A bit of truth from the person who said that all medications are a
double edged sword. Also true that the media tends to sensationalize
and the details don't always fully back up the headlines.
As someone who has been taking
Avandia since I was diagnosed with
diabetes over 4 years ago, I was iniitally alarmed to read this report
this morning. At that point the article itself had not yet been
released and so I was just reading the news reports off of Yahoo which
made for sensational headlines.
Last night I read the full NEJM article, which by the way does compare
Actos favorably to Avandia. One reason why is that there has been a
study specifically focusing on the cardiovascular effects of Actos;
heart attacks were 90% of those recorded in the control group and "a
secondary end point consisting of myocardial infarction, stroke, and
death from any cause showed a significant effect favoring
pioglitazone" with 16% fewer of these outcomes. While there is a
similar study now under way with Avandia, there have been NO studies
to date specifically focusing on Avandia and heart problems.
So what the authors of this study have done is look for clues in the
other studies that have been done on Avandia. Of 118 studies, they
found 48 that seemed to meet their criteria. 6 were discarded because
there was no incidence of heart problems reported for either the
Avandia or control groups. That exclusion may bias this new study to
some extent, IMHO, although it is unclear how large they were. The
second largest study among the 42 included, the ADOPT study, was also
the longest study in duration, covering 4 years. Almost all of the
other studies were of limited duration, covering only 6 months to 1
year. One was for 2 years, and 3 others for 3 years. The 4 year
ADOPT study, the longest one, contradicted the results of the others,
showing a 20% reduction in deaths among the Avandia group, even though
it showed 33% more cardiac events. The largest study showed a 20%
higher chance of death in the Avandia group of patients, quite a bit
less than the composite "average"--more on that below.
The author of the study notes that 26 of the studies were never
published, and that many of the studies had few cardiovasular events;
the chart shows that of 42 studies, 3 had more than 3 myocaridal
infactions in the Avandia group of patients. There were 86 such events
in the Avandia group, and 72 in the various control groups. This
includes over 15,000 patients taking Avandia, and 12,000 in the
control groups. Strangely enough that works out to 20% more myocardial
infarctions in the Avandia group, which was, (coincidentally?) 20%
larger than the control group. Although deaths from myocardial
infarction were significantly (about 39%) higher in the Avandia group,
the authors are careful to note that "the included trials did not
describe adjudication of myocardial infarction or death from
cardiovascular causes. Time-to-event data for cardiovascular events
were not available in any of these trials... Because only summary data
were available, it was not possible to discern whether the same
patient had both events."
The authors write that:
"Our study has important limitations. We pooled the results of a
group of trials that were not originally intended to explore
cardiovascular outcomes. Most trials did not centrally adjudicate
cardiovascular outcomes, and the definitions of myocardial infarction
were not available. Many of these trials were small and short-term,
resulting in few adverse cardiovascular events or deaths [and]
considerable uncertainty about the magnitude of the observed hazard.
Furthermore, we did not have access to original source data for any of
these trials. Thus, we based the analysis on available data from
publicly disclosed summaries of events. The lack of availability of
source data did not allow the use of more statistically powerful time-
to-event analysis. A meta-analysis is always considered less
convincing than a large prospective trial designed to assess the
outcome of interest."
Which, of course is followed by the authors' conclusion that " Despite
these limitations, our data point to the urgent need for comprehensive
evaluations to clarify the cardiovascular risks of rosiglitazone," and
notes that "further analyses of data available to the FDA and the
manufacturer would enable a more robust assessment of the risks of
this drug."
I certainly would not dispute those conclusions, but my alarm level is
a bit lower having read the actual article rather than the news
reports. The news reports emphasize the most alarming statements in
the article, and in reading the article, I am not sure that the
authors did not have a predetermined agenda.
In the last year, Avandia was reported to have negative consequences
in retinopathy. When I read that, it seemed that this was extremely
rare and almost always occurs in patients with the edema side effect,
which I have not had. My retinologist, who I respect quite a bit, did
not think there was any reason for me to be concerned.
At that time I also talked to my doctor about stopping Avandia. Maybe
I have no
insulin resistance anymore, and if not, why am I taking
Avandia? He told me that he wanted me to keep taking it because it
protects against the loss of beta cell function. You may have to log
in to read this Medscape article, at
http://www.medscape.com/viewarticle/496269
which states that
"the addition of RSG (avandia) to SU (glucotrol) had a durable
effect on reducing insulin and improving pancreatic beta-cell function
compared with SU alone, which had deleterious effects on beta-cell
function. Thus, it appears that the addition of RSG to SU, even in
older subjects with compromised beta-cell function, is capable of
improving that function and, in so doing, seems to abrogate the
progressive decline in beta-cell function characteristic of the
disease."
When I first read that and another study I found at the same time 2
years ago, I was looking at the evidence that sulfonylureas "wear out
the beta cells." It was interesting to read studies that specifically
referenced the dosage of Avandia I was taking, and prescribed any
problems with sulfonylureas to dosages 3-4X higher than I was taking,
specifically noting that the same effects were not seen at my dosage.
Perhaps I am sticking my head in the sand, although I intend to
discuss this with my doctor the next time I go in, and have scheduled
a C-peptide test with my next labs to see how it has changed since
the last time, even though my doctor cautions that beta cell output
declines with age even in non-diabetic individuals.
Even so I would caution against panic based on this latest report,
which actually contains no information that had not been previously
reported. The authors are right to call for more study, and disucssing
the issue with your doctor if you take Avandia seems like a good idea.
Morris
Morris
Avandia scare may be bogus 
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