Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102637

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Diabetes & Metabolic Syndrome: Clinical Research & Reviews

journal homepage: www.elsevier.com/locate/dsx

Bladder cancer with pioglitazone: A caseecontrol study

Bhanu Malhotra a, Priya Hiteshi a, Persis Khalkho a, Ritu Malik d, Sanjay Kumar Bhadada a,
Anil Bhansali a, Nusrat Shafiq b, Sameer Malhotra b, Narendra Kumar c, Rajesh Rajput d,
Ashu Rastogi a, *
a
Deptt of Endocrinology, PGIMER, Chandigarh, 160012, India
b
Deptt of Pharmacology, PGIMER, Chandigarh, 160012, India
c
Deptt of Radiotherapy and Oncology, PGIMER, Chandigarh, 160012, India
d
Deptt of Endocrinology, PGIMS, Rohtak, Haryana, 124001, India

a r t i c l e i n f o a b s t r a c t

Article history: Background: Varied reports suggest a contentious relationship of bladder malignancy with pioglitazone
Received 20 May 2022 in patients with type 2 diabetes.
Received in revised form Aim: To study an association (prevalence and predictors) of bladder malignancy with pioglitazone
27 September 2022
therapy in Asian-Indian type 2 diabetes patients.
Accepted 29 September 2022
Method: In this observational multicenter study, type 2 diabetic patients attending out-patient diabetes-
clinic were evaluated. A detailed history of anti-diabetic medication, dose, duration, pioglitazone usage,
Keywords:
time since initiation of pioglitazone, physical examination, biochemical tests and details pertaining to
Diabetes mellitus (DM)
Bladder cancer
prevalent neuropathy, retinopathy and nephropathy were recorded. Details of bladder cancer or any
Cancer malignancy (if present), time since diagnosis, risk factors for bladder cancer and histopathology records
Malignancy were noted. The study cohort was divided into two groups-pioglitazone ever users (Group A) and never
PPAR gamma Agonist users (Group B).
Thiazolidinediones Results: A total of 8000 patients were screened out of which 1560 were excluded. Among 6440 included
Pioglitazone patients, 1056 (16.3%) patients were in group A and 5384 (83.6%) group B. Patients on pioglitazone were
older (59.1 vs 57.7 years, p < 0.001), had longer duration of diabetes (12.7 vs 10.6 years, p < 0.001) with
poor glycemic control (HbA1c 8.5 vs 8.3%, p < 0.01). A total of 74 patients had prevalent bladder cancer
[16 (1.5%) in Group A and 58 in Group B (1.0%)]. Prevalent bladder cancer was not significantly greater in
ever-users (odds ratio OR ¼ 1.29, 95% confidence interval CI, 0.83e2.00) compared to never-users (odds
ratio OR ¼ 0.94, 95% confidence interval CI, 0.834e1.061) of pioglitazone (p ¼ 0.207). However, history of
hematuria in pioglitazone-users; while older age (>58 year), history of smoking and hematuria in the
whole cohort were significant associated with bladder cancer. In the entire study cohort, 254 patients;
3.5% of males (128 out of 3575) and 4.6% of females (126 out of 2713) developed any malignancy. Age was
significantly associated with prevalent malignancy in people with diabetes (odds ratio OR 1.036, 95%
confidence interval CI: 1.022e1.051, p ¼ 0.00) on multivariate forward regression.
Conclusion: Pioglitazone use in Asian-Indians is not associated with an increased bladder cancer risk.
However, pioglitazone should be restricted in individuals with history of hematuria. Age more than 58
years is a significant risk factor for development of any malignancy, particularly bladder cancer.
© 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.

1. Introduction Prevalence of malignancies is observed to be increased in diabetes

Diabetes is a complex metabolic disease characterized by hy-
perglycemia and the complications emerging from the same [1].
* Corresponding author. Room no-16, Deptt. Of Endocrinology Nehru Extension
Block PGIMER, Chandigarh, 160012, India.
E-mail address: ashuendo@gmail.com (A. Rastogi).
and this causation is both epidemiological and biological [2]. The
biological links between cancer and diabetes include hyper-
insulinemia, hyperglycemia and fat induced chronic inflammation
[2,3]. In addition, pharmacotherapy also influences the pathogen-
esis of diabetic oncopathy [2]. While metformin has been shown to
exert anti-tumorigenic effects [4], insulin and sulfonylureas have
been implicated in increased risk of certain cancers [5]

