REVIEW

Pioglitazone: an agent which reduces

stroke, myocardial infarction and death
and is also a key component of the
modern paradigm for the optimum
management of type 2 diabetes
R.E.J. RYDER

Abstract

A
randomised controlled trial (RCT), the PROactive
study, was undertaken to see if pioglitazone
improved cardiovascular outcomes in type 2 dia-
betes. Initially the results were controversial and piogli-
tazone was not widely recognised as a beneficial agent
for cardiovascular disease. A meta-analysis of rosigli-
tazone studies raising the possibility that it was associ-
ated with cardiovascular harm received worldwide media
attention and the negative concern spread to involve Bob Ryder at the EASD in
pioglitazone through presumed class-effect. A careful Athens where the
re-look at the detail of the PROactives primary compos- PROactive data were first
ite endpoint, which led to the controversy over the out- presented
come, suggests that medical statistics may have been
inadequate to reveal the real clinical effect. A number of
other studies support the interpretation that piogli-
Abbreviations and acronyms
tazone significantly improves cardiovascular outcomes.
While the potential risk:benefit of pioglitazone needs to CHM Commission on Human Medicines
be acknowledged, it now also needs to be recognised CHMP Committee for Medicinal Products for Human Use
that pioglitazone and metformin are the only glucose- CI confidence interval
lowering agents with RCT data demonstrating a reduc- CIMT carotid artery intimamedia thickness
tion in stroke, myocardial infarction and death in type 2 CV cardiovascular
EASD European Association for the Study of Diabetes
diabetes. Furthermore there now exists a strong case
EMA European Medicines Agency
that even in type 2 diabetes patients without known
FDA Food and Drug Administration
cardiovascular disease, the modern paradigm for man- GLP-1 glucagon-like peptide 1
agement should involve the combination of metformin, HbA1C glycated haemoglobin A1C
pioglitazone and glucagon-like peptide 1 agonists used IVUS intravascular ultrasonography
early and aggressively to achieve a target glycated hae- MI myocardial infarction
moglobin A1C <6%. TZD thiazolidinedione/glitazone
Br J Diabetes Vasc Dis 2011;11:113-120. PPAR peroxisome proliferator-activated receptor
PROactive PROspective pioglitAzone Clinical Trial In
macroVascular Events
RCT randomised controlled trial
UKPDS United Kingdom Prospective Diabetes Study
Correspondence to: Dr R.E.J. Ryder
Diabetes and Endocrine Unit, City Hospital, Dudley Road, Birmingham
B18 7QH, UK.
Tel: +44 (0)121 507 4591; Fax: +44 (0)121 507 4988 Key words: cardiovascular disease, exenatide, glitazone, GLP-1
E-mail bob.ryder@nhs.net agonist, liraglutide, metformin, myocardial infarction, ominous
octet, pioglitazone, rosiglitazone, stroke, type 2 diabetes, TZD

THE
The
BRITISH
Author(s),
JOURNAL
2011. Reprints
OF DIABETES
and permissions:
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Figure 1. Examples from the British newspapers to illustrate the worldwide high profile media attention in 2007 that followed the publication of Nissen and
Wolskis meta-analysis in the New England Journal of Medicine raising the possibility of cardiovascular harm related to rosiglitazone use

