Vytorin: Dis-Enhance-d
A long awaited study – the Enhance study – indicates that the combination medicine Vytorin not only doesn’t stop the growth of plaque but may actually increase it, which isn’t particularly pleasing to Merck and Schering-Plough, the pharmaceutical giants that make the drug.
We’ve all seen the annoying commercials ad naseum. Cholesterol comes from two sources: Fettuccine Alfredo and your grandfather, Alfredo. The various people from whom you’ve allegedly inherited your tendency are dressed in outfits that kind of match the look of the foods that cause your cholesterol to increase. If you’ve been lucky enough to have avoided these ads, I’ve included one at the bottom of this post so that you can be as annoyed as the rest of us. I never watch TV other than the occasional football game (or in the case of this past weekend, every NFL playoff game), and I’ve seen the Vytorin commercials countless times. I’m sure it’s one of the most heavily run ads on TV.
Vytorin is a combination of Zocor (simvastatin), the first statin drug approved, and Zetia (ezetimibe), an inhibitor of cholesterol absorption from the GI tract. It is expensive and gives Merck, the maker of Zocor, a way to continue harvesting loads of money from a drug that has now gone off patent and is available as a generic.
Results of the Enhance study have been withheld for some time now giving critics of the drug industry cause for claiming that the companies involved were fiddling with the results to make them more to their liking. Meanwhile millions of people are taking Vytorin while God only knows how much money is being spent promoting it.
Now, as reported in a front page story in today’s New York Times, the results are in, and they are disastrous.
The Enhance trial was meant to prove that Vytorin’s combination of Zetia and Zocor would reduce the growth of fatty plaque in the arteries more than Zocor alone. Instead, the plaque actually grew almost twice as fast in patients taking the combination.
Reducing plaque growth is crucial, because plaque formation — known as atherosclerosis — can lead to the blockages and blood clots that cause heart attacks and strokes, said Dr. Howard N. Hodis, a cardiologist at the University of Southern California. That is why the trial’s finding is worrisome, Dr. Hodis said.
Indeed. I’m glad I’m not one of the 5 million people who are taking Vytorin.
The article contains a statement from a cardiologist at the Cleveland Clinic, a hotbed of statinators if there ever was one.
Dr. Steven E. Nissen, the chairman of cardiology at the Cleveland Clinic, said the results were “shocking.”
“This is as bad a result for the drug as anybody could have feared,” said Dr. Nissen, a widely published researcher and senior consulting editor to the Journal of the American College of Cardiology. Millions of patients may be taking a drug that does not benefit them, raising their risk of heart attacks and exposing them to potential side effects, he said. Patients should not be given prescriptions for Zetia unless all other cholesterol drugs have failed, he said.
Like the statinator of the deepest dye that he is, Dr. Nissen neglected to mention the name of the the statin drug Zocor that makes up the other half of Vytorin.
Another statinator weighs in with a difference of opinion:
Dr. Michael Davidson, a cardiologist in Chicago who has conducted clinical trials of Zetia for Merck and Schering, said the Enhance results did not necessarily mean the drug did not work. Many of the patients in the trial may have been on statins for many years before the trial began, so adding Zetia may have had only marginal benefits compared with its use in a population not as extensively treated for cholesterol, he said.
Still, he said, patients should generally receive a statin before getting Zetia.
Hmm. I’ll bet he does. But let me get this straight. The study shows an increase in plaque, the very condition one hopes would be prevented by the drug therapy under evaluation, and this guy says the results “did not necessarily mean the drug did not work”?
The really tough thing for the statinators and other worshipers at the alter of the lipid hypothesis to come to grips with is that the Enhance study showed that those subjects taking Vytorin reduced their LDL-cholesterol by 40 percent more than those taking the statin alone ( 58% drop on Vytorin – 41% drop on Zocor), yet plaque increased in the subjects on Vytorin. But do you hear any head scratching over this? Anyone saying, ‘whoa there, a lower cholesterol equals more plaque’? Any body at all (other than yours truly, of course) seizing on the obvious? Nope. Not a one. The cry of the herd is ‘back to statins alone.’
Maybe it’s just me, but I would like to think that if I believed with all my heart that LDL-cholesterol caused plaque formation, and then a study came along showing a huge decrease in LDL-cholesterol accompanied by an increase in plaque formation, that my faith might be a little bit shaken. But not so with the statinators.
