Pioglitazone: Hype and hopeSS Jadhav, VK Shivane, AR Lila, TR Bandgar, NS Shah
Department of Endocrinology, King Edward Memorial Hospital, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.138765
Source of Support: None, Conflict of Interest: None
Given the humongous problem that diabetes is, and its chronicity, it follows that any antidiabetic drug stands a chance of exposure to millions of people and for a significant duration of time. Hence, the need for strict pharmacovigilance in the regulation of antidiabetic drugs (ADAs) cannot be overemphasized. Among the host of ADAs, very few drugs have been able to stand the test of time; the most remarkable ones being metformin, sulfonylureas and insulin. We have witnessed the rise and fall of several drugs like phenformin, older sulfonylureas, troglitazone and rosiglitazone. The recent controversy boils around Pioglitazone, the only drug of the class "Thiazolidinediones" available for clinical use in India.
The Ministry of Health and Family Welfare had suspended the manufacture and sale of Pioglitazone under Section 26A of the Drugs and Cosmetics Act, 1940 through a notification issued on June 18, 2013. However, the ban was revoked on 31 st July 2013 based on the recommendation by the Drug Technical Advisory Board (DTAB). This controversy has created a huge outcry by the patients, the doctors and the pharmaceutical industry alike. The present article is a viewpoint that looks at the evolution of Pioglitazone and places the controversy in perspective.
"Thiazolidinediones" have a turbulent historical course. Troglitazone introduced in March 1997 was withdrawn in 2000, for its association with liver toxicity. Rosiglitazone introduced in 1999 was shown to be associated with a significant increase in the risk of myocardial infarction.  As a result, United States Food and Drug Administration (US FDA) has put restrictions on the prescription of Rosiglitazone which requires enrolment in the "Risk Evaluation and Mitigation Strategy (REMS)" However, the evolving data still questions the cardiovascular risk associated with Rosiglitazone. 
Pioglitazone was approved by US FDA on July 15, 1999 as an adjunct to diet and exercise. It was approved in India in 2002. American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) and other authorities place Pioglitazone as a third tier agent in the management of diabetes after life style modification and metformin.  Pioglitazone has been consistently associated with reduced cardiovascular risk including that of myocardial infarction and mortality.  However, Pioglitazone is associated with fluid retention that may worsen heart failure. US FDA has put a boxed warning contra-indicating its use in patients with NYHA III and IV symptoms and reducing the dose while exercising caution in patients developing any signs of heart failure.  Also, the association of Pioglitazone with fractures is well described.  However, the adverse event that has proven to be most controversial is its association with bladder cancer.
Pioglitazone and bladder cancer
Based on an epidemiological study conducted in France which suggests an increased risk of bladder cancer with Pioglitazone, France suspended its use in 2011 and Germany has recommended not to start Pioglitazone in new patients. The European Medicine Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) concluded in its review that there is a small risk of bladder cancer with Pioglitazone, however it finds the overall benefits to outweigh the risks in type 2 diabetes patients.  US FDA in 2011 recommended not to use Pioglitazone in patients with active bladder cancer and that it should be used with caution in patients with a prior history of bladder cancer. 
The situation in India
On the basis a recent report of 9 cases of bladder cancer in Pioglitazone users, the drug was recently banned temporarily. In light of this, it is prudent to review the scientific evidence for bladder cancer with Pioglitazone use as well as, to know the practical implications of this controversy.
The first major report of potential/possible risk of bladder cancer with Pioglitazone came from the ProActive study Pioglitazone (which was used in doses from 15 to 30 to 45 mg, force titrated depending on tolerability) showed a significant 16% reduction for the main secondary endpoint (all cause death, myocardial infarction, stroke) after a mean 34.5 months, however, there was no significant difference in primary end point (HR 0·90, 95% CI 0·80-1·02, P = 0·095) which was composite of all-cause mortality, non-fatal myocardial infarction including silent myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. There was no difference in overall malignancy incidence, but an imbalance was observed in bladder malignancies (Pioglitazone 14, placebo 5) which was not significant.  However, it is argued that one patient in the placebo group had benign histology and if excluded, the result tilted towards significant association.  Recently published 6 yrs follow up of the ProActive study participants showed that the imbalance in bladder cancer incidence in the original double-blind period did not persist on follow up. For a combined double-blind and follow-up period (up to 9.5 years in total; mean 8.7 years), incidence of bladder malignancy in the Pioglitazone and placebo groups was similar (HR = 1.00, 95% CI [0.56, 1.80). 