https://doi.org/10.1016/j.dsx.2022.102637
1871-4021/© 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.
B. Malhotra, P. Hiteshi, P. Khalkho et al.
Thiazolidinediones are a class of oral glucose lowering drugs
that exert anti e diabetic action by acting as peroxisome
proliferator-activated receptor-gamma (PPAR-gamma) agonists
and thereby lowering insulin resistance. Their use has been mini-
mized due to controversy in regard to safety. Marketing of trogli-
tazone was discontinued because of hepatotoxicity [6] and use of
rosiglitazone restricted because of cardiovascular disease [7]. Pio-
glitazone is the only thiazolidinedione available and commonly
used to treat patients with diabetes. The use of this drug declined
after pre-clinical and clinical evidence from PROactive: (PRO-
spectivepioglitAzone Clinical Trial In macroVascular Events) study
[8] that suggested its association with bladder cancer. Subsequent
observational studies seemed to support this finding and indicated
a dose-dependent relationship. Due to the increased risk of bladder
cancer, the US FDA added a warning against use by patients with
active bladder cancer and its marketing was suspended in some
countries including India. Most of the evidence regarding piogli-
tazone and bladder cancer risk was from observational studies
which mainly depended on secondary administrative databases.
Biases related to cohort or case/control selection, indication bias
related to drug use, bias of cancer ascertainment, immortal time
bias and prevalent user bias were not fully addressed in most
studies. Though dose and duration response relationship was
estimated in some of these studies, the effect of different daily
dosing was not considered. Given the ethnic variation in the
prevalence of bladder malignancy and a recent meta-analysis [9]
reporting that risk varies by the choice of comparison group and
geographical region, the conclusions from these prospective
studies and trials can neither substantiate the causal association
between pioglitazone and bladder cancer; nor refute it completely
with confidence.
With the advent of newer drugs like Sodium-glucose transport
protein 2 (SGLT-2) inhibitors, Glucagon like peptide 1 (GLP-1) an-
alogues and Dipeptidyl peptidase-4 (DPP-4) inhibitors and the
emerging evidence to suggest their protective cardio-renal and
metabolic effects, there was a paradigm shift in the management of
diabetes [10]. However, the wide clinical use of these newer drugs
is precluded due to their high cost. India, widely acknowledged as
the “Diabetes capital of the world” has huge burden of patients with
Type 2 diabetes. Indian Asian diabetes phenotype is characterized
by higher insulin resistance [11]. Hence pioglitazone still remains a
useful cost-effective add-on oral anti-diabetic medication (OAD).
Pioglitazone provides effective (lowering HbA1c by 0.5e1.5%) and
durable glycemic control in combination with other oral anti-
diabetes drugs as well in combination with insulin [12].The con-
flicting reports of pioglitazone and cancer warrant more pharmaco-
epidemiologic studies from different parts of the world including
India because of ethnic variations in sensitivity to PPAR agonists
and differing dosing regimens compared to the Caucasian cohorts.
The present study is aimed to assess the prevalence of any
malignancy and bladder malignancy in Indian diabetic patients on
pioglitazone in this study. We further evaluated the risk factors and
predictors for the same to ascertain the association between pio-
glitazone and bladder cancer.
2. Materials and methods
2.1. Subjects
Adult patients with type 2 diabetes attending outdoor diabetes
clinic of two tertiary care centers during duration of April 2018 to
February 2021 were screened for inclusion in the study protocol.
The study included type 2 diabetes patients of age more than 50
years with diabetes duration of more than 2 years and willing to
provide informed consent. The patients were required to be on
2
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102637
stable dose of antidiabetic drug/insulin for at least one year prior to
enrollment in the study. Patients with bladder cancer or any other
malignancy diagnosed before the onset of diabetes mellitus were
excluded. These patients were enrolled during their routine phys-
ical appointment in the clinic. The study was approved by Institute
Ethics Committee vide letter No: PGI/IEC/2014/2341.
2.2. Data collection
A written informed consent was obtained from all included
participants. The following information of the eligible subjects was
recorded.
1. Duration of diabetes
2. Details of medication received
3. Dose and duration of pioglitazone therapy
4. Duration since the diagnosis of bladder cancer
5. Any other malignancy and details pertaining to it.
A detailed information regarding risk factors for bladder cancer
such as smoking, tobacco chewing, occupational exposure to aro-
matic dyes, paint, fertilizers, pesticides, rubber, metal, leather was
obtained. In addition, history of recurrent urinary tract infections,
renal calculi, cystopathy, hematuria, prior chemo-radiation and
family history of bladder or any other malignancy was noted.
Patients were divided into two groups on the basis of ever-users
(Group A) or never-users (Group B) of pioglitazone.
Definitions. The data were divided in to two groups:
Group A: Pioglitazone Users (n ¼ 1056) - These patients are
exposed to pioglitazone for more than 6 months or more.
Group B: Pioglitazone never users (n ¼ 5384): These patients are
exposed to anti-diabetic medications other than pioglitazone.
If the patient had bladder cancer/any other malignancy, then the
histopathology report (if available) was enclosed with the consent
form.Other variables recorded included: demographic and socio-
