Mohan, V

Shashank, R Joshi

Mohan, V.

Joshi, Shashank R.

Publications of the IAS Fellows

© JAPI • VOL. 55 • JULY 2007 www.japi.org 477
Editorial
The Rosiglitazone Controversy : The Indian 
Perspective
V Mohan*, Shashank R Joshi**
In this era of evidence based medicine and drug discovery we are fortunate to get new molecules 
as treatment options but they are under continuous 
pharmacovigilance.The arrival of the thiazolidione 
compounds (also known as ‘glitazones’) with the 
introduction of troglitazone for treatment of type 2 
diabetes heralded a new era in the management of type 
2 diabetes. For the first time, a class of drugs to address 
the main pathophysiological defect in type 2 diabetes 
namely, impaired insulin action (or insulin resistance) 
had become available.1 Hardly had the euphoria 
regarding troglitazone settled with sales in excess of 
2.1 billion dollars, when the drug had to be abruptly 
withdrawn following its hepatotoxic effects leading to 63 
deaths in the United States.2 The introduction of the two 
subsequent drugs in this class namely rosiglitazone and 
pioglitazone was therefore viewed with great suspicion 
with the Food and Drug Administration (FDA) initially 
recommending mandatory liver function tests.3 It soon 
became apparent that these two classes of drugs were 
not hepatotoxic and liver function tests were soon 
declared unnecessary. However, they were not without 
side effects. Weight gain, pedal edema, a mild drop in 
haematocrit and fluid overload had been reported from 
studies abroad4 and from India.5 A slight increase in risk 
of cardiac failure has also been documented with both 
rosiglitazone6 and pioglitazone7 and these side effects 
appear to be a class effect. Meanwhile, there were also 
exciting positive developments. The ADOPT study 
showed that rosiglitazone scored over both Metformin 
and Glyburide (Glibenclamide) with respect to slowing 
down of monotherapy failure in newly diagnosed type 
2 diabetic subjects.8 Going a step further, the “DREAM” 
study showed a 62% risk reduction in development of 
diabetes in subjects with pre-diabetes,6 albeit, the effect 
*Madras Diabetes Research Foundation and Dr. Mohan’s Diabetes 
Specialities Centre, Gopalapuram, Chennai, India. **Department 
of Endocrinology, Seth G.S. Medical College and KEM and Lilavati 
Hospital, Mumbai, India.
being sustained only as long as the drug is taken.9 These 
two studies thus raised the possibility for the first time 
of using this class of drugs as first line therapy in type 
2 diabetic subjects, or indeed even at the stage of pre-
diabetes, if lifestyle measures failed. It is against this 
background that the recent rosiglitazone controversy 
which has shaken the medical world via lay media 
should be viewed.
The whole controversy erupted after a statistical 
tool called meta-analysis was published in a leading 
medical journal. In this era of evidence based medicine 
clinicians have to rely on mathematical tools and 
biostatisticians. Variability is an inherent characteristic 
of the biological world .Human biology usually follows 
Gaussian (normal) distribution and at best we rely on 
95% confidence intervals.  When sufficient numbers 
are not available to get a 95% confidence intervals 
then biostatisticians pool data and do a meta-analysis 
of a well recognized databases like Medline etc. Such 
database search small studies which can be collated 
and need to be homogenous both in design and study 
pattern. The current controversy shows us how such 
meta-analytical tools can be misleading and lead to 
even inaccurate conclusions. Nevertheless when doubts 
are created in suspicious human clinical minds it can 
significantly impact a trend. India is the epicenter 
of Diabetes epidemic with 42 million Indians being 
diabetic.10 The Asian Indian community both native and 
migrant is particularly vulnerable and susceptible to 
cardiovascular disease .Thus such doubt however small 
must be clarified from the Indian perspective
A recent meta analysis published in the New England 
Journal of Medicine (NEJM) by Nissen et al11 has raised 
concerns regarding the increased risk of coronary artery 
disease among subjects on rosiglitazone treatment. 
Analysis of 42 trials showed the risk for myocardial 
infarction to be 1.43 times higher, and death due to 
cardiovascular causes to be 1.6 times higher, in subjects 
on rosiglitazone treatment compared to the control 