I posted a week or so ago about a study showing that a low-carb diet acted on the same place in the enzymatic pathway that produces cholesterol as the statin drugs do, but without the side effects. If you really fear LDL-cholesterol, why not treat it with a low-carb diet instead of turning to drugs that can often turn on you? It’s never made sense to me.
For those of you fortunate enough to have missed the Vytorin commercials, here is one for your viewing pleasure. As you watch, ponder on the message in this ad that was beamed to hundreds of millions of people while those PBs (poor bast**ds) on the Vytorin study were having their plaque grow. Kind of creepy.
Dr Mike,
I know you said not to ask medical questions, but will you answer a supplement question? I hope so. It’s so hard to know what to do. One could easily be swallowing 100 pills a day, I think. Based on your comments about how important these nutrients are, each day I take:
2 tsp Carlson’s Fish Oil
20,000 IU Vitamin D3 gelcaps
400 mg Mg Glycinate
Is there anything else I should add or change/increase/decrease?
I’m a 43 year old healthy female, mother of 3 young children, and follow a LC diet. I’m at a good weight. I reside in Northern VA.
If you can’t answer, I understand. I’m just confused about supplements…as usual.
Hi Elle–
I would be careful taking 20,000 IU of vitamin D3 daily without checking a blood vitamin D level (ask for a 25(OH)vit D level). You can get too much, especially if you’re taking the cod liver oil as well. Get a blood test and take enough vit D3 to keep you in the normal range. Click here for everything you ever wanted to know about vitamin D.
Cheers–
MRE
What a bunch of crap. The drugs companies can poison the world and get rich. One expert said this means you should not take any drug that has not been on the market for at least 7 years, since you can’t count on their so -called “research.”
I hope Cox goes to prison.
You may get your wish.
Dr. Mike: thanks again for your sharp eye and great insights on this topic.
Dr. Howard Brody also had an interesting post about the “Enhance” study today on his blog. I’ll paste just the intro and you and your other readers can check out the complete commentary if you like:
* * * *
http://brodyhooked.blogspot.com/
Wednesday, January 16, 2008
Now That We’ve Been ENHANCED–What’s the Message?
Since I last blogged about the ENHANCE trial:
http://brodyhooked.blogspot.com/2007/12/new-cholesterol-controversies-regaining.html
…the big news of the week, that I’m a couple of days late commenting on, is the mind-numbing flop of the ENHANCE trial. When Merck and Schering-Plough started to do the usual Pharma tapdance, specifically calling in an expert consultant group to change the trial’s endpoints before the results were announced (without the supposed principal investigator even being at the meeting), we all started to predict that the study results were not favorable to the companies’ drug, and that skullduggery was afoot to re-spin the results to somehow make the sow’s ear look like a silk purse. Few of us guessed just HOW totally disastrous the results actually were, as finally revealed this week– that the drug ezetimibe (Zetia), added to a statin (as in the combination drug Vytorin), not only failed to improve arterial wall plaque in any demonstrable way, but may even have worsened it.
* * * *
By the time I got to the end of Dr. Brody’s commentary I was cheering because I think maybe the mainstream is starting to get it. Tiny, incremental steps maybe….but they’re finally beginning to get it. (Or maybe I’m just the naive, pollyanna type.)
Cheers and Best Wishes,
W
Hey Wil–
Thanks for the link. And sorry it took me so long to get it up.
Cheers–
MRE
Is this related to the NYTimes story found here:
http://www.nytimes.com/2008/01/17/business/17drug.html?em&ex=1200718800&en=76d9c23de0108a70&ei=5087
It might require a free login to view the story, I don’t know for sure. If you cannot view it let me know and I will send it to you in an e-mail.
Basically, it calls into question the whole cholesterol->heart disease hypothesis.
Hey Dave–
See today’s post.