economic characteristics, physiological parameters (blood pres-
sure, pulse rate, weight, height, body mass index (BMI) and waist
circumference), change in glucose-lowering therapy and reason(s)
for change, glycated hemoglobin (HbA1c) level and other laboratory
parameters (blood test and urine test results), occurrence of major
and minor hypoglycemic events, comorbidities (including micro-
vascular and macrovascular complications), co-medications, and
patient-reported outcomes. The values of Hba1c, blood glucose and
renal function tests, at the last available visit were considered for
analysis.
Duration of diabetes was assessed as time since diagnosis of
diabetes. Hypertension was defined as BP > 130/80 mm Hg or the
history of use of anti-hypertensives. In line with the observational
nature of the study, information with regard to glycemic control
and other clinical variables was collected as measured in routine
clinical practice at each site, according to the prevalent standard of
care.
The baseline characteristics, micro and macrovascular compli-
cation, incidences of bladder cancer and other malignancies were
compared between the two groups. The study cohort was further
divided into two groups including those with malignancy (group I,
n ¼ 254) or without malignancy (group II, n ¼ 6186). We also
compared the baseline characteristics and risk factors for the
development of any malignancy.
2.3. Vascular complications
The presence of vascular complications was assessed by history
as well as relevant investigations. Diagnosis and classification of
B. Malhotra, P. Hiteshi, P. Khalkho et al.
complications was based on best clinical judgement of the in-
vestigators as per current American Diabetes Association (ADA)
recommendations [13]. Additional information on mortality was
obtained from hospital medical records in case of in-hospital death.
2.4. Statistical analysis
Data analysis was performed using the Statistical Package of
Social Sciences (SPSS) version 21. Normality of the data was eval-
uated by Kolmogorov-Smirnov test & Shapiro-Wilk test. In case of
normal distribution, mean with SD was used for descriptive sta-
tistics. Prevalence of the complications in subgroups was compared
by chi square tests. The significance test was two-tailed and p-value
less than 0.05 was considered statistically significant. ROC analysis
was done to derive age and Hba1c cut-offs. Multiple logistic
regression analysis with stepwise additions of variables (age,
duration of diabetes, Hba1c and hypertension) was performed to
determine the predictors of bladder cancer and any malignancy.
3. Results
3.1. Patient enrollment
8000 patients were screened out of which 6440 patients were
included for analysis as shown in Fig. 1. 5428 patients were enrolled
from PGIMER, Chandigarh and 1012 patients from PGIMS, Rohtak. A
total of 1560 were excluded from the study due to either shorter
duration of diabetes (<2 years) or age <50 years or not on any oral
anti-hyperglycemic agents. The data were divided in to two groups
based on pioglitazone use: pioglitazone users (n ¼ 1056) and pio-
glitazone never users (n ¼ 5384). The study cohort was further
divided into two groups including those with bladder malignancy
(n ¼ 254) and those without malignancy (n ¼ 6186).
3.2. Baseline characteristics
Patients on pioglitazone were older (59.1 vs 57.7 years, p < 0.01),
Fig. 1. CONSORT statement elaborating the inclusion and reasons for exclusion in the study.
3
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102637
had longer duration of diabetes (12.7 vs 10.6 years, p < 0.01 and had
poor glycemic control (HbA1c difference 8.5 vs 8.3%, p ¼ 0.01) in the
two groups. The mean dose of pioglitazone in ever users was
25.5 mg/day. Prevalence of CAD was significantly lower (11.1 vs
15.6% p < 0.001), but hypertension (69.3 vs 64.8% p < 0.01) and
stroke (CVA) were significantly higher (7.4 vs 2.9%, p < 0.001) in
Group A compared with Group B. Amongst microvascular compli-
cations, neuropathy (25.3 vs 29.1%, p ¼ 0.01) and nephropathy (11.4
vs 18.8%, p < 0.001) were significantly lower in Group A but there
was no significant difference in the prevalence of retinopathy
(Table 1).
3.3. Malignancy outcomes
A total of 74 patients (21(28.4%) females and 53 (71.6%) males)
were found to have bladder cancer; (16 (1.5%) in Group A; 58 in
Group B (1.0%). There was no statistically significant difference in
the prevalence of bladder cancer in the pioglitazone-users versus
pioglitazone never-users (p ¼ 0.27). The odds for prevalent bladder
cancer amongst ever-users of pioglitazone was 1.29 (95% CI,
0.83e2.00) and 0.94(95% CI, 0.83e1.06) amongst never-users of
pioglitazone (p ¼ 0.20). Amongst the risk factor co-variates; age
>58 years, history of smoking (former and current smoker) and
hematuria were significant predictors for development of bladder
cancer in people with diabetes irrespective of thiazolidenedione
use. (Table 2). People with diabetes having history of hematuria had
significant increased odds (OR 214.58 (62.83e732.76; p < 0.001) of
developing bladder cancer independent of age (Table 3).
In the entire study cohort, 3.5% of males (128 out of 3649) and
4.6% of females (126 out of 2791) developed any malignancy. There
was no statistically significant difference in the prevalence of any
malignancy (other than bladder cancer) in the two groups
(p ¼ 0.10). Of all the malignancies, breast cancer was the most
common malignancy in females (Table S1). Patients harboring
malignancy were older (>58 years), smokers and had history of
aromatic dye or radiation exposure (Table 4). On multivariate for-
ward regression to identify the predictors for prevalent
B. Malhotra, P. Hiteshi, P. Khalkho et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102637