group.11 In other words, rosiglitazone was associated 
with a 43% increase in risk of myocardial infarction 
which was statistically significant and 64% increase in 
478 www.japi.org © JAPI • VOL. 55 • JULY 2007
death from cardiovascular causes which however was 
not statistically significant. Analyses of the 42 studies 
showed that 40 of them were small and all these put 
together did not yield statistically significant difference 
for myocardial infarction (MI) between groups. Of the 42 
studies included 30 were unpublished and none of them 
were designed to address Myocardial Infarction as either 
primary or secondary endpoint. Medline or standard 
database search was excluded and the manufacturer’s 
website was the source. Several studies in published 
literature which addressed specifically cardiovascular 
issues were excluded. Thus it was a weak and flawed 
metaanalysis. In contrast, combining ADOPT and 
DREAM, the two large studies showed a significant 
difference in MI between the study groups although 
either study alone did not show a statistically significant 
risk of coronary artery disease. A major limitation of this 
meta-analysis is that it was confined to summary data 
and was not extrapolated to the actual data sets where 
time to events would have added valuable information. 
An accompanying NEJM editorial admits these serious 
limitations in the metaanalysis and states “the weakness 
which are largely related to the quality of the available 
data, are nonetheless substantial. A few events either 
way might have changed the findings for myocardial 
infarction or for death from cardiovascular causes. In 
this setting, the possibility that the findings were due 
to chance cannot be excluded”.12   
An independent analysis by GlaxoSmithKline 
published by Ronald L Krall in the Lancet Online 
May 30, 2007 showed the incidence of the composite 
cardiovascular endpoints was 1.75 events per 100 
patient- years for the rosiglitazone containing regimen 
and 1.76 events per 100 patient-years for the non-
rosiglitazone containing regimen (hazard ratio 0.93, 
95% CI : 0.80 – 1.10).13 Responding quickly to the 
metaanalysis by Nissen et al [10], the Rosiglitazone 
Evaluated for Cardiac Outcomes and Regulation of 
Glycemia in Diabetes (RECORD) study investigators 
did an unplanned interim analysis of their results two 
years before the study was scheduled to conclude.14 
The RECORD study focused on comparing the 
hospitalization or death from cardiovascular causes in 
subjects receiving metformin or sulfonylurea [n=2220] 
with add-on rosiglitazone (rosiglitazone group), 
against combination of metformin plus sulfonylurea 
(control group) [n=2227]. The results indicated no 
statistically significant differences in the overall risk 
of hospitalization or death from cardiovascular causes 
between the study groups.14  The results were (not 
surprisingly) inconclusive as this is an interim analysis 
after 3.75 years of median follow up and thus lacked 
adequate power as the original analysis was planned 
to be done after 6 years of median follow up.
A series of three editorials in NEJM15-17 subsequently 
discussed the rosiglitazone controversy at length, which 
thanks to media hype, political interference and other 
non-scientific reasons has snowballed into a veritable 
medical storm, the like of which has not been witnessed 
in recent times. 
From a purely statistical perspective, these results 
would indicate a slight increase in risk for MI / 
coronary artery disease among subjects on rosiglitazone. 
However, a closer analysis of these data would indicate 
that the presently available data are not conclusive as 
none of the studies had cardiovascular disease (CVD) as 
primary end-points except RECORD. In the RECORD 
study, only an interim analysis was published which 
had inadequate power to assess CVD outcomes. Neither 
ADOPT nor DREAM had CVD as primary end-points 
and neither showed a significant increase in CVD risk 
by themselves. Adding up studies which individually 
show no risk and ending up with a result that shows 
risk may be statistically acceptable, but is it clinically 
relevant?  Several Societies like the American Diabetes 
Association, Endocrine Society in the US, American 
Association of Clinical Endocrinologists have come 
out with statements urging physicians and patients 
not to panic and stop the medication but to undergo 
a reevaluation by their treating physicians and make 
