Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials

publicité
Acta Diabetol
DOI 10.1007/s00592-013-0504-8
ORIGINAL ARTICLE
Thiazolidinediones and cancer: results of a meta-analysis
of randomized clinical trials
Matteo Monami • Ilaria Dicembrini
Edoardo Mannucci
•
Received: 1 May 2012 / Accepted: 6 July 2013
Ó Springer-Verlag Italia 2013
Abstract Recent epidemiological data have contributed
to the formulation of the hypothesis about the long-term
safety of pioglitazone, a thiazolidinedione (TZD), with
respect to malignancies, in particular bladder cancer. The
primary aim of this meta-analysis of randomized clinical
trials, not designed a priori to test this hypothesis, was to
explore whether TZDs affect the risk of cancer. A metaanalysis was performed including published and unpublished randomized trials with a duration of at least
52 weeks, enrolling patients with or without diabetes,
comparing TZDs with either placebo or other drug therapies on various different outcomes. We found 22 trials
reporting at least one cancer and enrolling 13,197 patients
to TZD (pioglitazone: n = 3,710 and rosiglitazone:
n = 9,487) and 12,359 to placebo or active comparator
groups. The mean follow-up was 26.1 months. Overall,
those assigned at random to TZDs had a significant
reduction (MH-OR 0.85 [0.73–0.98]; p = 0.027) in the
incidence of malignancies, with no significant difference in
Communicated by Antonio Secchi.
Electronic supplementary material The online version of this
article (doi:10.1007/s00592-013-0504-8) contains supplementary
material, which is available to authorized users.
M. Monami (&)
Geriatric Cardiology, Careggi Teaching Hospital, Florence, Italy
e-mail: [email protected]
I. Dicembrini
Obesity Agency, Careggi Teaching Hospital, Florence, Italy
E. Mannucci
Diabetes Agency, Careggi Teaching Hospital, Azienda
Ospedaliero-Universitaria Careggi, Via delle Oblate 4,
50141 Florence, Italy
e-mail: [email protected]
effect between pioglitazone and rosiglitazone. Specifically,
subgroup analyses showed a significant reduction for rosiglitazone (MH-OR 0.82 [0.69–0.98]; p = 0.029), but not
for pioglitazone (MH-OR 0.66 [0.34–1.28]; p = 0.22). In
further subgroup analyses of site-specific malignancies
based on the data from four trials, the risk of bladder cancer
with pioglitazone (MH-OR) was 2.05 [0.84–5.02];
p = 0.12. Further, rosiglitazone, but not pioglitazone, was
associated with a significantly reduced risk of bowel cancer. In contrast, pioglitazone, but not rosiglitazone, was
associated with a significant reduction in breast cancer. The
present meta-analysis of trials, not designed a priori to test
the hypothesis, provides reassuring evidence that TZDs are
not associated with risk of overall malignancies. In fact,
they are compatible with the possibility of a decreased risk
of cancer. In site-specific subgroup analyses, for rosiglitazone, there was a significant decreased risk of bowel
cancer. Subgroup analyses for pioglitazone did not allow to
exclude an increased risk of bladder cancer, while the risk
of breast cancer was significantly decreased. While these
data are also useful to formulate not test hypotheses, they
provide somewhat more cogent evidence than the previously published epidemiological data.
Keywords Thiazolidinediones Cancer Type 2 diabetes
Introduction
Recent epidemiological data have raised concerns on the
long-term safety of pioglitazone with respect to malignancies, showing an association with bladder cancer [1, 2].
These results, which were in line with reports from some
large-scale randomized trials [3–6], prompted regulatory
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authorities to modify the labels of pioglitazone-based
products; in some countries (i.e., France), the drug was
withdrawn from the market.
Little systematic information is available on the effect of
thiazolidinediones on other types of malignancies, different
from bladder cancer. Many experimental studies had
shown that thiazolidinediones, as a class, could inhibit
proliferation of some types of cancer cells in vitro and
in vivo [7, 8], although pilot studies with these drugs as
anti-cancer therapy provided unsatisfactory results [9, 10].