Cheers–
MRE
Hey Mike,
I have been following this a little more closely than I otherwise might because as you know I got drawn into a debate with Dr David Sullivan, “a specialist at Sydney’s Royal Prince Alfred Hospital and the (Australian) Heart Foundation’s spokesman on cholesterol” whose comment on ENHANCE I’ll post for anyone else interested in the sort of contortions apparently necessary when you are a “spokesman on cholesterol” these days”
He says:
One of the things that concerns me most about this issue is that there has yet to be any interest from any news outlet in this country – and considering the number of people who must be taking these drugs here …
But your press and it seems congressmen are a little more concerned, as this piece in Newsweek shows – http://www.newsweek.com/id/94969
Apart from the amusing reference to the obvious (but thankfully doomed) attempt to “put lipstick on this pig” two things don’t quite gel. One (of the many) excuses for the long (almost 2 year) delay in publication was apparently that “the data was biologically implausible”!!- we should certainly pause to consider that one! – but contrast that with the claim that Carri Cox is in the clear because “These trades go back to the spring of 2007 and the data for this trial were only unblinded about two weeks ago”. Well I’d say they can’t have it both ways – either they have been scratching their heads about “biologically implausible data” for two years or it was “unblinded” two weeks ago … because surely until it was unblinded no one could tell how “plausible” it was?
Cheers,
Malcolm
Hey Malcolm–
It is amazing to see the contortions. We have a relatively small study that shows no benefit, so therefore we need a larger study that could possibly show some benefit. Crazy. You could just as easily say that we need a larger study because it might show more damage. Yeesh.
And the what-did-they-know-and-when-did-they-know-it scenario is also beyond belief.
Cheers–
MRE
Ok – I don’t see that this study demonstrated anything other than an elaborate waste of money to demonstrate absolutely nothing.
They measured IMT changes in a bunch of folks all treating their cholesterol numbers.
Baseline mean for Vytorin group 0.68mm – after 2 years treatment mean = 0.6911mm
Baseline mean for Zocor group 0.69mm – after 2 years treatment mean = 0.6958mm
Baseline mean for no treatment ??? after 2 years no treatment ??? unknown
mean IMT for Zocor group after 2 yrs 0.0047mm > Vytorin group
Can anyone point me to a study that establishes any clinical significance to a change of 1/2 of a thousanth of a mm in an IMT measurement? Can anyone point me to a study that establishes the acceptable SD for the measurement of IMT?
Sorry – but for me this study was snake oil from the very beginning.
Hi Labrat–
It demonstrated that a very expensive drug taken for 2 years didn’t do squat in terms of treating that which is was prescribed for.
Cheers–
MRE
Oops, Dr Mike, I just realized my dose of Vitamin D3 is 2,000 IU. Sorry about that!
You said, “In this study Vytorin unquestionably brought LDL down better than statins alone.” My point was that there are people in whom STATINS ALONE DO NOTHING.
Hence their choice is total cholesterol levels over 400 or taking something like Zetia.
So the logic that they should just take a statin doesn’t apply to them. No one is addressing the problems of this population.
Whether or not a microscopic difference in plaque, with a poor P value, assuming that artery thickness is, indeed, directly related to plaque, means anything in terms of cardiac events remains to be seen. It’s my understanding that it’s unstable plaque that is the problem.
The CV events, although larger (something like 2 events instead of 1) were suggestive but not statistically significant.
I am committed to LC, as I think it has a lot of other benefits, especially for a person with diabetes. But someone needs to address the problems of those in whom LC alone is not sufficient to reduce astronomical cholesterol levels.
Even if you don’t believe in the cholesterol hypothesis when cholesterol levels are in a highish range, we know that people with really astronomical levels in familial hypercholesterolemia do often die from heart attacks in their 20s. Therefore, it can’t be totally irrelevant.
Hey Gretchen–
The data indicates that people with familial hypercholesterolemia (FH) do indeed die at greater rates from heart disease than do those without the disorder, although not to as great an extent as might be imagined. But people with FH also die a little less frequently from other diseases, namely cancer, as compared to those without FH. Overall, in terms of all cause mortality there really isn’t much difference – if any – in those with FH and those without.
I suppose then that it would be an individual choice as to whether or not pursue cholesterol lowering at all costs verses just leaving it alone.
Is it possible that Vytorin reduced cholesterol without reducing apo-B so that in effect it reduced the size of the LDL and hence increased plaque?
Did they measure apo-B?
Could be. I don’t know if they measured apoB or not. As far as I know this study isn’t available in printed form. All I know about it is what the drug companies released in their press releases. I would like to see the actual study. If anyone comes across it, send it my way.