Azoulay et al. in a retrospective nested case control study  (Risk ratio of 1.83, 95% confidence interval (CI) 1.10 to 3.05), Neumann et al., in a population-based French cohort study  (HR of 1.22 [95% CI 1.05, 1.43]), and a large cohort study using The Health Improvement Network database in the United Kingdom  (≥5 years of use, HR = 3.25, 95% CI = 1.08 to 9.71) by Mamtani have shown a significant association of bladder cancer risk with Pioglitazone use. However, in the French cohort study by Neumann et al., the main limitation was lack of adjustment for smoking which is one of the most important risk factors for bladder cancer. 
The same studies have demonstrated that the risk of bladder cancer increases with increasing duration of Pioglitazone use of more than 24 months (HR ranging from 1.75 to 3.25) ,, and in those with a cumulative dosage greater than 28,000 mg , (HR-1.75 to 2.54)
These observations are supported by several recently published meta-analysis. ,,
Nevertheless, certain studies failed to find a significant association between Pioglitazone and bladder cancer. Song et al. reported a retrospective matched case control study with 329 cases of diabetic patients with bladder cancer and 658 age- and sex-matched controls. They found OR of the history of Pioglitazone use of 2.09 in cases vs controls which was not significant (95% CI, 0.26 to 16.81; P = 0.488).  However, the study received criticism for significantly less prescription of Pioglitazone (cumulative median dose of 5,400.0 (interquartile range, 1,350.0 to 8,861.3) in cases vs. 7,275.0 [interquartile range, 3,450.0 to 17,025.0] in controls (P = 0.033), and median prescription days of 363.5 in cases [interquartile range, 100.3 to 632.3] vs 485.0 (interquartile range, 230.0 to 1,135.0) for controls,(P = 0.254),) and failure to achieve statistical significance despite a seemingly strong OR of 2.09.  Another study by Tseng et al. on Taiwanese population showed similar results of no significant association, the study being limited by a small number of events.  Fujimoto et al. too found no significant association in their retrospective cohort study of 663 Japanese patients with Type 2 diabetes on Pioglitazone with an overall hazard ratio of 1.75 (95% CI: 0.89-3.45). 
At the request of the US FDA, the drug manufacturer (Takeda) is conducting a 10-year, observational cohort study as well as a nested case-control study, in patients with diabetes who are members of Kaiser Permanente Northern California (KPNC) health plan, including 193,099 patients with diabetes. The primary outcome of the cohort study is an incident (new) diagnosis of bladder cancer identified from the KPNC cancer registry. The results of the planned midpoint interim analysis  were declared in 2011 which showed that overall, ever use of Pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9-1.5]). However, in the a priori category of >24 months of therapy, there was an increased risk (HR 1.4 [1.03-2.0]). Thus, concluding that short-term use of Pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.
Thus, the overall scientific evidence seems to be inconclusive. However, while analyzing the evidence one has to be vigilant about the heterogeneity of study designs and the lack of well-constructed prospective RCTs.
The molecular mechanism of carcinogenesis of bladder by Pioglitazone remains largely unknown. The preclinical studies have shown increased risk of bladder cancer in a dose-responsive pattern in rats which is species- and sex-specific. The female rats and mice of both sexes do not develop bladder cancer even when exposed to very high doses. The PPAR agonists, however, have been shown to be neither mutagenic nor genotoxic. Tseng et al. have suggested a "urolithiasis hypothesis" referring to the formation of urinary crystals, which subsequently cause bladder irritation, regenerative proliferation, hypertrophy, and cancer. An effect of increased urinary growth factors induced by PPAR agonists has also been proposed, but this requires more investigations. 
Practical impact of the pioglitazone controversy
The practical impact of the ban imposed on Pioglitazone is far reaching.
The changing stance of regulatory authorities regarding the ban leave the doctors and the patients in a state of uncomfortable uncertainties.
It is a well-known fact that Indian diabetics are more insulin resistant and Pioglitazone serves to strike exactly at the Achilles heel in its pathophysiology. A peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, Pioglitazone improves sensitivity of tissues to insulin, and offers significant glycemic durability (both as monotherapy and in combination with other ADAs), with minimal risk of hypoglycemia allowing tight glycemic control.  Moreover, some animal studies have shown that Pioglitazone reduces oxidative stress and thereby preserves beta-cell mass. 
