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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Vytorin: It's A Pity | Main | Whose Guess Is Better? »

April 2, 2008

Vytorin Numbers

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Posted by Derek

Thanks to a tip from “Jack Friday” of the Pharmagossip blog, I’ve read this paper which appeared in Atherosclerosis this past summer. A large multi-center team put a lot of work into studying the Vytorin combination (ezetimibe and simvastain, the cholesterol absorption inhibitor and a classic HMG CoA reductase inhibitor) in 72 healthy male subjects. I was initially excited about it, because reading the abstract it seems as if they’ve found a real difference between taking the combination versus taking the drugs by themselves, which is rather a hot topic these days. But read on.

The subjects were divided into three groups, receiving 10 mg/day ezetimibe (basically Zetia monotherapy), 40 mg/day simvastatin (Zocor monotherapy) or the combination (Vytorin). The results? Well, LDL cholesterol went down in all groups, as expected – this much was known already. (Total cholesterol was down as well, but this was basically all due to LDL reduction). Ezetimibe alone lowered LDL by 22%, simvastatin by 41%, and the combination lowered it by 60%: so far, so good. Those are just the kinds of numbers that convinced people to go on Vytorin in the first place.

Cholesterol synthesis showed an interesting pattern, but one that makes sense. Simvastain lowered it, as well it should – that’s the whole rationale for a statin in the first place. But ezetimibe actually increased it, which could be interpreted as the body’s attempt to get back to previous cholesterol levels after the dietary supply was cut off. The combination was a wash, as you’d expect – the two canceled each other out. These results have been found in other studies as well.

Meanwhile, cholesterol absorption was the flip side of endogenous synthesis. Ezetimibe lowered it (again, as well it should!), and simvastatin had essentially no effect. The combination, then, showed an overall lowering of cholesterol absorption – no surprises, and this, too, has been seen in other work.

The gene for the surface LDL receptor showed a different pattern. Ezetimibe by itself didn’t do much to its expression levels, but simvatatin sent it up (and thus the combination sent it up, too). When they looked at the actual LDL-receptor protein, though, none of the three regimens had an effect. The abstract for the paper makes more out of this than the paper itself does, to my eyes. The abstract singles out the combination therapy as upregulating the gene but not protein expression, as if that were some new effect, but simvastatin alone does the exact same thing. I didn’t see anything particularly surprising here, and the bottom line is that none of the three treatments did anything to LDL receptor protein levels, which is how real clinical effects would be expected show up.

The differences these investigators found with Vytorin as compared to its two components seem to me to be either already known, completely reasonable and expected, or so small that it’s uncertain if they exist. I have a feeling that that’s why this work was published in Atherosclerosis - a perfectly good journal, mind you, but if something dramatic had shown up, I’ll bet they could have made New England Journal of Medicine, JAMA, The Lancet, Nature Medicine or the like.

Overall, this study just seems to be confirmation of why Merck and Schering-Plough felt safe in making a big marketing play for Vytorin. If lowering LDL is good, and if lowering LDL is the reason that people take statins, then Vytorin does it even more. If you were shown these results without knowing that they were for Vytorin, you'd think that someone had discovered a real blockbuster of a new cholesterol-lowering drug. So we’re right back to asking why ENHANCE didn’t show a benefit in artery wall thickness. And that, no one knows.

Comments (13) + TrackBacks (0) | Category: Cardiovascular Disease


COMMENTS

1. statin skeptic on April 2, 2008 9:29 AM writes...

A growing body of evidence suggests that the marginal plaque regression and survival benefits offered by Zocor and other statins to be due to off-target anti-inflammatory rather than on-target HMG-coA inhibitory mechanisms. Perhaps Zetia somehow offsets the anti-inflammatory effects of Zocor so that Vytorin offers no benefit whatsoever rather than the small benefit offered by Zocor therapy.

I expect to see radically more effective dislipidemia therapies emerge that regress plaque thickness far more than the statins. LDL level is probably more of a red herring than an appropriate biomarker.

