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.

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.

Brief Title

Risk of Bladder Cancer in Type 2 Diabetes Patients With Pioglitazone Therapy "PROBE"

Official Title

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

Brief Summary

Pioglitazone, an agonist of the peroxisome-proliferator-activated receptor (PPAR), is a <br /> relatively new oral anti-hyperglycemic drug. Since its first approval in the USA in 1999, a <br /> potential link with bladder cancer has been a subject of debate. US Food and Drug <br /> Administration (FDA) in September, 2010 and European Medicines Agency in July, 2011 issued an <br /> alert about a potential relation between the occurrence of bladder cancer and the <br /> prescription of pioglitazone, based on the data from various studies. France banned its use <br /> in July 2011. <br /> <br /> Recently Pioglitazone was banned from India without any evidence of increased bladder cancer <br /> in our population. With this background, we plan to study the risk of bladder cancer in male <br /> type 2 diabetes subjects aged more than 50 years who are on pioglitazone therapy as compared <br /> to never-users of pioglitazone in a retrospective cohort design and provide the first data <br /> from India to the policy makers regarding the purported risk in our ethnicity and <br /> geographical area.

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.

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.