Introduction
Macrovascular disease is the main complication of type 2 dia-
betes. In the UKPDS, fatal CV events were 70 times more com-
mon than deaths from microvascular complications.1 In people
with diabetes the relative risk of CV disease is two to fourfold
compared with normal glucose tolerance.2-4 There is evidence
to suggest an association between insulin resistance and CV
risk.5 Metformin was the only glycaemic medication used in the
UKPDS which reduced insulin resistance; it was also the only
one associated with improved long-term macrovascular out-
comes.6 This led to the hypothesis that reducing insulin resis-
tance can improve CV outcomes. TZDs reduce insulin resistance.
The first RCT of a TZD in type 2 diabetes intended to assess the
impact on CV outcomes was PROactive, the first results of
which were published in 2005.7 The primary composite end-
point of this trial did not appear to show significant CV benefit
and as a result pioglitazone as a beneficial agent for CV disease
in type 2 diabetes was not widely recognised.
Decline of rosiglitazone
A meta-analysis of 42 separate studies involving rosiglitazone
was published in 20078 and showed that in rosiglitazone-treated
patients (n=15,560) compared with control patients (n=12,223)
the odds ratio of MI was 1.43 (95% CI 1.031.98; p=0.03) and
the odds ratio for death from CV causes was 1.64 (95% CI
0.982.47; p=0.06). However, it should be noted that of the 48
trials which met the pre-defined criteria for inclusion in this
meta-analysis, six were excluded as they did not report any MIs
or CV-related deaths.8 Nevertheless the results of this meta-
analysis led to the suggestion that rosiglitazone was associated
with CV harm in terms of a significant increase (p=0.03) in the
risk of MI (MI was recorded in 86 rosiglitazone-treated versus
72 control patients) and an increase in the risk of death from
CV causes that had borderline significance (p=0.06) (death
from CV causes occurred in 39 rosiglitazone-treated and 22
control patients). This result received attention in the worldwide
media (figure 1) and as a result concern about the use of rosi-
glitazone became widespread and encompassed pioglitazone
through an instinctive application of presumed class effect.
There was concern that both TZDs might be associated with
an increased risk of heart failure9 and this also received atten-
tion in the world wide media10 leading to Diabetes UK publish-
ing reassurance for patients on its website.11 Evidence came to
light that both agents may be associated with osteoporosis and
fracture12 increasing the negative attitude towards TZDs as a
class. A prospective RCT of rosiglitazone and CV outcomes was
published in 2009 and appeared to show no evidence of CV
harm associated with rosiglitazone.13 However, concerns were

