From: sbharris@ix.netcom.com (Steve Harris  sbharris@ROMAN9.netcom.com)
Newsgroups: sci.med.cardiology,talk.politics.medicine,sci.med
Subject: Re: JAMA on FDA & PHARMA: Lack of vigilance, lack of trust
Date: 30 Nov 2004 14:56:51 -0800
Message-ID: <79cf0a8.0411301456.40ec1078@posting.google.com>

"beachhouse" <sendnomail@please.com> wrote in message news:<cofb5f$1c10
> Have you seen the idiotic way the combination simvastatin/ezitimibe product
> t is being marketed to patients on T.V.?
> "it works on *both* kind of cholesterol....  you get cholesterol from your
> parents and from your food..."
> implication being that you need 2 drugs by necessity to achieve meaningful
> lipid lowering.
> what crap.


COMMENT:

Yes, the another ironic twist added inasmuch as probably THE main
mechanism of ezetimibe/Zetia cholesterol lowering is much like that of
bile acid binders: it prevents reabsorption of your own *hepatically
excreted* biliary cholesterol, too, as well as the cholesterol you
eat. Which means it also (and probably mainly) affects the cholesterol
you make, a.k.a. the cholesterol you "get from your
parents'[cholesterol control genes]".

The effect of Zetia is just too large to be affecting only the
cholesterol you absorb from your diet. I WISH you could lower LDL 25%
in anybody by merely removing most of the cholesterol from their diet.
But you can't, unless you really cut their calories and saturated fat
intake, too.

Zetia would presumably work reasonably well even in vegans (who by
definition eat no dietary cholesterol), though I can't find that this
interesting experiment has ever been tried.

That said, I agree that the jury's out on whether or not Zetia's or
Zetia combos are going to do anything clinically, anymore than bile
acid binding resins like cholestyramine/Questran did.

Note that the abstract below says it's not known how ezetimibe works,
but it's been recently found to bind to the aminopepdidase N (CD13)
receptor. That's an important viral endocytosis receptor. Maybe the
stuff will end up as a useful antiviral adjunct therapy, if it doesn't
help heart disease.

SBH



Can J Clin Pharmacol. 2003 Winter;10 Suppl A:13A-20A.

The pharmacokinetics of ezetimibe.

Simard C, Turgeon J.

Universite de Montreal, Quebec.

Ezetimibe is the first member of a new class of selective cholesterol
absorption inhibitors. The drug and its active glucuronide metabolite
impair the intestinal reabsorption of both dietary and hepatically
excreted biliary cholesterol through inhibition of a membrane transporter
yet to be identified. Absorption of ezetimibe is rapid and not altered by
food content following oral administration. The drug is not metabolized
by the cytochrome P450 system but extensive glucuronidation takes place
in the intestine. Consequently, plasma concentrations of ezetimibe
represent approximately 10% of total ezetimibe in plasma. Enterohepatic
recirculation observed for ezetimibe and its glucuronimide significantly
increases the residence time of these compounds in the intestine, at
their site of action. Elimination of ezetimibe glucuronimide appears
impaired in elderly patients and patients with renal insufficiency with
plasma concentrations increased 1.5- to 2-fold. So far, no drug
interaction study has been associated with major changes in either the
pharmokinetics of ezetimibe or coadministered drugs.

Publication Types:
    Review
    Review, Tutorial

PMID: 14571304 [PubMed - indexed for MEDLINE]

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.cardiology,sci.med
Subject: Re: What about VYTORIN?
Date: Fri, 03 Dec 2004 22:44:27 -0500
Message-ID: <corbn8$naj$1@reader1.panix.com>

Steve Marcus wrote:
>>Rind:
>>Actually, I think you could go further than that. There's no published
>>evidence that ezitimibe, one part of the combination being discussed,
>>has any clinical benefits either alone or in combination with other
>>drugs for cholesterol. It has been shown to reduce LDL levels, but that
>>is not the same as showing that it has a favorable effect on clinical
>>outcomes. (There are no trials showing it doesn't have clinical
>>benefits
>>either. No clinical endpoint trials have been published.)
>
>
> And again, that's about as disingenuous a post as one is likely to read on
> Usenet. First, Zetia, (ezitimibe) _has_ been shown to block absorption of
> cholesterol in the digestive tract.  Second, reduction of LDL levels _has_
> been shown, *in general*, to produce favorable effects on clinical outcomes;
> there's no need to show that reduction of LDL _by ezitimibe_ produces
> favorable effects on clinical outcomes.

I don't normally read sci.med.cardiology, so I just bumped into this.
I'll crosspost to sci.med in case there are responses.

What exactly is "disingenuous" about my post. I honestly believe we need
clinical trials of ezitimibe. You write that reduction of LDL levels in
general has been shown to have favorable clinical effects. Okay, please
point to a single primary prevention trial of lowering LDL, using a drug
other than a statin, that showed overall favorable effects on mortality.
I can point to several such trials that showed no benefit on mortality
and at least one that showed a statistically significant increase in
mortality.