decisions with them. Also they all again emphasize the 
relevance of good glycemic control. Even the US FDA 
has not withdrawn the drug but asked for strict review 
and some changes have been made on the prescription 
label. The US FDA website is periodically updated and 
it is worthwhile keeping updated. The EU regulatory 
agencies have also not withdrawn the drug.
What stance should we as physicians in India take 
at the present moment with respect to Glitazones in 
general and Rosiglitazone in particular?
This issue is of great importance with regard to 
Indians as it is well known that Indians are at high risk 
for both diabetes18 and premature CVD.19 According to 
the latest available prescription analysis by one of the 
agencies, rosiglitazone alone is used in 3.4% of patients 
and in combination with an additional OHA in 3.7% of 
patients (i.e. a total of 7.1% of type 2 diabetic patients 
in India are treated with rosiglitazone). 
In our experience, whenever glitazones are withdrawn, 
the glucose control almost certainly worsens. In 
several cases, the good glycemic control obtained with 
glitazones has not been matched by any other class 
© JAPI • VOL. 55 • JULY 2007 www.japi.org 479
of drugs, including in some cases, even by insulin. If 
rosiglitazone is withdrawn from the regime, a large 
number of these patients will need to go on to insulin 
injections. Indeed, the converse is also true. When these 
agents were introduced, several patients who were on 
insulin could go off injections altogether. Undoubtedly, 
patients’ safety comes first and there should not be any 
compromise on this score. However, if the evidence 
is not ‘black and white’ but ‘grey’ zone, it is our duty 
as physicians and diabetologists to shift the chaff 
from the grain when reviewing the evidence. A recent 
commentary in correlation with a similar combination 
with respect to ACE / ARB treatment in hypertension 
discusses at length, the limitations of such metaanalyses 
and cautions us about their overinterpretation.20 
At this juncture, we would recommend the following 
actions with respect to rosiglitazone while treating 
patients in India
1. Reassure patients and physicians  that there is 
nothing to panic.
2. Advise patients not to abruptly stop their medications 
but discuss it with their physician and under 
medical supervision of experts decide on case to 
case basis a plan which meets patient’s safety and 
therapy concerns.
3. Ensure that current glycemic  control & non 
glycemic comorbid conditions are  validated by 
not just fasting and postprandial blood glucose 
but do a glycosylated hemoglobin test, lipid 
profile,hematocrit and electrocardiogram(with or 
without an echocardiogram)
4. If they have established heart disease, it may 
be worthwhile to discuss with their physician 
/ cardiologist about stopping the drug and 
appropriately adjusting their anti-diabetic 
medications.
5.  If the physician is convinced about any concern 
then there are other options available in the same 
class, other class as well as Insulin. Both options 
need patient education and physician supervision 
to ensure patient safety risk as well as the glycemic 
control is well balanced as well as monitored 
periodically.
6. New patients with type 2 diabetes at risk of heart 
disease could probably be given alternate drug 
therapies until further evidence emerges with 
respect to the safety of this class of drugs.
7. Strict adherence to CVD risk reduction i.e. Aspirin 
(or Clopidrogel),  Statin, ACE (or ARB) inhibitors, 
weight reduction, tighter glucose and BP control and 
stricter cardiac evaluation in all diabetic patients. 
8. Individualized comprehensive evaluation and 
cardioprotective measures can be re-addressed and 
its an ideal opportunity for patient education to 
ensure that they are in control of their diabetes and 
vascular risk.
In India which is faced with the twin epidemic of 
Diabetes and Heart disease, it is mandatory that we 
follow standard guidelines which advocate routine 
co prescription of Aspirin (or Clopidrogel) and Statin 
with or without ACE (or ARB) for every diabetic adult 
patient especially above thirty  years of age. It is time to 
routinely use the polypill concept of SAMTA in every 
case to ensure that the vulnerable at risk Asian Indian 
Diabetic is protected from the ravages of the vascular 
complications.21
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