Cheers–
MRE
Did you ever notice that more Jarvik lowers his cholesterol, the more he looks like Gollum.
Hey Razwell–
Good observation. Maybe you’re on to something.
Cheers–
MRE
Dr. Mike, Can it be said that this study just proves our point about low cholesterol? Regardless of how it gets lowered, low LDL levels and small particles will always increase plaque? Am I coming to an conclusion that is not supported by these particular datum or is it something being completely overlooked? Did they bother to look at why the plaque increased, was it something related to the medication or a result of the lower cholesterol?
Thanks,
Dave
Hey Dave–
I don’t know that anyone really knows at this point why the plaque increased. And remember, although the plaque almost doubled, the change didn’t reach the level of statistical significance. We’ll have to see a lot more data to figure out what really went on hear. Another thing to remember is that these subjects were not normal subjects with high cholesterol levels, but were subjects who had familial hypercholesterolemia, a genetic disorder. Whatever happened to these subjects can’t necessarily be extrapolated to what would happen to subjects without this genetic disorder.
Cheers–
MRE
I used to love those commercials. Forget the content, they had striking visuals that got the message (two sources of cholesterol: genes and food) across very cleanly. I think they’re only really annoying with repetition. I haven’t tracked formally, but find a high concentration during football, the nightly news and other things that tend to draw a lot of middle aged and older men to viewing. When I watch the NBA, much lower incidence of Vytorin ads and very few of Dr. Jarvik from the Forbidden Zone on the PotApes. Law and Order, in reruns, tends to have a lower density of these ads (and ED ads) as well.
Quick question: Recently, saw an ED ad (I am immature, I find any ad where a man comes on and talks about his inability to rise to the occasion amusing, even if they are all actors) that targets people with diabetes and high blood pressure. If you have these conditions, apparently, you’re more liable to go on TV and brag about your difficulties. Or at least have difficulties. But, fortunately for you, there is ED Drug X (I can’t remember which one it is that’s plugging with this commercial… maybe the one with the bathtubs). Now, on to the question:
Perhaps a growth opportunity for PP/PPLP/The Next Book would be to tout it as a cure for ED. Since diabetes and high blood pressure are associated with ED, perhaps the best treatment for both would be the best treatment for ED.
Just a thought.
Last thing: given the media buying prerogatives of statin merchants, perhaps the cure is to watch less football.
Hello Mike,
Thanks for the article. I’ve been on Vytorin for 2 years, and was on Zocor prior to that for several years. Last week, I requested that my cardiologist prescribe something other than Vytorin for me.
I just checked my mail order prescription center to find that he prescribed Vytorin AGAIN! How can I convince my cardiologist that I am not comfortable continuing with Vytorin and that I want to return to Zocor or some other alternative?
Do you believe that continuing on Vytorin could be risky?
Yikes!
Carl.
This is a call you’re going to have to make with your own physician. I can’t give you medical advice over the internet.
Dr. Mike
MISREPRESENTING the data in the ENHANCE trial . I am NOT for the Lipid Hypothesis but atherosclerosis did NOT increase.
There was no benefit from an LDL reduction of 58 % but the plaque did NOT increase.
That NY Times article is incorrect.
Hey Razwell–
Actually you are correct, sort of. Plaque did increase, just not significantly. The amazing thing, however, for believers in the lipid hypothesis is that it didn’t DEcrease markedly. An element of the lipid hypothesis is the notion that elevated LDL increases plaque formation and reducing LDL decreases plaque formation. In the ACCORD study we have a situation in which a substantial reduction in LDL concentration not only didn’t reduce plaque, but actually increased it (although not to a statistically significant level).
The NY Times article wasn’t incorrect because there was an increase in plaque in the subjects taking Vytorin. Where they were wrong is in not reporting it as a non-statistically-significant increase in plaque. (I’m assuming the Times didn’t do that – I didn’t actually go back and read the article again.)
Cheers–
MRE
Dr. Eades
Cholesterol Theory proponents are now saying that the median LDL level of 134 mg/dl in the study was not low enough for any atherosclerotic plaque regression . They say you need to have LDL levels 100 mg/dl.
The study was flawed they say.
I know this is nonsense though.
Razwell
Nonsense to the max.