Before the statins, we had no evidence that using cholesterol-lowering
drugs for primary prevention is good. We still have no evidence for any
drugs other than that statins. Again, what exactly is disingenuous about
asking for some clinical-endpoint trials of ezitimibe? Post some data
rather than insults.

--
David Rind
drind@caregroup.harvard.edu

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.cardiology,sci.med
Subject: Re: What about VYTORIN?
Date: Sat, 04 Dec 2004 13:11:39 -0500
Message-ID: <cosuh8$7dj$1@reader1.panix.com>

Steve Marcus wrote:
> My point was simply this:  You concede that there are single primary
> prevention trials involving statins which demonstrate that lowering LDL has
> overall favorable effects on mortality.  So why would you believe that
> lowering LDL using a drug other than a statin would not have exactly the
> same favorable effects on mortality, _given the proposition that the
> non-statin drug hasn't been shown to harm people_?

No, I accept (I'm not sure what you think I'm "conceding") that there
are primary prevention trials showing that treating people who have
elevated LDLs with statins lowers mortality.

You seem to believe that the inescapable conclusion from this is that
using some other drug that lowers LDL will also lower mortality. While
this conclusion might be correct, there are lots of reasons to think it
might not be, including a whole series of clinical trials with drugs
other than statins that did not show any benefit on mortality and, in
fact, that showed a trend toward *increased* mortality in the people who
were treated.

When you say that ezetimibe hasn't been shown to harm people, you are
correct, but the studies that might show harm are the same ones that
might show benefit, and they haven't been published. It's not that I
think ezetimibe is some lethal poison -- if it had a huge effect on
increasing mortality, we would, of course, have learned that in the
initial trials. But if, like clofibrate, it causes a mild increase in
mortality when used for primary prevention, we won't find that out until
trials with clinical endpoints are performed. It took something like
10,000 people and ten years of follow-up to realize that giving
clofibrate for primary prevention was leading to increased deaths.

>
> By writing that you want to wait for so-called endpoint trials, your post
> becomes disingenuous.  The problem is, where will you draw the line and
> conclude that the endpoint has been reached?  Five years okay, or ten years?
> How about twenty years?

No, not a "so-called" endpoint trial. Just a normal, run-of-the-mill
randomized trial with a clinical endpoint. I don't care whether the
trial is 2, 5, 10, or 20 years -- just that its endpoint be morbidity
and mortality rather than a change in a blood test. If you think it
would take a 20-year trial to show a benefit with ezetimibe, you must
believe it's a pretty worthless drug. Most of the primary prevention
statin trials took about five years to show clinical benefits.

> Ezitimibe isn't rat poison.  It has been tested and there is no evidence
> that it has detrimental side effects other than those already shown in
> clinical studies.  These range from allergic reactions to pancreaitis to
> drug interactions.  Add simvasatin (so you get Vytorin and the usual side
> effects of statins rear their ugly heads.  All of this information comes
> with the drug, and a prescribing physician should explain this to patients,
> and require periodic testing for liver function abnormalities where statins
> are involved.

See my comments above. I don't think ezetimibe is rat poison. That
doesn't mean it's beneficial or even safe. What if it only caused as
many excess cardiac deaths as Vioxx? Do you believe that would have
shown up in the trials performed so far?

> For those with know coronary artery disease, and those with high risk
> profiles, there is no good reason to avoid the use of ezitimibe, along in or
> combination with a statin drug if needed.  Simply writing on Usenet that
> there are no endpoint clinical trials and we therefore aren't certain in the
> long term whether ezitimibe will kill you on its own, you are simply
> misleading and/or scaring people who definitely will benefit from the drug
> away from trying the drug.

The reason to avoid using ezetimibe alone in patients with known CHD is
that we have a class of drugs we know is of clinical benefit (the
statins) and a new drug with no proven clinical benefit. It would be
absurd at this point to treat someone with ezetimibe in preference to a
statin.

If a high risk patient with known CHD could not tolerate a statin or
could not achieve an adequate reduction in LDL with a statin alone, I
wouldn't criticize someone who chose to add in ezetimibe -- but they
should know they are doing so based on very weak evidence. This,
however, has nothing to do with primary prevention.

> You know very well what the data is; there doesn't seem to be any harm in
> using ezitimibe as part of a program of lowering LDL.  You also know very
> well what the meaning is of there being conflicting clinical studies.  And
> you know very well what the benefits of loweing LDL are for a significant
> number of people.  If you regard the term "disingenuous" as insulting, feel
> free to substitute another for a post that serves only to scare the people
> who would be helped by the drug away from using it.

Yes, I indeed know very well what the data are, and I interpret them
differently from you. I think they show that statins are good, and that
other lipid-lowering drugs that have been studied for primary prevention
are useless or harmful, and that we know nothing at all about what
happens clinically when ezetimibe is used for primary prevention.

Again, you seem to think that my not agreeing with you that people will
be clearly helped by ezetimibe makes me disingenuous. Why is that? Do
you really believe that your interpretation of the evidence is the only
possible correct one?

--
David Rind
drind@caregroup.harvard.edu