A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus

Background: Pioglitazone is a member of a recently developed class of gluco se-lowering agents, the thiazolidinediones. used in the treatment of type 2 diabetes mellitus. In the United States, it is approved for use both as mo notherapy and in combination with metformin. a sulfonylurea, or insulin: in Europe, it is approved for use in combination with metformin or a sulfonyl urea but not insulin. Objective: This article presents a systematic review of the published liter ature on the effectiveness of pioglitazone in the treatment of type 2 diabe tes, both as monotherapy and in combination with other antidiabetic agents. Methods: The peer-reviewed English- and foreign-language literature was sea rched using MEDLINE. PubMED, EMBASE, Science Citation Index, the Cochrane D atabase of Systematic Reviews. the Cochrane Controlled Trials Register, the UK National Health Service Centre for Reviews and Dissemination databases, and the Office of Health Economics Health Economic Evaluations Database. S earches were not limited to specific publication types, study designs, date s, or languages. The latest search was performed in March 2001. For a trial to be included in the review, at least 1 outcome measure had to involve th e effects of pioglitazone on glycemic control or cardiovascular risk factor s, or its side effects. Because of the heterogeneity of studies, no formal meta-analysis was performed. Results: Eleven studies met the inclusion criteria. 6 involving pioglitazon e monotherapy and 5 involving combination therapy. Full reports were availa ble for only 6 of the 11 studies. No studies directly compared pioglitazone with other antidiabetic drugs. Both as monotherapy and in combination ther apy, pioglitazone produced decreases in blood glucose levels (up to 95 mg/d L) and glycosylated hemoglobin (up to 2.6%). At doses of greater than or eq ual to 30 mg/d. pioglitazone was associated with reductions in triglyceride levels (similar to 30-70 mg/dL) and increases in high-density lipoprotein cholesterol (HDL-C) levels (similar to4-5 mg/dL). Pioglitazone treatment wa s associated with significant weight gain (up to 4 kg over 16 weeks). Adver se effects included mild edema (in up to 11.7% of patients) and a clinicall y nonsignificant decrease in hemoglobin concentrations. Abnormal results on liver function testing were no more common in treated patients than in con trol groups. Conclusions: Pioglitazone has been shown to reduce blood glucose levels in patients with type 2 diabetes. Although the observed decreases in triglycer ide levels and increases in HDL-C levels could be expected to lead to a red uction in cardiovascular risk, the effects of weight gain may counteract th is benefit. The evidence suggests that the preferred role for pioglitazone may be as an adjunct to metformin or a sulfonylurea in patients whose condi tion is not well controlled with monotherapy and for whom a metformin-sulfo nylurea combination is contraindicated. There is a need for large-scale, lo ng-term studies comparing the effectiveness of combination therapy that inc ludes pioglitazone with that of other combinations of antidiabetic drugs.