Permalink to Comment

2. sroy on April 2, 2008 9:33 AM writes...

There are also the numerous studies that show that statins work rather well (reduce MI risk) in people who do not get any worthwhile reduction in LDL levels. JUPITER just hit another big nail in the coffin of the cholesterol hypothesis for atherosclerosis in normal people. The precursor of JUPITER showed the same effect but JUPITER was larger and specifically to look for that effect.

Hereditary lipid disorders might have a cholesterol component just because the transport of cholesterol is so screwed up in those people. These people get xanthomas in their tendons and under their skin. How many patients taking lipid lowering drugs have it that bad?

Do you know that our popular theories on the etiology of atherosclerosis are based on what we learnt from various familial hypercholesterolemias. Somehow everone thought that atherosclerosis in most people occurs by the same process as that seen in people with rare and serious lipid transport disorders. Well, it turns out that is very likely not the case.

Permalink to Comment

3. RKN on April 2, 2008 9:38 AM writes...

I browsed the paper. Seems to me at least one big question remains: how exactly is Ezetimibe working to reduce LDL in humans? Yes it interferes with NPC1L1, but the authors found no significant change in the mRNA or protein expression for NPC1L1 in blood-borne mononuclear cells. But evidently in humans most NPC1L1 is expressed in the gut lining and hepatocytes. Maybe they looked in the wrong spot?

They allude to the caveat in the discussion:

Whether there is a correlation between NPC1L1 expression in PBMC and in the liver and intestinal wall, the main areas of NPC1L1 expression in
humans [21], remains to be established.

Permalink to Comment

4. ME on April 2, 2008 10:08 AM writes...

Derek,

The combo regimen also upregulated PCSK9 - a protease known to down regulate LDL receptors in hepatocytes. PCSK9 is the new hot target in CV medicine. Its a protease with no catalytic activity but people think it acts as a chaperone protein to transport LDL receptors. People with genetic mutations in PCSK9 that reduce its functional activity, have lower CV risks than the general population. All this is published work but I dont have links to the studies. But a quick search for PCSK9 in pubmed should get you all the information you need.

I think all the Vytorin study tells us is that lowering LDL-C using a combination of statins and cholesterol absorption inhibitors in FH patients does not provide a benefit over using statins alone. I find it mildly amusing that people start making all sorts of conclusions from the outcome of one sudy.

Lipid regulation in the body is a lot more complex than just reduce cholesterol synthesis and prevent cholesterol absorption. Maybe you can make nice commercials out of that simple concept but that is not the whole story.

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5. DrSnowboard on April 2, 2008 10:40 AM writes...

@ sroy on April 2, 2008 9:33 AM writes...
"Do you know that our popular theories on the etiology of atherosclerosis are based on what we learnt from various familial hypercholesterolemias. Somehow everone thought that atherosclerosis in most people occurs by the same process as that seen in people with rare and serious lipid transport disorders. Well, it turns out that is very likely not the case."

Actually I did. I did because I read Dereks previous post (extract below) which you commented on. Could we at least leave it a few days before you recycle?

"What they suggest instead is disturbing. The study may have been doomed from the start. The ENHANCE subjects were not taken from the general population, but rather were patients with a genetic abnormality in LDL handling, familial hypercholesterolemia. The idea was that these patients would be even more likely to show a benefit from Vytorin. But as the NEJM authors make clear, this may at one time have been a good patient population to show benefits in, but now the great majority of people with this condition are treated with statins starting at an early age. This, naturally, has an effect on their arterial walls. So the subjects of this trial may have already had a head start on reducing their arterial thickness, which means there may well have been a limit on what any particular therapy could have accomplished. Instead of being a better group to demonstrate your LDL-lowering powers in, they could well be worse."

Permalink to Comment

6. sroy on April 2, 2008 5:23 PM writes...