In India, for many patients with diabetes, Pioglitazone being an insulin sensitizer, comes as an agent that can delay the need of initiation of insulin therapy for years together. The drug's unavailability would have increased insulin use and also the use of more expensive incretin based therapies. These too are not immune to the carcinogenicity risk since association of pancreatic and thyroid cancers with incretin-based therapies is being reported.  Needless to say, the treatment cost may go up significantly. This invariably would have a bearing on the patient care in terms of glycemic control and the consequent complications. Direct comparison of the cost for the common brands available in India show that average daily dose of Pioglitazone (15 mg) costs INR 2 to 5 per day while that of incretin-based therapy (e.g. Vildagliptin 50 mg) costs INR 20-40 per day.
In a cost-effectiveness analysis based on data from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) Study and extrapolated to a lifetime modeling analysis, Valentine et al. showed that addition of Pioglitazone to existing therapy in patients with Type 2 diabetes at risk of cardiovascular events is cost-effective by currently accepted standards in the UK.  Similar cost effectiveness is also reported by several pharmacoeconomic studies from Germany, Switzerland and Canada. ,
While the data regarding the association of bladder cancer with Pioglitazone seems largely inconclusive, it is important for the physicians to weigh the risk benefit ratio judiciously. Incidence rate of bladder cancer are low in Indian men, varying from 2.6 to 4.8 per 100,000 in urban areas as against 23.8 per 100,000 in American men.  This might imply that the Indians are less prone to bladder cancer, either genetically or environmentally or both. On the contrary, India being the second global capital of diabetes, the incident morbidity and mortality from the complications of diabetes is enormous. Considering the millions of people exposed to Pioglitazone for many years, we could have expected an upsurge of bladder cancer cases being reported, however, this is not the case. However, the Indian literature is plagued by the lack of well-structured reporting systems or trials. Only one observational prospective Indian study by Balaji et al. showed no increased incidence of bladder cancer in the 958 diabetic patients treated with Pioglitazone (7.5/15/30 mg) for 2 years.  The doses available and prescribed in India are lower than that in Western countries (Pioglitazone 7.5 to 15 mg/day). Hence, at such low doses, the cumulative dose of 28,000 mg that has been implicated to be associated with bladder cancer would require a period of 5 to 10 years of uninterrupted prescription which is a significant therapeutic window during which a patient may get exposed to complications of uncontrolled glycemia.
Nevertheless, in today's world of litigations, we need to be vigilant while prescribing such drugs mired in controversy. The need for this is especially underscored by the fact that we are not parented by a unifying drug regulatory authority like US FDA which could systematically review the scientific evidence and formulate policies. The recent controversy over Pioglitazone ban calls for some introspection. There is a need for vital bodies like Drug Technical Advisory Board (DTAB), The Indian Council of Medical Research (ICMR) and Indian Pharmacopoeia Commission (IPC) to work jointly to arrive at a unified decision so as to give a valid positioning of such drugs. The associations of concerned specialists like Research Society for the Study of Diabetes in India (RSSDI), Association of Physicians of India (API) and Endocrine Society of India (ESI) should provide scientifically sound guidance. Above all, there is an unsurpassable need for generating indigenous data on various aspects of pharmacotherapy specific to our population. This requires a precise and unfailing pharmacovigilance system and reporting of adverse drug reactions (ADRs) by the physicians. After the failure of a similar programme in 1989, since 2010, the Ministry of Health and Family Welfare, in coordination with Indian Pharmacopoeia Commission (IPC) is running the Pharmacovigilance Program of India (PvPI) for nationwide unified ADR reporting system. Several reasons have been cited for poor reporting by the physicians including fear of implication, ignorance about reporting centers, lack of time and often irregular follow up by the patients. We need to overcome these and contribute to develop a strong Indian database.
The way forward
Till more robust scientific evidence surfaces, DTAB recommends that Pioglitazone could be prescribed with caution after carefully excluding the risk factors for bladder cancer like smoking, predisposing occupational hazards, family history of any malignancy, prior exposure to radiation or cyclophosphamide. The patients should be adequately counseled and a joint informed decision should be taken before prescribing Pioglitazone. Strategies to monitor for early detection of bladder cancer need to be formulated. It further recommends that the drug should be used cautiously in the elderly, the response to Pioglitazone should be assessed periodically and it should be withdrawn if efficacy is not documented. It should not be prescribed in the presence of active bladder cancer or uninvestigated hematuria.While it is important to exercise the principle of "primum non nocere" (do no harm), it is also wise not to miss the forest for the trees.