Table 1
Baseline characteristics and prevalent vascular complications of the study cohort as stratified by pioglitazone use.

Group A (Pioglitazone user) n ¼ 1056 (16.4%) Group B (Pioglitazone never user) n ¼ 5384 (83.6%) p-value

Age (years) 59.15 ± 8.50 57.72 ± 9.48 <0.001*

Gender (n %) M ¼ 663 (62.8%) F ¼ 393 (37.2%) M ¼ 2986 (55.5%) F ¼ 2398 (44.5%) <0.001*
Diabetes duration (years) 12.72 ± 6.82 10.61 ± 6.92 <0.01*
Hba1c at enrollment (%) 8.54 ± 2.25 8.30 ± 2.05 0.01*
Mean blood glucose (mg/dl) 189.31 ± 91.82 157.99 ± 77.19 <0.01*
BMI (kg/m2) 26.75 ± 4.38 26.77 ± 4.78 0.76
Creatinine (mg/dl) 1.06 ± 0.53 1.23 ± 1.03 <0.01*
eGFR (ml/min/m2) 75.51 ± 26.05 75.16 ± 47.36 0.23
No. of OADs 2.29 ± 1.09 2.43 ± 1.02 <0.01*
Hypertension (n%) 732 (69.3) 3490 (64.8) <0.01*
CAD (n%) 117 (11.1) 840 (15.6) <0.001*
CVA (n%) 78 (7.4) 154 (2.9) <0.001*
Neuropathy (n %) 267 (25.3) 1568 (29.1) 0.01*
Nephropathy (n%) 120 (11.4) 1012 (18.8) <0.001*
Retinopathy (n%) 151 (14.3) 686 (12.7) 0.17

p  0.05 was consider as significant; Values are expressed as mean ± standard deviation.
BMI ¼ body mass index, eGFR ¼ estimated glomerular filtration rate, OADs ¼ oral antidiabetic drugs, CAD ¼ coronary artery disease, CVA ¼ cerebrovascular accident.
eGFR was estimated by the CKD-EPI (Chronic kidney disease -Epidemiology Collaboration).