Epidemiological studies failed to detect any association of
thiazolidinedione use with the overall incidence of cancer
[11]. We have previously shown that rosiglitazone was not
associated with any increase in the overall incidence of
cancer in randomized trials available as of December 1,
2007 [12].
Interpretation of epidemiological data on the relationship between treatments and adverse events is always
problematic, because patients who receive any specific
drug are different from those who are prescribed alternative
therapies. Although many confounders can be controlled
and adjusted for in analysis, a complete elimination of this
prescription bias is impossible. On the other hand, randomized trials, which do not suffer from this limitation,
usually lack a sufficient sample size to verify the effects of
diabetes treatments on the incidence of cancer. Thiazolidinediones are the class of anti-hyperglycemic drugs, which
has been most widely studied, due to a relatively huge
number of longer-term available trials (either with metabolic or with cardiovascular outcomes) [3, 13–15]. Incident
malignancies reported as serious adverse events in those
studies can be a valuable source of information on the
effects of thiazolidinediones on cancer.
Materials and methods
approval process, were also searched for retrieval of
unpublished trials.
Study selection
A meta-analysis was performed including all randomized
clinical trials with a duration of at least 52 weeks, enrolling
patients with or without diabetes, comparing thiazolidinediones with placebo or active drugs (oral hypoglycemic agents
and/or insulin) different from other thiazolidinediones. Trials
with a shorter duration were excluded, due to the fact that
they could not yield relevant information on cancer incidence, which had been chosen as the principal outcome
variable. No review protocol was published elsewhere.
Data extraction and quality assessment
Results of unpublished trials were retrieved, if available, on
www.clinicaltrials.gov, www.clinicalstudyresults.org, FDA
(http://www.accessdata.fda.gov/scripts/cder/drugsatfda),
EMA (www.clinicaltrialsregister.eu), and GSK (http://
www.gsk-clinicalstudyregister.com) Web sites. All those
sources were also used to complete information on results of
published trials, when not reported in publications. A request
for further information was addressed to Takeda for trials on
pioglitazone with missing data, but the company declined.
For all published trials, results reported in papers were used
as the primary source of information, when available.
The quality of trials was assessed using some of the
parameters proposed by Jadad et al. [16]. In particular,
adequate reporting of randomization, allocation, blinding,
and patient flow, together with the description of intentionto-treat safety analysis, were independently assessed by
two investigators (M.M. and I.D.); conflicts were resolved
by a third investigator (E.M.). The score was not used as a
criterion for the selection of trials, whereas some items
were used only for descriptive purposes.
Data sources and searches
Data synthesis and analysis
An extensive MEDLINE and Embase search for ‘‘pioglitazone,’’ ‘‘rosiglitazone,’’ ‘‘troglitazone,’’ ‘‘rivoglitazone,’’
and ‘‘balaglitazone’’ was performed, collecting all randomized clinical trials on humans up to August 1, 2011.
The identification of relevant abstracts, the selection of
studies based on the criteria described above, and the
subsequent data extraction were performed independently
by two of the authors (I.D. and M.M.), and conflicts
resolved by the third investigator (E.M.). Completed but
still unpublished trials were identified through a search of
www.clinicaltrials.gov Web site. FDA (www.fda.gov) and
European Medicines Agency (EMA, www.ema.europa.eu)
reviews of approved drugs, as well as published information provided to FDA in response to queries during the
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The principal outcome was the effect of thiazolidinediones,
compared either with placebo or with active drugs, on the
incidence of cancer. Secondary outcomes included allcause and non-cardiovascular mortality, and cancer-related
mortality.
Pre-defined separate analyses were performed for trials
with different comparators and for site-specific malignancies.
Heterogeneity was assessed by using I2 statistics. If a
low heterogeneity was detected, both a random-effects
model and a fixed-effects model were applied. We report
the results of the random-effects models because the
validity of tests of heterogeneity can be limited with a
small number of component studies. To estimate possible
Acta Diabetol
Standard Error
Fig. 1 Funnel plot of standard
error by Mantel–Haenszel odds
ratio with 95 % confidence
interval (MH-OR, 95 % CI)
MH-Log Odds Ratio
publication/disclosure bias, we used funnel plots (Fig. 1)
and the Begg-adjusted rank correlation test [17, 18],
including published and unpublished, but disclosed, trials.