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raised regarding the design and conduct of that study.14 After
much deliberation, on 23 September 2010 the US FDA
announced further restriction in the use of rosiglitazone, while
at the same time the EMA CHMP recommended suspension of
marketing authorisation as it was felt that the risks of treat-
ment with this agent outweighed the benefits. The chair of the
CHM wrote to healthcare professionals to inform them of the
advice of the CHMP following this Europe-wide review.15
Reputation by association
It may be that the high-profile, well publicised story of the demise
of rosiglitazone has had an undeserved negative impact on the
profile of pioglitazone. Indeed in his keynote lecture Controversies
in diabetes: getting to the heart of the problem (which can be
viewed on the Lancet website16) to the Cardiology and Diabetes
at the Limits conference on 27 February 2011, prominent inter-
national diabetologist Professor Paul Zimmet lumped the TZDs
with sibutramine and rimonabant as drugs which had recently
bombed out from our therapeutic armamentarium. Despite this,
there is a considerable amount of evidence to suggest that pio-
glitazone is the only glucose-lowering medication, other than
metformin, to be associated with CV benefit. Furthermore it must
be underlined that stimulation of the PPAR-master switch with
a TZD, e.g. pioglitazone, is still regarded as the only therapeutic
strategy for targeting pathogenesis on a molecular basis,17 espe-
cially in high-risk patients with metabolic syndrome.18
Vascular effects of pioglitazone
CIMT is a marker of coronary atherosclerosis and independently
predicts CV events.19,20 An RCT showed that over an 18-month
treatment period pioglitazone slowed progression of CIMT
compared with glimepiride.21 IVUS is considered an accurate and
reliable approach to evaluating the effects of therapies on the
progression of coronary atherosclerosis.22 An RCT of pioglitazone
versus glimepiride was undertaken to assess progression of
coronary atherosclerosis in patients with type 2 diabetes using
IVUS23 and showed a significantly lower rate of progression of
coronary atherosclerosis with pioglitazone treatment.23 A retro-
spective cohort study using the UK general practice research
database to consider CV outcomes24 suggested a relatively
unfavourable risk profile of sulphonylureas compared with met-
formin. Interestingly, this study did not associate TZDs with risk
of MI. Pioglitazone was associated with a risk reduction in all
cause mortality compared to metformin, and also had a favour-
able risk reduction profile compared with rosiglitazone.24
The group who undertook the rosiglitazone meta-analysis
which started all the controversy8 undertook a similar meta-
analysis of pioglitazone trials.25 This analysis suggested that
unlike the meta-analysis with rosiglitazone, pioglitazone has a
favourable effect on ischaemic vascular events, and this would
appear to be distinct from its efficacy in reducing blood glu-
cose.25 The pioglitazone meta-analysis did show that treatment
with this agent significantly (p<0.002) increased the risk of heart
failure,25 but unfortunately the rosiglitazone meta-analysis did
not specifically report this parameter.8
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PROactive reconsidered
Thus, there is a wealth of data in support of pioglitazone as an
agent to reduce CV risk in type 2 diabetes. Nevertheless the
main evidence in this regard comes from more careful consid-
eration of the results of the PROactive study. The factor which
led to the initial failure to recognise the CV benefit of piogli-
tazone in the PROactive study was that the primary composite
endpoint, which had been declared before analysis of the result,
did not achieve statistical significance in favour of pioglitazone.
In the PROactive study, 5238 patients, all of whom had type 2
diabetes and evidence to suggest that they already had CV
disease, were randomised to receive pioglitazone or placebo in
a double blind fashion,7 with 2605 being assigned to piogli-
tazone and 2633 being assigned to placebo. The hazard ratio
for the primary composite endpoint was 0.904 in favour of
pioglitazone (CI 0.98021.081, p=0.0951). However, careful
reconsideration of the data that led to this apparently negative
result led to the realisation that the result may actually be hid-
ing evidence of CV benefit for pioglitazone.26
PROactive also had a main secondary endpoint which had
been declared before analysis of the results. This main second-
ary endpoint was death, MI and stroke the combination most
commonly used in CV outcome studies. Analysis of the main
secondary endpoint revealed a significant benefit for piogli-
tazone hazard ratio 0.841 (CI 0.7220.981, p=0.0273).
Examination of the initial PROactive results (table 1),7 gives an
insight into the possible explanation for the apparent discrep-
ancy between, on the one hand, the results with regard to
primary composite endpoint and, on the other hand, the
results with regard to the main secondary endpoint.
Revascularisation effects
The factors in the primary composite endpoint on the left-hand
side of table 1 show significant improvement with pioglitazone
compared with placebo when only the first six hard endpoint
outcomes are considered death, non-fatal MI, silent MI, stroke,
major leg amputation and acute coronary syndrome. It is only
when the two lower, procedure-based endpoints (coronary revas-
cularisation and leg revascularisation) are added into the equation
that statistical significance is lost. The problem is that it is difficult
to be sure what the results with regard to these two revasculari-
sation parameters mean. For example, in the pioglitazone group
there was a larger number of leg revascularisations which could
be due to these patients being preserved from death and their
legs being preserved from amputation through improvement in
vascular disease in the heart, the brain and the legs; whereas in
the placebo group there were more deaths and amputations and
legs were not preserved from vascular disease, so were not avail-
able for leg revascularisation and patients were not preserved
from death to be available for leg revascularisation.
Similarly with regards to coronary revascularisation there
may have been as many coronary revascularisations in the pio-
glitazone group as in the placebo group simply because
patients were being preserved from MI and death (which
occurred in the placebo group) to be available to have coronary
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Table 1. Numbers of first events contributing to the primary composite and main secondary endpoints in the PROactive study.

Primary composite endpoint Main secondary endpoint

Pioglitazone Placebo Pioglitazone Placebo

(n=2605) (n=2633) (n=2605) (n=2633)

Any endpoint 514 572 301 358

Death 110 122 129 142
Non-fatal MI (excluding silent MI) 85 95 90 116
Silent MI 20 23 NA NA
Stroke 76 96 82 100
Major leg amputation 9 15 NA NA
Acute coronary syndrome 42 63 NA NA
Coronary revascularisation 101 101 NA NA
Leg revascularisation 71 57 NA NA