Table 2
Risk estimates (odds ratio OR) for bladder cancer as stratified by demographic characteristics and risk factors in the whole study group.

Whole cohort

Bladder cancer (Risk covariates) Bladder cancer No bladder cancer p value Odds Ratio (95%CI)

Age > 58 years 46 3046 0.02* 1.70 (1.06e2.74)

Hba1c  8% 13 1631 0.75 1.13 (0.51e2.48)
BMI > 25 kg/m2 40 3771 0.52 1.17 (0.72e1.90)
Duration of diabetes 10.84 10.94 0.82 0.99(0.96e1.03)
Current Smoker 11 210 <0.001* 4.99 (2.59e9.61)
Former Smoker 12 442 0.003* 2.52 (1.35e4.72)
Tobacco Chewer 4 146 0.10 2.37 (0.85e6.59)
History of hematuria 29 47 <0.001* 84.55 (48.88e146.25)
Cystopathy 4 283 0.58 1.19 (0.43e3.30)
Renal/Bladder calculi 10 688 0.50 1.25 (0.64e2.45)
Recurrent UTI 4 161 0.12 2.14 (0.77e5.95)
Prior exposure to radiation 2 25 0.04* 6.87 (1.59e29.57)
Prior exposure to aromatic dye 0 1 1.00 1.01 (1.00e1.01)
Family history of Bladder cancer 1 ‘78 0.61 1.07 (0.14e7.85)
Nephropathy 14 1081 0.73 1.10 (0.61e1.99)
Hypertension 80 4079 0.72 1.09 (0.66e1.77)

Data represented as Odds ratio (95% confidence interval), Values are expressed as mean ± standard deviation, *p  0.05 was consider as significant; represents statistically
significant difference amongst the two groups of bladder cancer and no bladder cancer in the total study group. BMI ¼ body mass index, UTI ¼ urinary tract infection.

Table 3
Risk estimates (odds ratio OR) for bladder cancer as stratified by demographic characteristics and risk factors in the pioglitazone users (Group A).

Group A (Pioglitazone users)

Bladder cancer No bladder cancer P Odds Ratio (95%CI)

Age > 58 years 10 546 0.43 1.50(0.54e4.16)

Hba1c  8% 3 247 1.00 0.95 (0.19e4.78)
BMI > 25 kg/m2 32 3138 0.37 1.58 (0.57e4.41)
Duration of diabetes (years) 10.84 12.75 0.44 0.95 (0.87e1.03)
Current Smoker 2 40 0.13 3.56 (0.78e16.21)
Former Smoker 2 73 0.31 1.88 (0.42e8.46)
Tobacco Chewer 0 22 1.00 1.01 (1.00e1.02)
History of hematuria 10 8 <0.001a 214.58 (62.83e732.76)
Cystopathy 2 43 0.14 3.30 (0.72e15.00)
Renal/Bladder calculi 2 102 0.66 1.33 (0.29e5.84)
Recurrent UTI 0 24 1.00 1.01 (1.00e1.02)
Hypertension 12 719 0.62 1.33 (0.42e4.15)
CVA 0 78 0.62 1.01 (1.00e1.02)
Neuropathy 1 266 0.08 0.19 (0.02e1.47)
Nephropathy 6 114 0.001a 4.86 (1.73e13.63)
Retinopathy 2 149 1.00 0.85 (0.19e3.78)

Data represented as Odds ratio (95% confidence interval), Values are expressed as mean ± standard deviation.
BMI ¼ body mass index, CVA ¼ cerebrovascular accident; UTI ¼ urinary tract infection.
a
p  0.05 was consider as significant; represents statistically significant difference amongst the two groups of bladder cancer and no bladder cancer in the pioglitazone
users (Group A).

