Tolerability Outcomes of a Multicenter, Observational, Open-Label, Drug-Surveillance Study in Patients with Type 2 Diabetes Mellitus Treated with Pioglitazone for 2 Years

Abstract Objective: Pioglitazone (PIO), a thiazolidinedione (TZD), is reported to be highly effective in the treatment of type 2 diabetes mellitus, but is associated with edema, heart failure, and weight gain. This study documented long-term tolerability outcomes of patients taking pioglitazone and assessed how troublesome these adverse events were for the patients. Methods: This was a prospective, multicenter, observational, open-label, drug-surveillance study that followed patients for 2 years. Patients were already taking or received prescriptions for PIO (PIO group) or a non-TZD (comparator group). Data on glycosylated hemoglobin, fasting plasma glucose, and physician-assessed hypoglycemia were gathered every 4 to 6 months. Patients answered a questionnaire about edema, shortness of breath, and weight gain and were asked to self-assess how troublesome these events were. Peripheral edema and weight gain were selected for post hoc analysis. The Edema Severity scale (ranging from no edema to very deep edema causing gross distortion to amputation) was used to evaluate peripheral edema. Physicians determined the relationship between treatment and serious adverse events. Results: Investigators at 176 sites across Canada enrolled 1871 patients (53 patients in the comparator group were later excluded for receiving PIO). Data from 1527 PIO patients and 291 comparator patients were analyzed (mean age: 59.5 years PIO, 61.6 years comparator; males: 58.0% PIO, 59.8% comparator; white: 77.9% PIO, 81.4% comparator; mean weight: 87.2 kg PIO, 86.1 kg comparator). Median dose of PIO was 30 mg/d. Edema and weight gain were the only adverse events for which statistical models were fitted. Results at 2 years were as follows: peripheral edema—p25.1% (383/1527) of patients in the PIO group, 16.5% (48/291) in the comparator group (adjusted odds ratio [OR]: 1.92 [95% CI, 1.32–2.79]); pulmonary edema—1.3% (20/1527) PIO, 0.7% (2/291) comparator; heart failure—2.4% (37/1527) PIO, 1.4% (4/291) comparator; weight gain—49.6% (757/1527) PIO, 36.8% (107/291) comparator; mean weight gain—2.19 kg PIO (n = 1344), 0.34 kg comparator (n = 251) (adjusted OR: 1.70 [95% CI, 1.29–2.22]). Patient self-assessment at 2 years revealed: edema—rated very or extremely troublesome by 11.2% (29/258) PIO, 13.8% (5/36) comparator; shortness of breath on exertion—15.1% (174/1153) PIO, 16.2% (32/198) comparator (rated very or extremely troublesome by 8.6% [15/174] PIO, 21.9% [7/32] comparator); shortness of breath lying down and at night occurred less frequently (1.8%–4.5% in both groups) than shortness of breath on exertion; and weight gain—rated very or extremely troublesome by 4.8% (22/455) PIO, 2.9% (2/70) comparator. Deaths occurred in ∼2% of patients in each group (37/1527 PIO, 6/344 comparator); none of the deaths in the PIO group were judged by the investigators to be related to the study drug. Conclusions: After 2 years of treatment, the incidences of heart failure (2.4%) and pulmonary edema (1.3%) in the patients who received PIO in this observational study were low and consistent with published literature. In this study, patients in the PIO group experienced more peripheral edema (adjusted OR, 1.92) and greater weight gain (adjusted OR, 1.70) than did patients in the non-TZD (comparator) group. The subjective assessment of the troublesome nature of these adverse events on these patients taking PIO was low