MI=myocardial infarction; NA=not applicable. This table describes the events that make up the primary composite endpoint, so if death is not the first event,
it does not appear.
From Dormandy JA et al, Lancet 2005;366:1279-1289.
Reproduced with permission.7

revascularisation. Thus, looking at the results in this way, it may

Figure 2. KaplanMeier curve of the time to fatal/nonfatal stroke in
be that the choice of factors to be included in the primary
the patients in PROactive who had had a previous stroke. The solid line
composite endpoint has led to a superficial masking of the real represents the pioglitazone group; the dashed line represents the
effect. Indeed it could be argued that the pioglitazone, by pre- placebo group
serving people from death, MI and leg amputation to have
coronary and leg revascularisations, was actually showing its
positive effect on vascular disease, i.e. the higher numbers in
the last two lines in the first data column of table 1 compared
with the last two lines in the second column were actually
exposing benefit from pioglitazone. Simple statistical analysis
on all the data in the first two columns of table 1 added
together was not adequate to cope with this possibility and
hence the statistical outcome for the primary composite end-
point could well be misleading with regard to the actual clinical
outcome that it was supposed to be assessing. It is also possible
that improvements in atherosclerosis related to pioglitazone
use21,23 may have made the arterial disease more amenable to
coronary and leg revascularisation.
Further powerful evidence in favour of pioglitazone comes
from a subgroup analysis of 2445 patients from the PROactive Key: CI = confidence interval; HR = hazard ratio.
study that had a previous MI; pioglitazone was shown to sig- From Wilcox R et al, Stroke 2007;32:865-873.
Reproduced with permission.28
nificantly reduce (CI 0.520.99, p=0.045) the chances of these
patients having a further MI.27 Analysis of the impact of piogli-
tazone in 984 of the patients in the PROactive study who had
had a previous stroke showed a highly significant reduction (CI in serum triglycerides and increases in high-density lipoprotein
0.340.85, p=0.0085) in the chances of these patients having cholesterol levels than rosiglitazone.29,30 A head-to-head study
a further stroke (figure 2).28 between rosiglitazone and pioglitazone comparing the effects
on lipids29 showed a clear difference (figure 3). A 15% relative
Lipids increase in high-density lipoprotein seen with pioglitazone com-
It is not clear why pioglitazone and rosiglitazone, despite having pared with rosiglitazone is of the same order of magnitude to
similar effects on glycaemic control, might have such different that which has been associated with improvement in coronary
effects on CV outcomes. One possibility is through different atheroma31 or reduction in the instance of coronary heart dis-
effects on lipid profiles. Pioglitazone produces greater reductions ease32,33 with other lipid modifying drugs.

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unrelated toxic effects have emerged during development of

Figure 3. Changes in triglycerides, HDL-cholesterol (HDL-C) and
non-HDL-cholesterol (non-HDL-C) in the head-to-head study of
other PPAR agents.36 Thus it is not surprising to find differences,
pioglitazone versus rosiglitazone with regard to impact on lipids in as well as similarities, between pioglitazone and rosiglitazone.
patients with type 2 diabetes and dyslipidaemia
Heart failure
It is well known that TZDs may cause fluid retention and
Pioglitazone (n=363) oedema37 and as a result they may exacerbate pre-existing
20 Rosiglitazone (n=356)
18.6 heart failure in susceptible patients. However, it is important to
Change from baseline to endpoint (%)

