OBJECTIVES: To address effects of extended-release versus immediate-release glipizide on glucose control, insulin secretion, and compliance. METHODS: We included parallel randomized trials and cohort studies(only for compliance assessment) comparing extended-release versus immediate-release glipizide for type 2 diabetes. We searched Medline, EMBASE, the Cochrane Library, and Chinese Biomedical database, screened reference lists, and contacted pharmaceutical company. We pooled data using random-effect model and explored heterogeneity by pre-specified hypotheses. RESULTS: Sixteen trials involving 1062 patients and 2 retrospective cohort studies of 13452 patients were included. Trials are of inadequate quality. No trials reported patient-important outcomes. The reduction of fasting plasma glucose from the baseline appeared larger in extended-release than immediate-release glipizide (mean difference -0.30 mmol/L, 95% CI -0.57 to -0.03). The reduction was not significant different between two drugs in HbA1c (-0.03%, -0.20% to 0.15%) and 2-hour postprandial plasma glucose (-0.28 mmol/L, -1.12 to 0.55). Extended-release glipizide appeared to reduce insulin secretion from the baseline, whereas immediate-release formulation increased the secretion (fasting insulin: -0.86 vs. 0.28 μIU/ml; 2-hour postprandial insulin: -2.94 vs. 0.24 μIU/ml). Patients administering extended-release glipizide had less hypoglycemia (Peto odds ratio 0.26, 95% CI 0.08 to 0.81) and lower missed dosing (Peto odds ratio 10.24, 95%CI 5.22 to 20.08). The cohort studies showed results in compliance consistent with trials. CONCLUSIONS: The two drugs may have comparable effects on glucose control. Extended-release glipizide might achieve glucose control with decreased insulin secretion, and fewer hypoglycemic episodes. The findings are inconclusive due to inadequate study quality, short follow up, and unavailability of patient important outcomes.