Takeda Pharmaceutical Company Limited (Takeda), a research-based pharmaceutical company, announced the completion of the study to fulfill the post-marketing commitment and submissions of data to regulatory authorities from the Pan European Multi-Database Bladder Cancer Risk Characterization Study, a large (n= 112,674), multi-database retrospective matched cohort study conducted in four European countries, for pioglitazone containing medicines, including Actos (pioglitazone HCI) with up to 10 years of follow-up demonstrate that there is no association between the use of pioglitazone and the risk of bladder cancer, (hazard ratio [HR] 0.99 [95 per cent CI: 0.75, 1.30]).
These results are consistent with those of a 10-year, prospective cohort study, conducted by the University of Pennsylvania and division of research at Kaiser Permanente Northern California (KPNC), which demonstrated no increased risk of bladder cancer among patients ever exposed to pioglitazone ([HR] 1.06 [95 per cent CI 0.89-1.26]). Additionally, both studies found no association between the risk of bladder cancer and cumulative dose of pioglitazone, or duration of pioglitazone exposure.
“Actos is an important treatment option for patients with type 2 diabetes. These data further reinforce the positive benefit/risk profile for Actos,” said Alfonso Perez, MD, vice president, clinical research, Takeda.
“These long-term studies underscore Takeda’s commitment to ensuring physicians have the best available information to make treatment decisions.”
The data from the Pan European Multi-Database Bladder Cancer Risk Characterization Study also shows a mortality decrease with ever use of pioglitazone (adjusted HR 0.67 [95 per cent CI: 0.64, 0.70]).This study was completed as part of the post-marketing request from the Committee for Medicinal Products for Human Use (CHMP). In addition to the European Medicines Agency (EMA), the results from the Pan European study were also submitted to the US Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA). The data will be shared with additional regulatory authorities in accordance with local requirements around the world.
“Patient safety remains a top priority for Takeda,” said Perez. “Throughout a product’s lifecycle we continue to monitor and conduct additional research to further our knowledge. This milestone is an important example of Takeda’s commitment to conducting further research and sharing the outcomes with regulatory agencies, physicians, and others.”
The retrospective cohort study of the European Union (EU) medical record databases was conducted using six medical records databases across four countries, including Finland, The Netherlands, Sweden, and the United Kingdom. Type 2 diabetes patients treated with pioglitazone were matched equally with patients with similar characteristics who were not treated with pioglitazone. Patients were matched based on diabetes duration, diabetes complications, cardiovascular complications, and previous antidiabetic drug use. This study design was developed to minimize treatment allocation bias, an issue seen in some previous epidemiological studies of pioglitazone.
Pioglitazone is a thiazolidinedione for the treatment of type 2 diabetes in adults as an adjunct to diet and exercise.
Unlike many oral antidiabetic drugs, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPAR?). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR? nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Therefore, pioglitazone is a medication that depends on the presence of insulin for its mechanism of action, and it decreases insulin resistance in muscle and the liver, resulting in increased insulin-dependent glucose disposal as well as decreased hepatic glucose output.
Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with sulfonylurea, metformin, or insulin.