However, because these tests have low statistical power
when the number of trials is small [19], undetected bias
may still be present. The Duval and Tweedie’s trim and fill
method was used for the estimation of results after correction for publication bias. Mantel–Haenszel odds ratio
with 95 % confidence interval (MH-OR) was calculated for
all the adverse events defined above, on an intention-totreat basis, excluding trials with zero events. A sensitivity
analysis was performed, for the main analysis and for the
predefined separate analyses, including also trials with zero
events, using continuity correction.
The meta-analysis was reported following the PRISMA
checklist [20]. All analyses were performed using Comprehensive Meta-analysis version 2, Biostat, (Englewood,
NJ, USA) and SPSS 18.1.
This research was performed independently of any funding, as part of the institutional activity of the investigators.
Results
The trial flow summary is reported in Fig. 2. Of the 72
identified trials that fulfilled the inclusion criteria, information on cancer incidence was available in 46 studies. In
particular, the number of cases of malignancies was disclosed in 28 out of 33 trials with rosiglitazone, 18 out of 36
trials with pioglitazone; none of the three trials with troglitazone was disclosed. The characteristics of the studies
included in the analysis are summarized in Table 1. The
majority of the retrieved trials showed an adequate quality
for the parameters considered (Table 1). Among the studies
actually retrieved, 24 reported zero events, and therefore,
they were not included in the main analysis, but only in the
confirmatory analysis with continuity correction.
In the 46 trials reporting information on cancer, which
enrolled 14,666 and 13,970 on thiazolidinediones and
comparators, respectively, with a mean follow-up of
83.7 weeks, the number of incident cases was 342 and 457,
respectively; therefore, the observed yearly incidence of
cancer was 1.5 % with thiazolidinediones and 5.3 % with
comparators. The 22 trials reporting at least one event
enrolled 13,197 and 12,359 patients in thiazolidinedione
(pioglitazone: n = 3,710 and rosiglitazone: n = 9,487) and
control groups, respectively, with a mean follow-up of
26.1 months. Recorded cases of incident cancer were 342
and 457 in the thiazolidinedione and control groups,
respectively, with an yearly incidence of 0.95 and 1.12
cases/patient*year for drug and comparators, respectively.
I2 for all thiazolidinediones, rosiglitazone, and pioglitazone
was 0.1, 0.1, and 28.4, respectively (all p [ 0.10). Overall,
thiazolidinediones were associated with a significant
reduction (MH-OR 0.85 [0.73–0.98]; p = 0.027) in the
incidence of malignancies (Fig. 3); a separate analysis for
rosiglitazone (17 trials) yielded similar results (MH-OR
0.82 [0.69–0.98]; p = 0.029), whereas results for pioglitazone were not statistically significant (MH-OR 0.66
[0.34–1.28]; p = 0.22), due to the smaller number of
available disclosed trials (n = 5). Similar figures were
obtained in the confirmatory analysis with continuity correction performed on 46 trials, including those with zero
events (MH-OR 0.86 [0.74–0.99], p = 0.034; 0.83
[0.70–0.98], p = 0.034; 0.92 [0.71–1.19], p = 0.52, for all
thiazolidinediones, rosiglitazone, and pioglitazone,
respectively). Kendall’s tau was -0.34 (p = 0.026), suggesting the possibility of publication bias; this was confirmed by the visual analysis of funnel plot (Fig. 1). Using
the Duval and Tweedie’s trim and fill method, which
suggested the addition of 8 undisclosed trials, the estimated
MH-OR was 0.88 [0.76–1.02].
When different comparators were analyzed separately,
rosiglitazone was associated with a significantly lower
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Fig. 2 Trial flow summary
incidence of malignancies in comparison with placebo (9
trials; MH-OR 0.58 [0.35–0.96]; p = 0.036), whereas a
nonsignificant trend toward reduction was observed in
studies versus sulfonylureas (6 trials; 0.75 [0.55–1.02];
p = 0.068). A lower number of disclosed trials (2 versus
placebo and 2 versus sulfonylureas) was available for
pioglitazone, with no significant result (MH-OR 0.75
[0.31–1.81], p = 0.52 and 0.58 [0.15–2.24], p = 0.43,
respectively). Similar results were obtained when performing the same analyses using continuity correction
(data not shown).
