Pharmacotherapy of diabetes and cancer risk

Abstract

Lines of reports published recently analyzing the association between pioglitazone use and bladder cancer and the subsequent actions taken by regional regulatory agencies and international diabetes organizations rekindle a longrunning controversy over diabetes treatment and cancer risk. An interim report of an ongoing cohort study, one of the representative papers published in the April issue of Diabetes Care, examined the association between pioglitazone therapy and the risk of bladder cancer in 193,099 diabetic patients in the Kaiser Permanente Northern California (KPNC) Diabetes Registry between 1997 and 2002. The patients were C40 years of age and the group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among those who did not use pioglitazone. Overall, the short-term use of pioglitazone was not associated with a risk of bladder cancer [HR 1.2 (95% CI 0.9–1.5)], but its use for more than 2 years was weakly associated with an increased risk (OR 1.4, 95% CI 1.03–2.0) [1]. Surprisingly, France suspended the use of pioglitazone at the beginning of June 2011 and Germany has recommended that pioglitazone should not be started in new patients, based on a recently conducted retrospective cohort study by the French National Health Insurance Agency (Caisse National d’Assurance Maladie) which followed diabetic patients taking antidiabetic medicines between 2006 and 2009. The US Food and Drug Administration (FDA) soon issued a Drug Safety Communication on June 15, 2011 (updated on August 5) regarding the ongoing safety review of pioglitazone and the increased risk of bladder cancer [2]. Based on a review of the data from the KPNC epidemiological study, FDA stated that the long-term use of pioglitazone ([1 year) may be associated with an increased risk of bladder cancer. The FDA acknowledged that the finding was still of nominal statistical significance, and is advising health-care professionals not to use it in patients with active bladder cancer and to prescribe the drug with caution for patients with a prior history of bladder cancer, weighing the benefits of blood glucose control against the unknown risks of cancer recurrence. One month after the FDA’s communication, the European Medicines Agency (EMA) issued a recommendation and the EMA’s Committee for Medicinal Products for Human Use concluded that the benefits of pioglitzone outweigh its risks in a limited population of type 2 diabetes patients, despite the small risk of bladder cancer with this drug. The Committee has made recommendations to reduce the risk of bladder cancer in patients taking the medicines [3]. The series of events mentioned above reminded us of a recent outbreak of controversy related to a possible association between the long-acting insulin analog glargine and an increased risk of cancer. On June 2009, the diabetes community was suddenly shaken with a story relevant to patients with diabetes treated with insulin, when four registry studies that analyzed the association of insulin glargine with the risk of cancer were published in Diabetologia. The American Diabetes Association (ADA) immediately released a statement noting that ‘‘findings from these research papers are conflicting and inconclusive, and the ADA cautions against over-reaction and advises patients using insulin not to stop taking it until more information is available.’’ Regulatory agencies such as the EMA and FDA, international organizations such as the International Diabetes Federation (IDF), K. Kaku (&) M. Hashiramoto Division of Diabetes, Metabolism, and Endocrinology, Kawasaki Medical School, Kurashiki, Japan e-mail: kka@med.kawasaki-m.ac.jp