14.9 14.9* recognise that in the PROactive study, there was a significant
15
increase in heart failure in the pioglitazone group compared
10 7.8 with placebo and also in heart failure leading to hospitalisation,
5 3.8* but there was no difference in heart failure leading to death in
the PROactive study between pioglitazone and placebo.7
0 Indeed, in a detailed analysis of the patients in PROactive
-5
who developed serious heart failure38 subsequent all-cause
mortality was proportionately lower with pioglitazone (40/149
-10 [26.8%] versus 37/108 [34.3%] with placebo; p=0.1338).
-15 -12.0* Significantly fewer pioglitazone patients with serious heart
Triglycerides HDL-C Non-HDL-C failure went on to die, have a non-fatal MI or a stroke (34.9%
with pioglitazone versus 47.2% with placebo; p=0.025).38
*p<0.001 between treatment groups
When considering the matter of heart failure in this context it
Based on the data in Goldberg RB et al, Diabetes Care is important to emphasise that the pioglitazone group in gen-
2005;28:1547-1554.29 eral,7,27,28 as well as those with serious heart failure,38 had sig-
nificantly less death, MI and stroke. TZDs do not affect actual
left ventricular function9,39 and fluid retention may respond to
diuretics, perhaps amiloride or spironolactone in particular.9
Figure 4. The ominous octet of factors combining in the pathophysiol-
ogy of type 2 diabetes43
Fractures
The TZDs have been associated with increased risk of fractures
especially in females.12,40 For pioglitazone, the excess risk of
Decreased fractures was 0.8 fractures per 100 patient-years of use (1.9 in
the pioglitazone-treated group versus 1.1 in the comparator-
Incretin Insulin Glucose uptake treated group).41 This represents a tiny risk. Furthermore, the
effect secretion by muscle majority of fractures observed in female patients who received
pioglitazone were in the distal upper limb (forearm, hand and
Neurotransmitter wrist) or distal lower limb (foot, ankle, fibula and tibia).41 While
dysfunction HYPERGLYCAEMIA this fracture risk should not be dismissed, it may represent rela-
tively minor potential harm when the potential CV benefit of
Glucagon
Hepatic glucose pioglitazone is taken into consideration.
Lipolysis output
secretion Renal glucose
re-absorption
Bladder cancer
Diabetes itself may be associated with an increased risk of blad-
Increased der cancer.44 In preclinical studies with pioglitazone bladder
cancer incidence was higher in male rats treated with piogli-
tazone - an observation which was not seen in female rats or in
either sex at higher doses.45 Recent studies suggest this may be
Why pioglitazone and rosiglitazone should be different with a rat specific problem.46 In the PROactive RCT7 there were
regard to CV outcomes and effects on lipids is not known but 16/2605 cancers in the PROactive group compared to 6/2633 in
the PPARg activity exhibited by pioglitazone is recognised to the placebo group (p=0.069). However before the data were
enhance the lipid profile, notably by reducing triglyceride lev- unblinded the 20 bladder cancer cases were reviewed by external
els.34 However, PPAR agonists have complex biological effects, experts who adjudicated that 11 could not plausibly be related to
resulting from the activation or suppression of dozens of treatment. Of the 9 remaining 6 were in the pioglitazone group
genes35 and the patterns of gene activation or suppression differ and 3 in the placebo group (p=0.309).7 Interestingly there were
substantially among various PPAR agonists, even within closely significantly fewer breast cancers in the pioglitazone group
related compounds.8 Accordingly, many different and seemingly (3/2605 v 11/2633, p=0.034).7 Nevertheless this has led to a