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Results on most frequent malignancies are summarized
in Fig. 4. In trials with available information with this
respect [3; see Electronic supplementary material for 26A,
27A, 34A], pioglitazone was associated with an increased
risk of bladder cancer, which did not reach statistical significance; conversely, no apparent effect was detected for
rosiglitazone. Rosiglitazone, but not pioglitazone, was
associated with a significantly reduced risk of bowel cancer. Conversely, pioglitazone, but not rosiglitazone, was
associated with a significant reduction in breast cancer. No
other significant effect, either harmful or beneficial, was
Acta Diabetol
Table 1 Moderators and outcome variables in individual studies included in the meta-analysis
Study (Reference)a
Trial duration
(weeks)
Number of
patients (ID/C)
Age
(years)
Cancer mortality
(n, ID/C)
Malignancies
(n, ID/C)
Pioglitazone
Versus placebo
Non-diabetic patients
Ramachandran (1A)
204/203
45
0/0
NR/NR
Gavrila (2A)
52
7/7
48
0/0
0/0
Aithal (3A)
52
30/31
53
0/0
0/0
Han (4A)
Geldmaker (5A)
52
78
40/43
14/15
39
71
0/0
0/0
0/0
0/0
96
Sanyal (6A)
DeFronzo (7A)
156
80/83
46
0/0
NR/NR
125
303/299
52
2/0
3/8
156
2,605/2,633
62
NR/NR
97/99
Diabetic patients
Dormandy (8A)
Versus none
Diabetic patients
Jin (9A)
30/30
52
0/0
NR/NR
123
294/294
58
0/0
NR/NR
Derosa (11A)
52
175/175
56
0/0
0/0
Derosa (12A)
108
175/175
56
0/0
NR/NR
52
15/15
57
0/0
0/0
Nakamura (13A)b
52
15/15
57
0/0
0/0
Heliovaara (14A)
52
29/30
57
0/0
NR/NR
Tan (15A)
52
91/109
59
0/0
NR/NR
Giles (16A)
52
151/149
64
0/0
NR/NR
Jain (17A)
56
251/251
52
0/0
0/2
1,051/1,046
54
0/0
NR/NR
Kaku (10A)
52
Versus acarbose
Diabetic patients
Versus voglibose
Diabetic patients
Nakamura (13A)
Versus glibenclamide
Diabetic patients
Tolman (18A)
144
Versus gliclazide
Diabetic patients
Perriello (19A)
52
146/137
58
0/0
NR/NR
Matthews (20A)
52
317/313
58
0/0
0/0
Yamanouchi (21A)
Derosa (22A)
52
52
38/37
69/66
55
57
0/0
0/0
0/0
0/0
Tan 2004 (23A)
52
121/123
55
0/0
NR/NR
Mazzone (24A)
72
230/228
59
1/0
NR/NR
Nissen (25A)
78
270/273
60
0/0
3/4
Versus glimepiride
Diabetic patients
Versus metformin
Diabetic patients
Yamanouchi (26A)
52
38/39
55
0/0
0/0
Derosa (27A)
52
69/67
54
0/0
0/0
Versus others
Diabetic patients
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Table 1 continued
Study (Reference)a
Abe (28A)
Trial duration
(weeks)
96
Number of
patients (ID/C)
Age
(years)
Cancer mortality
(n, ID/C)
Malignancies
(n, ID/C)
31/32
66
0/0
0/0
Versus vildagliptin
Diabetic patients
Bolli (29A)
52
281/295
57
0/0
0/5
67.4
4,446/4,606
56.1
3/0
103/118
Ratziu (30A)
Esposito (31A)
52
52
32/31
50/50
53
45
0/0
0/0
0/0
0/0
049653/331 (32A)
52
706/325
45
0/1
1/2
Totals
Rosiglitazone
Versus placebo
Non-diabetic patients
AVA102672 (32A)
52
934/467
74,1
1/0
6/5
049653/330 (32A)
52
1,181/382
44
0/0
1/2
AVA102670 (32A)
