Meta Analysis suggests link between Rosiglitazone and advers

Ok, so this has been in the news all over - I am trying to re-tell this
story combining information from various sources and my
perceptions/comments on the same.



Rosiglitazone (marketed as AVANDIA by GSK) has been recently linked to
an increased incidence of myocardial infarctions and death from related
cardiovascular events in a recent meta-analysis conducted by
researchers at the Cleveland Clinic Foundation, OH. This meta-analysis
pooled data from 42 "eligible" randomized control trials (involving a
total of 27,843 patients - 15,560 patients randomly assigned to
regimens containing rosiglitazone and 12,283 patients on regimens
without rosiglitazone) and reported an increased odds of having a
myocardial infarction (1.43, 95% confidence interval [CI], 1.03 to
1.98; p=0.03) in the group taking Rosiglitazone. Similarly, the odds of
death from an all-cause cardiovascular event was reported as 1.43 (95%
confidence interval [CI], 1.03 to 1.98; P=0.03) (Nissen et al, NEJM)



These findings have been widely reported in the press as "43% increase
in risk of heart attacks in patients taking Avandia" and "over 60%
increase in risk in death from heart problems due to diabetic drug". As
such, the impact of the study led FDA to issue a drug warning on
rosiglitazone about the adverse cardiovascular effects of the drug.



So much for the bare-facts. But what does all this technical
"mumbo-jumbo" translate to? Is rosiglitazone a great, novel drug which
helps control blood-sugar in type 2 diabetics or is it another vioxx
(rofecoxib, the Merck drug which was removed from the market after
evidence linked it to cardiovascular mortality)?



There are quite a few things we need to consider here:



1. Diabetics are inherently more susceptible to adverse cardiovascular
effects. In fact, more than 65 % of all deaths in diabetics is due to
cardiovascular diseases (American Diabetes Association).



2. The study conducted was a meta-analysis, which pools data from a lot
of different studies. It is important to recognize that while pooling
data from different sources to derive conclusions, we are inherently
assuming that the data-sources are similar to each other - a fact that
is blatantly violated by any meta-analysis. This means that the
base-line susceptibility of all patients for adverse cardiovascular
events is NOT the same.



3. Besides, the researchers admit that most of these 42 trials were not
primarily conducted to assess the cardiovascular adverse effects of
rosiglitazone. Hence, many of these studies have not reported
cardiovascular events accurately or consistently. Hence an
interpretation of these studies is more or less, guess-work. Also, many
of these studies were short-term and hence they concluded before any
significant number of cardiovascular events could have occured.



4. Given the small number of cases of non-fatal heart attack overall
when all trials were combined (86/14,371 for those taking Avandia
versus 72/11,634 in the control groups), small changes either way could
dramatically alter the statistical perception of risk.



Hence, in the light of all these facts, drawing a firm conclusion
regarding the cardiovascular safety of rosiglitazone is definately a
dicey situation. However, a few interesting facts remain:



1. Rosiglitazone is indeed a great drug for type 2 diabetics. While the
long term effects of rosiglitazone on micro and macro vascular
complications of diabetes are not known (since the drug has been around
for only 7-8 years) it does attack the central pathogenesis of type 2
diabetes (insulin resistance) by increasing insulin susceptibility.



2. Various biological modes have been proposed as to the adverse
cardiovascular effects of thiazolidenediones. Rosiglitazone has a
tendency to increase LDL in patients treated for atleast 20 weeks - a
potential mechanism for myocardial infarctions. Also studies have shown
an increased incidence of heart failure precipitated by rosiglitazone
in susceptible patients.



3. Various drug development trials have reported "abandoned" PPAR
agonist agents due to evidence of direct myocardial toxicity in phase 1
trials. (e.g. Muraglitazar - stopped after phase 2 and 3 trials).

This is from The latest NEJM:





Original Article

Published at www.nejm.org May 21, 2007 (10.1056/NEJMoa072761)



Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.







ABSTRACT



Background Rosiglitazone is widely used to treat patients with type 2
diabetes mellitus, but its effect on cardiovascular morbidity and
mortality has not been determined.



Methods We conducted searches of the published literature, the
Web site of the Food and Drug Administration, and a clinical-trials
registry maintained by the drug manufacturer (GlaxoSmithKline).
Criteria for inclusion in our meta-analysis included a study duration
of more than 24 weeks, the use of a randomized control group not
receiving rosiglitazone, and the availability of outcome data for
myocardial infarction and death from cardiovascular causes. Of 116
potentially relevant studies, 42 trials met the inclusion criteria. We
tabulated all occurrences of myocardial infarction and death from
cardiovascular causes.



Results Data were combined by means of a fixed-effects model. In
the 42 trials, the mean age of the subjects was approximately 56 years,
and the mean baseline glycated hemoglobin level was approximately 8.2%.
In the rosiglitazone group, as compared with the control group, the
odds ratio for myocardial infarction was 1.43 (95% confidence interval
[CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from
cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06).



Conclusions Rosiglitazone was associated with a significant
increase in the risk of myocardial infarction and with an increase in
the risk of death from cardiovascular causes that had borderline
significance. Our study was limited by a lack of access to original
source data, which would have enabled time-to-event analysis. Despite
these limitations, patients and providers should consider the potential
for serious adverse cardiovascular effects of treatment with
rosiglitazone for type 2 diabetes