4
B. Malhotra, P. Hiteshi, P. Khalkho et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102637

malignancies in the whole cohort; age was significantly associated
with prevalent malignancy (OR 1.036, 95% CI: 1.022e1.051,
p < 0.01).
4. Discussion
The present study was aimed to find an association of bladder
cancer or any malignancy among people with diabetes on piogli-
tazone therapy compared to pioglitazone never-users. We found a
non-significant increased risk of bladder cancer amongst the pio-
glitazone users compared to never-users. However, the bladder
cancer risk was found to be significantly more in those with history
of hematuria, smoking and age more than 58 years.
The PROactive trial first brought into attention the risk of
bladder cancer associated with the use of pioglitazone in humans
[8]. Subsequently, several observational studies were conducted to
assess an association of bladder malignancy risk with pioglitazone.
Majority were population-based cohorts studies that derived in-
formation from administrative insurance databases, which
included the Kaiser Permanente Northern California (KPNC) [14]
database in the United States, the US pharmacy claims database, the
National Health Insurance (NHI) reimbursement databases of
Taiwan [15], the national health insurance in France (the CNAMTs
study: CaisseNationaled’AssuranceMaladie des Trav-
ailleursSalarie's) [16], General Practice Research Database (GPRD)
[17] or the Health Improvement Network (THIN) [18] in United
Kingdom (UK).
The PROactive trial [8] found an imbalance in bladder cancer
cases between pioglitazone and placebo, relative risk of 2.36
(0.91e6.13). It is worth noting that among the 20 cases of bladder
cancer in the original report, 11 (8 in the pioglitazone group and 3 in
the placebo group) were diagnosed within one year of randomi-
zation, which may refute a causal relation. In the six-year interim
analysis [19]of the trial; the estimated relative risk (95% CI) of
bladder cancer was 0.57 (0.26e1.25) in the analysis of the follow-up
period only, and 1.06 (0.59e1.89) in the analysis of the double-blind
period plus the follow-up period.None of these suggested a
significantly higher risk of bladder cancer associated with the use of
pioglitazone, similar to the present study. In the present study, the
odds for prevalent bladder cancer amongst ever-users of pioglita-
zone was 1.29 (95% CI, 0.83e2.00; p ¼ 0.20).
Our results are also similar to the KPNC study [14] which was a
10-year observational study of patients with diabetes. They found a
non-significant increased risk for bladder cancer in ever use of
pioglitazone (1.2; 95% CI 0.9e1.5), similar to our study. But in the
midpoint interim analysis [20], patients who used pioglitazone for
>24 months showed a significant risk of bladder cancer. A higher
risk was also observed in those with cumulative dose of >35 gm
(HR 1.43, CI ¼ 1.03e1.99) at 2 and 8year analysis [21]. No significant
association between pioglitazone and bladder cancer was noted in
the National Health Insurance database of Taiwan [15] with 54,928
patients of type 2 diabetes (165 incident cases of bladder cancer).
Among them 10 (0.39%) were ever users and 155 (0.30%) were
never users of pioglitazone. We also identified 74 cases of bladder
cancer in the present study (16 cases in pioglitazone ever-users and
58 in never users), out of a total of 6440 individuals. Most of the
studies including datasets of more than 2 million people suggest a
numerically increased risk of bladder cancer amongst pioglitazone
ever users which was not statistically different from pioglitazone
never users.
However, contrary to ours and prior studies, the French CNAMTS
insurance database study [16] that comprised of 1,55,535 piogli-
tazone users out of 1,491,060 diabetic nonusers (ratio of 1:10)
found a 1.22-fold higher risk of bladder cancer (175 bladder cancer
cases) with a doseeresponse relationship at a cumulative dose of
>28 gm (HR 1.36 (1.04e1.79) and 1.75 (1.22e2.50), respectively).-
Similarly, another nested case-control study using the UK general
practice research database found an increased rate of bladder
cancer (rate ratio 1.83, 95% CI 1.10 to 3.05) in pioglitazone ever-
users [17]. But, using the same database; Wei and Colleagues [22]
found no difference for bladder cancer with adjusted hazard ratio
(95% CI) of 1.16 (0.83e1.62) for pioglitazone versus the other oral
glucose-lowering drugs. Another retrospective study analyzing the
THIN database reported a HR 0.93 (0.68e1.29) for bladder cancer
with significant risk for the longest duration (5 years) of therapy
[3.25 (1.08e9.71)], and for the longest time (5 years) since initi-
ation of therapy [2.53 (1.12e5.77)] [18].
An explanation of no association of bladder cancer with piogli-
tazone use in the present study could possibly be related to the
lower daily dose and cumulative exposure to pioglitazone. Lower
dose is more often prescribed in Asian-Indians due to lower body
mass index (BMI), to minimize the adverse effects of weight gain or
fluid retention, and avoid the potential risk of bladder cancer. A
systematic review and comparison with European Medicines

Table 4
Risk estimates for any malignancy (other than bladder cancer) in the whole study group.