54
966/483
73,2
3/0
9/5
52
22/44
47
0/0
0/0
Diabetic patients
Rahman (33A)
BRL-049563/351 (32A)
52
30/30
NR
0/1
0/0
Hwang (34A)
52
43/46
54
0/0
0/0
Bertrand (35A)
52
98/95
65
0/0
NR/NR
Dargie (36A)
52
110/114
64
1/0
2/3
Hedblad (37A)
52
277/278
67
3/1
3/3
80
NCT00386100 (38A)
348/340
51
NR/NR
1/1
Berberoglu (39A)
104
26/23
60
0/0
0/0
49653/135 (32A)
Gram (40A)
104
104
116/111
187/184
68
56
0/0
NR/NR
4/7
3/8
52
20/40
58
0/0
0/0
52
16/15
56
0/0
0/0
Versus life style
Non-diabetic patients
Oberbach (41A)
Versus metformin
Non-diabetic patients
49653/392 (32A)
Diabetic patients
NCT00679939 (38A)
114/11
64
0/0
0/0
1,103/1,122
59
NR/NR
70/81
52
384/203
60
0/0
3/0
49653/097 (32A)
148
122/120
56
0/0
1/4
49653/080 (32A)
Versus gliclazide
156
104/99
56
0/0
1/3
144
43/41
58
0/0
0/2
52
50/49
53
0/0
0/0
78
333/339
61
NR/NR
1/4
Home (42A)
52
286
Versus glibenclamide
Diabetic patients
Hanefeld (43A)
Diabetic patients
NCT00367055 (38A)
Versus glimepiride
Diabetic patients
Derosa (44A)
Versus glipizide
Diabetic patients
Gerstein (45A)
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Table 1 continued
Study (Reference)a
Trial duration
(weeks)
Number of
patients (ID/C)
Age
(years)
Cancer mortality
(n, ID/C)
Malignancies
(n, ID/C)
Versus sulfonylureas
Diabetic patients
Hamann (46A)
52
294/301
59
2/1
0/0
Home (42A)b
286
1,117/1,105
57
NR/NR
73/89
260
1,456/2,895
57
NR/NR
60/120
Versus metf. or glib.
Diabetic patients
Kahn (47A)
Versus insulin
Diabetic patients
Ko (48A)
Totals
52
56/56
58
0/0
0/0
94.1
10,220/9,364
57.6
10/4
239/339
104
49/81
40
0/0
NR/NR
104
142/134
52
0/0
NR/NR
104
291/215
46
0/0
NR/NR
Troglitazone
Versus placebo
Non-diabetic patients
Schuster (49A)
Diabetic patients
Hodis (50A)
Totals
ID/C interventional drug/comparator, CV cardiovascular, NR not reported
a
b
See Electronic supplementary material
Studies with multiple comparators
observed for any other type of cancer, including hepatocellular carcinoma (Fig. 4).
Information on cancer-related mortality was available in
57 trials, enrolling 10,768 and 8,652 patients on thiazolidinediones and comparators, respectively, with a mean
follow-up of 68.5; yearly cancer-related mortality was 13
and 4 with thiazolidinediones and comparators, respectively. MH-OR for cancer-related mortality (N = 9 trials
with events) was 1.79 [0.68–4.69], p = 0.24 (3.90
[0.43–35.45], p = 0.23, and 1.48 [0.51–4.34], p = 0.47,
for pioglitazone and rosiglitazone, respectively).
Conclusions
In type 2 diabetes, the choice among the many available
drugs is often driven by their glucose-lowering efficacy and
short-term adverse effects, such as weight gain and hypoglycemia. On the other hand, there is increasing evidence
that long-term treatments for diabetes could affect the risk
of other, more relevant health outcomes, such as major
cardiovascular events [21], bone fractures [22, 23], or
cancer [24].
