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This review aimed to address effects of sustained-release versus immediate-release glipizide on glucose control, insulin secretion, and compliance. We searched Medline, EMBASE, the Cochrane Library, and Chinese Biomedical database from inceptions to May 31, 2011, screened reference lists of relevant studies, and contacted pharmaceutical companies. Randomized trials and cohort studies were included. We pooled data using a random-effect model. Nineteen trials involving a total of 1440 patients and 2 retrospective cohort studies with a total of 13452 patients were included. Trials were of low quality. No trials reported patient important outcomes. The reduction of fasting plasma glucose from the baseline appeared larger for sustained-release than for immediate-release glipizide (mean difference −0.26 mmol/L, 95% CI −0.52 to −0.01). The reduction was not significantly different between the two drugs for HbA1c (−0.03%, −0.20% to 0.14%) or 2-hour postprandial plasma glucose (−0.21 mmol/L, −0.96 to 0.55). Sustained-release glipizide appeared to reduce insulin secretion from the baseline, whereas the immediate-release formulation increased the secretion (fasting insulin: −1.04 vs. 0.88 μIU/ml; 2-hour postprandial insulin: −2.94 vs. 0.24 μIU/ml). Patients administering sustained-release glipizide had less hypoglycemia (Peto odds ratio 0.21, 95% CI 0.08 to 0.52) and lower missed dosing (Peto odds ratio 11. 42, 95% CI 6.47 to 20.18). The cohort studies showed patient compliance results consistent with those of the trials. Sustained-release glipizide appears to achieve similar glucose control with decreased insulin secretion, fewer hypoglycemic episodes, and higher patient compliance than immediate-release glipizide. However, these findings are inconclusive due to inadequate study quality, short follow up, and unavailability of patient important outcomes.