even though Vytorin did lower the ldl more than the Zocor alone. This study got a lot of publicity for a number of reasons, but from a scientific standpoint it called into question the use of LDL as a target for cholesterol lowering. In addition to the multiple studies that show lowering LDL with a statin leads to fewer heart attacks and strokes, the SANDS study seems to confirm that LDL is indeed important, but in light of ENHANCE, how you get there is critical. You need to lower the LDL with a statin, but if you can not achieve LDL goals with a statin, you should add another medication like Zetia. The SANDS study is also important, because is suggests that patient with diabetes should be treated even more aggressively than current standards.

Zetia In, Vytorin Out.
Simvistatin, which is now generic, may be appropriate for many patients. However, it is not the most powerful statin. Newer drugs like Lipitor and Crestor are much more potent (and have CIMT, IVUS and other strong data to support preventing and even reversing atherosclerosis). At maximum dose, simvistatin 80mg can reduce LDL cholesterol by less than half, where as Lipitor and Crestor can achieve this at 20mg and 10mg respectively. Also, the higher the dose (regardless of potency) of a statin, the higher the chance of side effects. Thus, if you need your LDL reduced more than 40%, simvistatin is not likely going to be able to do this. In this situation, more potent statins such as Crestor and Lipitor should be used (as opposed to adding Zetia or starting with/switching to Vytorin which will decrease the LDL to goal, but may not lead to actual changes in the arteries). If a more potent statin can not achive LDL goals at a lower dose, a higher dose should be used. If this doesn't work (based at least on the diabetic patients in SANDS), then Zetia should be added since benefit was shown. Thus,
There is now really no good reason to ever start taking Vytorin.


ACD22 said...

Thanks for this very useful explanation of the circumstances in which Zetia is useful. And thanks generally for maintaining this blog; no doubt it takes valuable time.

druprep said...

You are clearly compensated by AZ and Pfizer and should post that on your blog in fairness. What's amazing is you don't even have the correct doseage used in ENHANCE. Both arms were treated with 80mg of Simva and all the regression had already taken place because the patients were on statins their whole life. Take 5 minutes and look at the baseline cIMT of Enhance and compare it to Crestors Meteor trial and Lipitor's ASAP trial. Crestor 40 was only able to slow the progression of plaque against placebo with much thicker IMT's. They missed their endpoint as well of showing actual REGRESSION. But im sure you dont see drug reps in your practice because we add no value to an educated man like yourself. Its an easy mistake getting the doseage wrong and not comparing studies closely.

Dr. Matthew Mintz said...

I apologize for the error in the ENHANCE doses in my recent post. The correct dose of Zocor was 80mg. As an academic general internist who teaches and sees patient, it is very difficult to post to a blog. I try to be as accurate as I can, but I am far from perfect.
I can assure that I am not paid by AZ or Pfizer to bash Vytorin, as suggested by your post. I will admit to receiving honoraria over the course of many years from many drug companies, including Merk, for speaking on a variety of topics including dyslipidemia, diabetes, asthma and COPD.
You should not make assumptions about my daily practice. From your posting the word "we", I am gathering that you are a drug rep. You can ask any of you counterparts that call on me (I am at the George Washington University School of Medicine) that I am one of the few physicians who does speak to reps. I get my information from multiple sources such as journals, CME, and unbiased sources like The Medical Letter. However, though the information a representative may bring me is potentialy biased, it may be something that I had not seen in the aforementioned sources, and thus at least deserves to be heard.
Now, to your point, it seems that what you are saying is that since most of the patients in ENHANCE were on statins (80%) for many years before starting the study, their CIMT's were thinner than in the other studies (0.70mm in ENHANCE vs. 1.2mm in METEOR), and therefor it would be harder to show any benefit of adding Zetia to 80mg of Zocor. Though this may be true, and one should be careful in comparing across studies, the fact remains that both Lipitor and Crestor have been shown to delay the progressions of atherosclerosis and Vytorin has not. The fact that METEOR did not show statistic regression is a minor point, it DID show delay in progression. It may be that ENHANCE was just poorly designed if the primary intent was to show delay in progression, but I was not involved in the design of the study. All the available evidence to date shows that outcomes (heart attack and stroke) correlate to LDL reduction with a statin. There is no outcome, IMT or IVUS data with Vytorin. In addition, due to other effects of statins (lowering blood pressure, CRP, etc.) there is reason to believe that some of the cardiovascular benefits of statins go beyond ldl reduction.
Though Merk did an excellent job at marketing the two sources of cholesterol, it never made a scientific case of why this was important and currently has no studies to back this up. Until then, it seems prudent for any patient needing medications to lower their LDL to start with a statin first. If the patient's goal can not be obtained with the maximum dose of a statin, the adding Zetia is a reasonable option.

druprep said...

Thanks for your response. I am a rep so of course I'm bias too, we just want everyone to know the correct information not just what the media reports and then make decisions. Just interested if you've heard any noise from the National Heart Lung and Blood Institute's SANDS study that was published in JAMA April 9th issue? Google it if you can, it looked at a small group of diabetics and added Zetia to an "agressive" arm with Atorvastatin. Anyway I'd love to hear your thoughts, which may help me in the field-the more agressive group was treated to 70 LDL-C and showed plaque regression and a smaller left ventricle size. (they also treated SBP more aggressively)

Dr. Matthew Mintz said...

Read the second part of the initial post under "for those who want more info" which details the SANDS trial and how this compares to ENHANCE. Essentially, LDL is clearly important ans SANDS indicates that if a statin can not get you to goal, then Zetia is clearly a good option.
Unfortunately, the study does not indicate how many patients in the intervention group were not at goal, and how they got there. We know that more medication (meaning statin plus zetia) was used, but we don't know how many patients in the intervention group took Zetia.

Anonymous said...

Considering the new SANDS article being published in this weeks JACC, the IDEAL trial and the SEARCH trial, you may need to reconsider the position that high dose statins are necessarily better than lower doses. The goal is clearly lowering LDL, not how you do it.

Anonymous said...

Typical dipshit teacher who sucks as a IM physician. "I can't really take good care of my patients so I think I should teach." Sounds like a typical loser politician who couldn't make it as an attorney, so why not go into politics and live off the tit of the country. You are a loser Mintz.

Unknown said...

Humana medicare drug plan charge to me for 90 days of Zetia 10mg is 192.00.
For Vytorin the same 90 days of 10/40 is 100.00.
So adding Zetia to Zocor or its generic is much more expensive. To me that is a valid and compelling reason to use Vytorin. These prices as of 6/2009.

Dr. Matthew Mintz said...

curley coco,
the issue is what is your bad cholesterol (LDL) without Vytorin, what is your LDL goal, and what is your cost for lowering that goal.
For example, if your LDL is200, and you need it to be 100, then you will need max doses of Vytorin, Lipitor or Crestor to get the job done. You need to price these out. If the Lipitor or Crestor is the same or lower price thant Vytorin, then I would recommend those because you are lowering the LDL with the statin alone.