Risk factors Any malignancy No malignancy p value CI

Age >58 years 158 3009 <0.001* 1.73(1.34e2.25)

Hba1c  8% 250 1394 0.74 0.94 (0.64e1.36)
BMI > 25 kg/m2 144 3745 0.32 1.14 (0.87e1.48)
Current Smoker 17 204 0.004* 2.10 (1.26e3.50)
Former Smoker 24 430 0.12 1.39 (0.90e2.15)
Tobacco chewer 5 145 1.00 0.83 (0.34e2.05)
Hematuria 38 38 <0.001* 28.46 (17.7e45.52)
Cystopathy 15 272 0.25 1.36 (0.79e2.33)
Renal calculi 36 662 0.08 1.37 (0.96e1.97)
Recurrent UTI 8 157 0.54 1.24 (0.60e2.57)
Radiation exposure 20 7 <0.001* 75.44 (31.59e180.18)
Aromatic dye exposure 1 0 <0.001* 25.45 (22.55e28.71)
Family h/o bladder cancer 4 75 0.55 1.30 (0.47e3.59)
Hypertension 160 4062 0.38 0.89 (0.68e1.15)
Prior CAD 32 925 0.30 0.82 (0.56e1.19)
Diabetic Neuropathy 59 1776 0.06 0.75 (0.55e1.01)
Nephropathy 47 1085 0.69 1.06 (0.77e1.47)
Retinopathy 24 813 0.08 0.69 (0.45e1.05)
CVA 6 226 0.27 0.63 (0.28e1.44)

Data represented as Odds ratio (95% confidence interval), *Represents statistically significant difference between ever-users or never users.
BMI ¼ body mass index, CAD ¼ coronary artery disease, CVA ¼ cerebrovascular accident.

