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

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ClinicalTrials.gov Identifier: NCT01935466
Recruitment Status : Completed
First Posted : September 5, 2013
Last Update Posted : January 25, 2022
Information provided by (Responsible Party):
Ashu Rastogi, Postgraduate Institute of Medical Education and Research

Brief Summary:

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.

Condition or disease Intervention/treatment
Bladder Cancer Drug: Pioglitazone

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2 diabetes patients in India as well, by the notification from Government of India based on a case series - the ban was revoked a few days later due to lack of evidence.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

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Study Type : Observational
Actual Enrollment : 6107 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Pioglitazone and Risk of Bladder Cancer in Patients With Type 2 Diabetes Mellitus"PROBE-PIO"Study
Study Start Date : July 2013
Actual Primary Completion Date : October 2021
Actual Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Group/Cohort Intervention/treatment
Ever users of Pioglitazone
Drug: Pioglitazone
Ever users of Pioglitazone
Other Names:
  • Pioglit,
  • Pioz

Other drugs
Never users of pioglitazone

Primary Outcome Measures :
  1. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01935466

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Deptt of Endocrinology
Chandigarh, India, 160012
Sponsors and Collaborators
Postgraduate Institute of Medical Education and Research
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Responsible Party: Ashu Rastogi, Assisstant Professor, Postgraduate Institute of Medical Education and Research
ClinicalTrials.gov Identifier: NCT01935466    
Other Study ID Numbers: PROBEPIO
First Posted: September 5, 2013    Key Record Dates
Last Update Posted: January 25, 2022
Last Verified: January 2022
Keywords provided by Ashu Rastogi, Postgraduate Institute of Medical Education and Research:
Bladder cancer
Type 2 Diabetes
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Urinary Bladder Diseases
Urologic Diseases
Male Urogenital Diseases
Hypoglycemic Agents
Physiological Effects of Drugs