Different agents have been reported either to increase or
to reduce the incidence of cancer [24]. With respect to
thiazolidinediones, available epidemiological studies provided discordant results, suggesting either a harmful, neutral, or beneficial effect [11, 12, 25–27]. In a previous
meta-analysis performed on a smaller number of trials, we
had previously failed to detect any significant effect of
rosiglitazone on the incidence of cancer [12]. The results of
the present meta-analysis, which was performed on all
molecules of the class and includes more recent trials, seem
to exclude any increase in the risk of malignancies with
thiazolidinediones. Conversely, the incidence of cancer in
thiazolidinedione-treated patients is actually lower than
that observed in comparator groups. This result should be
considered with caution, because the trials included in the
meta-analysis were not specifically designed for the
assessment of the effects of treatment on the incidence of
malignancies. Therefore, cases of cancer were only reported as treatment-emergent serious adverse events, with no
formal adjudication. Furthermore, in the large majority of
trials, no specific follow-up was planned after the end of
the treatment period; this means that cases of cancer that
developed during the trial, but were diagnosed later on,
could have been overlooked. Another major limitation is
that cases of cancer detected early after the initiation of
treatment, which probably preexisted to drug exposure,
were included in the analysis. These biases could have
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Fig. 3 Mantel–Haenszel odds
ratio with 95 % confidence
interval (MH-OR, 95 % CI) for
incident cancer for each
individual trial
MH odds ratio and 95% CI
Statistics for each study
First Author (Ref.)
Bolli (29A)
DeFronzo (7A)
Dormandy (8A)
Jain (17A)
Nissen (25A)
PIOGLITAZONE
04965/3310 (32A)
04965/331 (32A)
04965/080 (32A)
04965/097 (32A)
04965/135 (32A)
AVA 102670 (32A)
AVA 102672 (32A)
Dargie (36A)
Gerstein (45A)
Gram (40A)
Hanefeld (43A)
Hedblad (37A)
Home (42A)
Home (42A)#
Kahn (47A)
NCT00367055 (38A)
NCT00386100 (38A)
ROSIGLITAZONE
OVERALL
MH odds Lower Upper
ratio
limit
limit Z-Value p-Value
0,094
0,364
0,990
0,198
0,756
0,659
0,161
0,229
0,311
0,240
0,531
0,899
0,597
0,685
0,252
0,359
3,734
1,004
0,798
0,871
0,994
0,182
0,977
0,825
0,849
0,005 1,704
0,096 1,385
0,744 1,317
0,009 4,154
0,168 3,409
0,338 1,283
0,015 1,781
0,021 2,535
0,032 3,038
0,026 2,176
0,151 1,865
0,300 2,697
0,181 1,968
0,112 4,181
0,028 2,269
0,094 1,374
0,192 72,641
0,201 5,016
0,579 1,101
0,625 1,213
0,724 1,364
0,008 3,900
0,061 15,682
0,694 0,980
0,733 0,982
-1,600
-1,483
-0,069
-1,042
-0,365
-1,227
-1,489
-1,201
-1,005
-1,269
-0,988
-0,190
-0,847
-0,410
-1,229
-1,496
0,870
0,004
-1,375
-0,818
-0,038
-1,090
-0,016
-2,184
-2,206
0,110
0,138
0,945
0,297
0,715
0,220
0,136
0,230
0,315
0,204
0,323
0,849
0,397
0,682
0,219
0,135
0,384
0,996
0,169
0,413
0,970
0,276
0,987
0,029
0,027
0,1
0,2
0,5
Favours TZDs
produced a background noise, determining an underestimation of actual differences between groups.
Another major limitation is represented by incomplete
disclosure of data. In fact, a complete description of serious
adverse events was available for most trials with rosiglitazone, but not pioglitazone, even after a formal request to
Takeda. The higher number of trials available for analysis
could be responsible for the fact that rosiglitazone resulted to
be significantly associated with a reduced risk of malignancies, whereas pioglitazone missed the threshold for statistical
significance, despite a MH-OR lower than that of rosiglitazone. On the other hand, the possibility of selective
reporting of favorable results for pioglitazone cannot be
excluded. In fact, the distribution of results from disclosed
trials suggests a selective reporting bias, which produces an
overestimation of the benefits of thiazolidinedione therapy.