Hi DrSnowboard,

Maybe I should rephrase it to be more direct-

If ezetimibe did not add to the therapeutic effect of a statin in these patients, it has almost no chance of having a therapeutic effect in the normal statin-using population.

Do you think that ENHANCE chose these patients because of altruism? They are historically considered the ideal group for testing any cholesterol lowering drugs. The therapeutic effects of such drugs are far more obvious in these patients than in the general population.

Even drugs like fibrates and probucol which have statistically insignificant therapeutic effects in large studies have a worthwhile effects in these patients.

Permalink to Comment

7. sroy on April 2, 2008 6:20 PM writes...

This is truly tragic. Once again productive people are paying for the mistakes of the "brave decision makers". There is something dysfunctional about a system that gives so little money to those who created the means for the company to profit, but so much to those who helped to crash it because of their blustering incompetence.

Sometimes these upper management types remind me of viruses. The MO is similar- Infect healthy productive cells, divert resources to make more of (or more for) themselves, and thus kill/damage that cell to go on and infect other cells. Rinse and repeat.

http://tinyurl.com/2alp6v

Schering-Plough Will Cut Jobs, Number of Plants

By Lisa Rapaport

April 2 (Bloomberg) -- Schering-Plough Corp. said it will cut 10 percent of its jobs and shut plants to save $1.5 billion, just two days after a panel of doctors said the cholesterol pill Vytorin shouldn't be used as an initial treatment.

The plan calls for trimming 10 percent of costs based on 2007 spending and ``simplifying'' product lines including its animal health business, the Kenilworth, New Jersey-based company said today in a statement. Jim Kelly, a Goldman, Sachs & Co analyst, said on March 31 that the panel's recommendation may erode Vytorin and Zetia sales, which reached $5 billion last year, by 24 percent in 2008.

Permalink to Comment

8. anon on April 2, 2008 10:20 PM writes...

Can anyone say with scientific assurance that Vytorin will not show superior clinical outcomes compared to statins alone?

Permalink to Comment

9. Morten on April 4, 2008 1:09 AM writes...

*The* LDL receptor? I know there's more than one... and isn't it more like ten?

Permalink to Comment

10. aida on April 6, 2008 7:50 AM writes...

i have a home work , that i have to get all the combinations for these number from 1 to 42 i have to use from i to 42 and do all the combinations how can i do this ,

Permalink to Comment

11. RKN on April 7, 2008 8:59 AM writes...

i have a home work , that i have to get all the combinations for these number from 1 to 42 i have to use from i to 42 and do all the combinations how can i do this ,

Before I answer, may I suggest you not use "i" as both a pronoun and an iteration index in the same sentence (such as it was)?

Okay.

Answer: n!/((n-k)! * k!),

where n=42 (in your case), and k=dimension of the combination to consider.

Caveat: by the time 5

Permalink to Comment

12. RKN on April 7, 2008 9:03 AM writes...


Arggh, fouled by the parser.

Let's try again:

Caveat: by the time k is greater than 5 or less than 37 your little hand is going to be mighty sore from writing.

Permalink to Comment

13. Marilyn Mann on July 12, 2008 6:12 PM writes...

I'm pretty late to the party here, since Derek's post is from April and it is now July. The interesting thing about that study to me is that it is consistent with the theory behind pleiotropic effects of statins. Inhibition of HMG-CoA reductase results in decreased cholesterol synthesis, as well as effects unrelated to cholesterol lowering, with both of these occurring through the mevalonate pathway. The pleiotropic effects of statins involve reduction in levels of Rho-kinase, a substance with inflammatory vascular effects. Thus, the increase in HMG-CoA reductase activity with ezetimibe is not a good sign, because it implies that ezetimibe may increase production of Rho kinase.
In the July 2008 Cleveland Clinic Journal of Medicine, there is an editorial by Allen Taylor that discusses some of the issues in more detail. You can also look at articles by James K. Liao of Brigham and Women's on pleiotropic effects of statins.

Marilyn Mann

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