5
B. Malhotra, P. Hiteshi, P. Khalkho et al.
Agency Assessment Report regarding utilization of pioglitazone in
Indian diabetic patients also observed the difference in dose as was
observed in the present study [23]. In the GPRD (UK) database,
pioglitazone is used most commonly with metformin at 30 mg,
whereas in India, pioglitazone is used in doses as low as 7.5 mg/day
and mostly used in combination with metformin and sulphony-
lurea at a dose of 15e30 mg/day [24]. There is also regional varia-
tion in pioglitazone prescription with greater use in northern and
western India compared to central and southern India with no
studies from east India [24].
An enhanced risk of any malignancy in the present study may be
attributed to older age, as an increasing age was found to be the
most important factor for prevalent malignancy after multivariate
regression analysis. Interestingly, hypertension [25e27], which has
been prior attributed to be associated with an increased risk of
malignancy was not found to be statistically associated with cancer
risk in the present study. A significant positive association of
bladder cancer and hypertension was demonstrated in Swedish
cohorts [HR1.25 (1.00e1.55) and Taiwanese database study (HR,
1.55; 95% CI, 1.12e2.13) [26,27]. The association between cancer and
hypertension is complex due to common risk factors specifically
the overexpression of angiotensin receptors and the down-
regulation of the angiotensin-converting enzyme [28]. Overall,
the association between bladder cancer risk and presence of hy-
pertension and diabetes duration is unclear and needs further
investigation.
Pioglitazone has been associated with the risk of worsening
diabetic macular edema (DME) that is more pronounced when
pioglitazone is used with insulin. DME is possibly related to direct
vasodilation, increased vascular endothelial permeability and renal
sodium retention effect of pioglitazone. In the present study, the
prevalence of retinopathy of any grade was similar in those
receiving pioglitazone or not. Diabetic retinopathy has not been
shown to worsen with pioglitazone therapy and presence of reti-
nopathy in the absence of macular edema is not a contraindication
for pioglitazone. A Japanese study found that for the patients
without DME, the occurrence of DME was extremely low after
taking pioglitazone [29]. However, for patients with DME, caution is
needed before prescribing pioglitazone. We had earlier observed
that retinopathy is the least prevalent of microvascular complica-
tions in a large north Indian cohort of diabetic individuals [30]. The
vascular complications of diabetes were recorded from history and
medical records limiting the accurate prevalence of retinopathy
especially asymptomatic non-proliferative retinopathy.
We also observed that patients on pioglitazone were older,
longer duration of diabetes and had poor glycemic control. This
reflects the real world scenario of glycemic control in Asian Indians
and the existing clinical practice and clinician's apprehension in
initiating pioglitazone late in the course of diabetes management
due to potential concern for bladder cancer or other adverse effects.
These observations are also a corollary to the existing guidelines
that suggest metformin as first line followed by sulfonylurea or
DPP-4 inhibitors as add on due to their cost effectiveness. In India,
pioglitazone is available as a triple drug combination with met-
formin and sulfonylureas and is often added as third or fourth drug
despite its glycemic durability. Our findings concur with a retro-
spective study from North India which reported that metformin
remains the most preferred drug across the entire duration of
diabetes, to be followed by sulfonylureas and dipeptidyl peptidase-
4 inhibitors [31].
This study is of significant clinical relevance and has practical
implication particularly for Asian-Indians. Pioglitazone is a potent
insulin sensitizer, preserves beta-cell function, causes durable
6
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102637
reduction in HbA1c, corrects multiple components of metabolic
syndrome and improves nonalcoholic fatty liver disease/nonalco-
holic steatohepatitis. Since Asian Indians have higher insulin
resistance, the insulin-sensitizing effect of the drug is likely to
benefit more in this subset of population. This was demonstrated in
a cross-sectional study comparing the effects of pioglitazone
(30 mg once daily for 16 weeks) in Asian Indians with Caucasians
[32]. Insulin-resistant Asian Indians responded favourably to pio-
glitazone with improvements in insulin sensitivity, cardiovascular
and inflammatory risk markers, and vascular responses to insulin
while the same was not observed for Caucasians [32]. The beneficial
effects of pioglitazone on adipose tissue further adds to the utility
of this drug in Asian Indians, who have higher visceral adiposity
despite lower BMI. Pioglitazone, can retard the atherosclerotic
process[33] and has been shown to reduce cardiovascular events in
large randomized prospective cardiovascular outcome trials.[8, 34,
35]With healthcare expenses attributable to diabetes increasing
rapidly, pioglitazone as cost-effective drug requires reconsideration
in the therapeutic armamentarium for the disease.
Strengths and limitations: The data collection was rigorous and
demographic, anthropometric details were gathered not only from
the records but also by live patient examination and in-person in-
terviews. All the cases of malignancies were identified by the review
of histopathological details of the underlying malignancy including
bladder cancer. We were able to identify 74 cases of bladder cancer, a
sizeable number when we compare with the previous Taiwanese
insurance databases of 1 million people from Taiwan. However,
there were some limitations in the study. The sample size needed to
test the hypothesis was significantly affected by the lack of recruit-
ment of the required numbers which was related to the factors
beyond our control including the COVID-19 pandemic. The retro-
spective nature of record review for diabetic complications and in-
clusive population attending tertiary care hospital limit the
generalizability of the results. A survival analysis comparing the
incidence of bladder cancer between diabetic patients with and
without the history of pioglitazone use was not included in this
study.Also, the cumulative dose of pioglitazone was calculated as the
amount of drug prescribed since the first prescription made at the
tertiary hospital until the day of diagnosis of bladder cancer. These
calculations were based on a review of medical records, which
caused difficulties in calculating pioglitazone intake prior to visiting
the tertiary center. As a result, the actual cumulative dose of pio-
glitazone may have been underestimated.
Conclusion: Pioglitazone use in Asian-Indians in the routine
dose of 15e30 mg per day is not associated with statistically sig-
nificant bladder cancer risk. However, the use of pioglitazone
should be restricted in individuals with prevalent risk factors,
especially those with history of hematuria. Diabetic individuals
with old age and history of smoking need periodic screening for
early detection of common malignancies including breast (women)
and colorectal (men) cancer.
Declaration of competing interest
None.
Acknowledgements
We thank ICMR, New Delhi for funding the study with
research grant number 5/4/5-7/Diab.16-NCD-II to Dr Ashu Rastogi.
We thank the participants for their time during questionnaire
completion. We also thank Mrs Reshma, Miss Raveena Singh for
data entry.
B. Malhotra, P. Hiteshi, P. Khalkho et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102637

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