There is some debate on whether the Indian regulatory agency ought to have banned anti-diabetes drug pioglitazone given the large diabetic population in India.
The decision to ban is a correct and proactive step considering the harm that it may cause in patients who have been taking the drug for over two years.
Since hardly any meaningful pharmacovigilance (drug safety) data arises in India from pharmaceutical companies, the Indian regulatory agency has had to rely on studies and data received from other countries to take this important step. This, I have tried to explain below in detail.
Pioglitazone is indicated for type 2 diabetes either on its own or combined with other oral anti-diabetic agents or insulin. The potential risk of bladder cancer with pioglitazone was first identified at the time of licensing in 1999, and observed in male rats in an animal toxicity study that supported the initial license application. There was no evidence of a similar risk in humans at that time. The license-holder committed to investigate the risk further in animal studies and observational studies in human use. Since then, it has been a subject of regular debate arising out of results from various studies.
Nearly 10 years later, in September, 2010, the US Food and Drug Administration (FDA) issued an alert about a potential relation between the occurrence of bladder cancer and the prescription of pioglitazone at high doses for long periods. In April 2011, researchers (Piccini et al), used the FDA Adverse Event Reporting System database to reveal evidence that supported a significant risk of bladder cancer associated with pioglitazone irrespective of treatment duration.
In July 2011, the European Medicines Agency issued a warning about the potential for bladder cancer with pioglitazone. In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial, the reported incidence of bladder cancer was higher among participants randomised to pioglitazone than among those randomised to placebo (14 v 6 cases), although this failed to reach statistical significance.
However, it was later reported that one case in the placebo group was not cancerous, and the exclusion of this case resulted in a statistically-significant increased risk of bladder cancer (14 v 5 cases). In observational studies, a signal was observed in the US FDA adverse event reporting system. Furthermore, an interim analysis of an ongoing US cohort did not find an association between pioglitazone and bladder cancer overall but found a 40% increased risk in patients who used the drug for more than 24 months.
Subsequently, researchers evaluated 1,15,727 patients who initiated diabetes therapy from 1988 to 2009 with data from the General Practice Research Database (GPRD) which anonymous patient records from over 600 UK GPs. The researchers identified cases of bladder cancer and matched them to up to 20 healthy control patients. The results revealed that patients who had taken pioglitazone at any time were found to have a 83% higher risk of bladder cancer.
In 2011, the French regulatory authority AFSSAPS suspended the use of pioglitazone -containing products for the treatment of type 2 diabetes in France on the basis of a small increased risk with statistical significance of bladder cancer in patients treated with pioglitazone observed in a French database study (CNAMTS) independently conducted by French authorities. Germany followed suit.
The same year, after finalising its review, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) confirmed that these medicines remain a valid treatment option for certain patients with type 2 diabetes but that there is a small increased risk of bladder cancer in patients taking these medicines.
However, the CHMP also concluded that the small increased risk could be reduced by appropriate patient selection and exclusion, including a requirement for periodic review of the efficacy and safety of the individual patient’s treatment.
The major correlation between pioglitazone and bladder cancer is the duration of therapy for over 24 months and cumulative dose of more than 28000 mg which means the average daily dose of pioglitazone would be about 40 mg/day. The decision is totally dependent on the prescriber and the dose prescribed depends on the patient’s blood sugar control.
In India, there is poor knowledge amongst many general practitioners who prescribe this drug on the correct dosage and the issues concerning the products. I have been reading in several snippets, like this one, from India that there have been no side-effects to pioglitazone. This is completely wrong.
All medications are chemical entities and have side-effects. It is another issue that many pharmaceutical companies in India do not have a systematic way of collecting and analysing adverse drug events for their products or simply do not collect. The information given to physicians by medical representatives can be misleading as it is not unknown for only good things about the drug to be vocally-stated and adverse events ignored or understated. In general, drugs are sold to patients in strips and not packs with detailed product information leaflets. In some such leaflets for pio, the bladder cancer risk is not mentioned.
Is pio so indispensable?
The management of diabetes concentrates on keeping blood sugar levels as close to normal without causing hypoglycemia. This can usually be accomplished with diet, exercise, and use of appropriate medications (insulin in the case of type 1 diabetes; oral medications, as well as possibly insulin, in type 2 diabetes). While medicines are useful, lifestyle changes are equally, if not more, important in achieving control.
Patient education, understanding, and participation is vital, since the complications of diabetes are far less common and less severe in people who have well-managed blood sugar levels. Attention is also paid to other health problems that may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.
In addition to switching the patient to other anti-diabetic medication there is great benefit in stressing on lifestyle changes that include diet control and exercise to have near-normal blood sugar.
At the end of the day the choice before the patient is clear and simple. Would you rather enjoy a healthy life style by maintaining blood sugar through diet and exercise and live long or pop pills that hold a risk of developing cancer!
Dr Pipasha Biswas is Chairperson, Drug Safety and Pharmacovigilance Committee at the Faculty of Pharmaceutical Medicine, Royal College of Physicians, London. She is also Qualified Person for Pharmacovigilance (QPPV) and Director, Pharmacovigilance and Pharmacoepidemiology, at Symogen Limited.
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