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Key messages
Medical statistics applied to the primary composite
endpoint in the PROactive study were inadequate to
reveal the real clinical effect of pioglitazone
Pioglitazone and metformin are the only glucose-
lowering agents with RCT data demonstrating a
reduction in stroke, MI and death in type 2 diabetes
There is a strong case for a paradigm shift in our
approach to the management of type 2 diabetes
involving the combination of metformin, pioglitazone
and GLP-1 agonists used early and aggressively to
achieve a target HbA1C <6%
search for a possible link between pioglitazone and bladder can-
cer. A midpoint analysis of a 10 year longitudinal cohort study of
193099 patients has recently been published.45 Bladder cancer
occurred in 90/30173 pioglitazone treated patients and
791/162926 non-pioglitazone users. Detailed analysis of the data
suggested that overall ever use of pioglitazone was not associ-
ated with risk of bladder cancer but use for more than 2 years
was weakly associated with increased risk.45 The authors of that
paper did acknowledge that there were proportionately more in
situ cancers among the pioglitazone users and that this might be
observed if pioglitazone-treated patients underwent greater sur-
veillance for bladder cancer - which might happen as a result of
awareness of a possible association between pioglitazone and
bladder cancer. Spontaneous reports of bladder cancer to the
FDA Adverse Event Reporting System were higher for piogli-
tazone than other diabetes treatments.47 However as it is known
that a possible link between bladder cancer and pioglitazone is
being actively pursued, it is quite likely that bladder cancers are
more likely to be reported in pioglitazone treated patients than
in non-pioglitazone treated patients.
On June 9 2011, as a result of an internal analysis of a
French database in which pioglitazone users were compared
with non pioglitazone users, the French regulatory body sus-
pended new prescriptions of pioglitazone. On June 23 2011
the EMA issued a statement that the CHMP considered that the
French study strengthened the signal of a small increased risk
of bladder cancer but that the Committee found that the study
had several methodological limitations, which limit the strength
of evidence provided by these epidemiological data.48
The Association of British Clinical Diabetologists (ABCD)
have written to MHRA stating its view that far more harm than
good will be done if pioglitazone is suspended and that on cur-
rent evidence the risk/benefit balance is strongly in favour of
continuing the current licence for the use of pioglitazone to
reduce the risks of diabetes-driven morbidity and mortality.49
The CHMP of the EMA will consider the issue further at its
meeting in July 2011.
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Conclusion
In summary, there is reasonable concern that the high profile
story of the demise of rosiglitazone has led to a lower than
appropriate appreciation of the potential CV benefit of piogli-
tazone in the management of type 2 diabetes. While the
potential risk:benefit of pioglitazone needs to be acknowl-
edged in terms of fracture risk and a possible weak risk of
bladder cancer, it also needs to be recognised that pioglitazone
and metformin are the only glucose-lowering agents used in
type 2 diabetes that have proven benefit on CV disease. Type 2
diabetes is more than anything a disease of people dying pre-
maturely of CV disease. Pioglitazone should be particularly
considered in patients with known vascular disease, especially
MI27 and stroke.28 The risk of heart failure should be taken
into account and, if there is concern, left ventricular function
can be assessed with echocardiography prior to commencing
treatment.
Even in patients who do not already have known CV disease
there is an increasingly strong case developing in favour of using
the combination of metformin, pioglitazone and a GLP-1 ago-
nist in the modern management of type 2 diabetes.42 This case
is argued by Professor Ralph DeFronzo who, in print42 as well as
in a webcast,43 describes an ominous octet of factors combin-
ing in the pathophysiology of type 2 diabetes (figure 4). With
regard to these eight factors he points out that sulphonylureas
only improve insulin secretion and that even this effect is tran-
sient. By contrast, GLP-1 agonists impact on five members of the
ominous octet, pioglitazone on four and metformin on two, and
that the effects of these agents are complementary and some at
least are sustained. As a potent insulin sensitiser, pioglitazone
reduces hepatic glucose output and increases glucose uptake in
muscle. It improves and preserves pancreatic beta-cell function
and therefore insulin secretion and it is also a potent inhibitor of
lipolysis. At the level of the liver, metformin is a potent insulin
sensitiser reducing hepatic gluconeogenesis and in muscle it
provides an additive effect to pioglitazone in promoting glucose
uptake. GLP-1 analogues increase the incretin effect, increasing
insulin secretion, reducing glucagon secretion and hepatic
glucose output. Finally GLP-1 agonists act on the brain reducing
appetite and promoting weight loss. DeFronzo42,43 reminds us
that even at the stage of impaired glucose tolerance, individuals
have lost >80% of their beta-cell function. Therefore he argues
that the modern paradigm for the management of type 2 dia-
betes would involve intensive management at the earliest stages
using metformin, pioglitazone and GLP-1 agonists in combina-
tion with a view to achieving a target HbA1C <6%.42,43 It is worth
noting in particular that the combination of these agents does
not require expensive home glucose monitoring and these
agents are not associated with a risk of hypoglycaemia.
Conflict of interest
R.E.J.R. has previously received educational sponsorship,
speaker fees and consultancy fees from a number of pharma-
ceutical companies including Eli Lilly, GlaxoSmithKline, Novo
Nordisk, Sanofi-Aventis, and Takeda.
VOLUME 11 ISSUE 3 . MAY/JUNE 2011

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VOLUME 11 ISSUE 3 . MAY/JUNE 2011