Risk of Bladder Cancer in Type 2 Diabetes Patients With Pioglitazone Therapy "PROBE" (PROBE-PIO)

January 23, 2022 updated by: Ashu Rastogi, Postgraduate Institute of Medical Education and Research

Pioglitazone and Risk of Bladder Cancer in Patients With Type 2 Diabetes Mellitus"PROBE-PIO"Study

Pioglitazone, an agonist of the peroxisome-proliferator-activated receptor (PPAR), is a relatively new oral anti-hyperglycemic drug. Since its first approval in the USA in 1999, a potential link with bladder cancer has been a subject of debate. US Food and Drug Administration (FDA) in September, 2010 and European Medicines Agency in July, 2011 issued an alert about a potential relation between the occurrence of bladder cancer and the prescription of pioglitazone, based on the data from various studies. France banned its use in July 2011.

Recently Pioglitazone was banned from India without any evidence of increased bladder cancer in our population. With this background, we plan to study the risk of bladder cancer in male type 2 diabetes subjects aged more than 50 years who are on pioglitazone therapy as compared to never-users of pioglitazone in a retrospective cohort design and provide the first data from India to the policy makers regarding the purported risk in our ethnicity and geographical area.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Very recently, pioglitazone was banned for use in type 2 diabetes patients in India as well, by the notification from Government of India based on a case series - the ban was revoked a few days later due to lack of evidence.

The incidence rates of bladder cancer among different ethnicities differ markedly, with Caucasians having the highest incidence. Another important distinction pertains to the dose of pioglitazone- the daily dose of pioglitazone used in the previous studies (from western countries) was 45 mg, which is higher than currently prescribed in India (7.5-30 mg). Therefore the risk of bladder cancer in Indian patients cannot be extrapolated from studies conducted in other regions of the world. Consequently, it is an interesting issue to explore the risk of bladder cancer amongst the pioglitazone-users in our settings with different ethnicity and risk profile. There has been a single report of eight cases of sporadic bladder cancer from India.10 However, the study had no denominator and there has been no further study from India exploring the relationship between pioglitazone and bladder cancer.

Furthermore the risk of bladder cancer is highest in males greater than 50 years. The other risk factors are smoking, occupational exposure to aromatic amines in metal, leather, and paint industries etc., all of which are more common in males. The increase, if any, in the rate of bladder cancer with pioglitazone is expected to be highest in this group.

The results from currently available studies either in-vitro, animal, human (observational) on the link between pioglitazone and bladder cancer are not consistent. Whether the positive link in patients using pioglitazone in some studies could be due to the drug per se, or due to the underlying disease of diabetes, the interactions with other concomitant drugs, the inherent flaws associated with study designs and statistical analyses, or the different ethnicities between studies, are worthy of discussion. Diabetes per se may increase the risk of cancer, probably via the activation of the Ras/Raf mitogen-activated protein kinase pathway in association with a reduction of the expression of epidermal growth factor receptor. In fact, epidemiologic studies also suggest an increased risk of bladder cancer in diabetic patients, independent of the commonly used oral anti-diabetic agents or insulin.

Hence we plan to investigate the risk of bladder cancer in type 2 diabetes subjects using pioglitazone as compared to those who have never been exposed to pioglitazone. We will thoroughly scrutinize the records and also interview the subjects regarding other risk factors for bladder cancer in addition to pioglitazone.

Study Type

Observational

Enrollment (Actual)

6107

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
      • Chandigarh, India, 160012
        • Deptt of Endocrinology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Sampling Method

Non-Probability Sample

Study Population

The study group will comprise of male type 2 diabetes subjects having used pioglitazone for one year or more. The control group will include male type 2 diabetes subjects on medications other than pioglitazone adjusted for age, household income, anti-diabetic drugs, HbA1c,smoking, renal function and other bladder disorders.

Description

Inclusion Criteria:

  1. Male Type 2 diabetes subjects with age >50 year
  2. On anti-diabetic drugs and/or insulin for≥ 1 year
  3. Patient willing to provide informed consent to be included in the study

Exclusion Criteria:

  • 1. Bladder cancer diagnosed before the onset of Diabetes mellitus. 2. Patient not willing to participate in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Pioglitazone
Ever users of Pioglitazone
Drug: Pioglitazone
Ever users of Pioglitazone
Other Names:
  • Pioglit,
  • Pioz
Other drugs
Never users of pioglitazone

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bladder cancer rate
Time Frame: Prevalent bladder cancer on pioglitazone or anti diabetic drugs for 1 year
Kaplan-Meir survival curves will be generated for the two groups of pioglitazone users and non-pioglitazone users. All the data at the time point of interview will be considered censored. Bladder cancer rates among pioglitazone users and non-users will be compared by hazard ratio (HR) after Cox regression. Adjustment for various confounders like age, diabetes duration, region of residence, occupation, smoking, urinary tract disease, use of other medications like sulfonylurea, metformin, insulin, DPP-IV inhibitors and other cancers before baseline would be done.
Prevalent bladder cancer on pioglitazone or anti diabetic drugs for 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Postgraduate Institute of Medical Education and Research

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2013

Primary Completion (ACTUAL)

October 1, 2021

Study Completion (ACTUAL)

October 1, 2021

Study Registration Dates

First Submitted

August 22, 2013

First Submitted That Met QC Criteria

August 30, 2013

First Posted (ESTIMATE)

September 5, 2013

Study Record Updates

Last Update Posted (ACTUAL)

January 25, 2022

Last Update Submitted That Met QC Criteria

January 23, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PROBEPIO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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