Some of the drugs to which thiazolidinediones have
been compared in clinical trials, most notably insulin [28]
and sulfonylureas [13, 14, 29–31], have been associated
with an increased risk of cancer; however, the apparent
protection from malignancies conferred by rosiglitazone
was still clearly detectable (and statistically significant)
when the analysis was restricted to placebo-controlled trials. This finding suggests that the difference between
thiazolidinediones and comparators is due, at least partly,
to a beneficial effect of these drugs, and not only to the
detrimental action of comparators. Such an effect is not
surprising, considering the amount of experimental evidence suggesting an inhibitory action of thiazolidinediones
on cancer cell growth [32, 33].
123
1
2
5
10
Favours Comparator
The increased risk of bladder malignancies with pioglitazone, suggested by some epidemiological studies [1, 2,
6], but not confirmed by others [34], is not statistically
significant in the present meta-analysis. However, our
results are compatible with those reported by the European
Medicinal Agency (EMA), which provided a (statistically
significant) OR estimate of 2.14 [6]. Details on the methods
of the EMA analysis, which was probably performed on
patient-level data, are not available. However, we should
be aware that our meta-analysis is affected by incomplete
disclosure, with missing information on some relatively
large trials [14, 35, 36]. In fact, the present risk estimate is
based on the results of only four disclosed trials; the limited
size of samples (and the small number of cases) in disclosed studies accounts for the large confidence intervals,
ranging from a 16 % protection to a fivefold increase in
risk. The higher risk of bladder cancer with pioglitazone is
consistent with the results of some experimental studies
[37, 38], although other authors had reported a protective
effect in vitro [39]. Quite interestingly, no increase in risk
of bladder cancer was observed with rosiglitazone, suggesting that the detrimental effect of pioglitazone, if confirmed, could be due to a PPAR-c-independent mechanism.
On the other hand, thiazolidinediones could be protective for other types of cancer. In this meta-analysis, rosiglitazone was associated with a reduced risk of bowel
cancer, and pioglitazone appeared to confer protection
from breast cancer. These results are in line with some
previous studies in vitro [32, 33]. However, the limited
number of reported cases for each type of malignancy
Acta Diabetol
Fig. 4 Subgroup analyses of Mantel–Haenszel odds ratio with 95 % confidence interval (MH-OR, 95 % CI) for most frequent malignancies
suggests caution in interpreting data. On the other hand, the
previously described reduction in risk of hepatocellular
carcinoma [40–43] was not confirmed, although this could
depend on the small number of cases, with some large trials
(including PROACTIVE) not reporting this specific result.
The few cancer-related deaths reported in trials were
more frequent in thiazolidinedione-treated patients,
although the between-group difference was far from
reaching statistical significance. It should be considered
that, in the majority of cases, deaths from cancer occurred
during the trials were probably determined by malignancies
which preexisted to the initiation of treatment; on the other
hand, most of the deaths determined by cases of cancer,
which emerged during the active treatment phase probably
occurred after the termination of follow-up, and were
therefore missed in the present analysis.
In conclusion, available data from disclosed clinical
trials do not allow to exclude an association between
pioglitazone exposure and bladder cancer, which is not
present for other molecules of the class, such as rosiglitazone. On the other hand, thiazolidinediones could reduce
the overall incidence of cancer, mostly because of a
reduced risk of bowel and breast malignancies. The possible negative effects of each molecule on specific cancer
types should be carefully considered when prescribing a
long-term drug treatment; in fact, the indication of regulatory bodies to avoid pioglitazone therapy in patients at
high risk for bladder cancer appears to be fully justified.
However, a correct choice among available treatment
options should be based on a comprehensive assessment of
the risk–benefit ratio, which should include other adverse
events (i.e., in the case of pioglitazone, bone fractures, and
heart failure) together with possible favorable outcomes on
different hard end points, such as myocardial infarction,
and, possibly, reduced overall cancer risk.
Conflict of interest Matteo Monami has received speaking fees
from Bristol Myers Squibb, Merck, Novartis, Novo Nordisk, and
Takeda. Ilaria Dicembrini has received speaking fees from Novo
Nordisk. Edoardo Mannucci has received consultancy fees from
Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers
Squibb, Merck, and Novartis, and research grants from Merck,
Novartis, and Takeda.
123
Acta Diabetol
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