IntroductionWe aim to evaluate the efficacy and safety of pioglitazone/metformin fixed-dose combination (FDC) versus uptitrated metformin in patients with type 2 diabetes mellitus (T2DM) without adequate glycemic control.MethodsA total of 304 patients were recruited from 15 hospitals in China and randomly assigned (1:1) to the test group (pioglitazone/metformin FDC, 15/500 mg) or the control group (uptitrated metformin, 2000-2500 mg/day). The primary endpoint was the proportion of patients with glycated hemoglobin A1c (HbA1c) <= 6.5% and <= 7.0% at week 16. The secondary outcomes included the change from baseline in glucose, serum lipids, and liver function. Full analysis set (FAS) and per-protocol set (PPS) were used for analyses.ResultsIn the test group, 103 (69.59%) patients reached HbA1c <= 7.0% (FAS, P = 0.009), with 68 (45.95%) patients achieved HbA1c <= 6.5 (FAS, P = 0.043). More reduction in HbA1c, homeostatic model assessment for insulin resistance, and diastolic pressure was found. Bodyweight, body mass index, and high-density lipoprotein cholesterol increased markedly. The changes of triglycerides, alanine transaminase, aspartate aminotransferase, and high-sensitivity C-reactive protein decreased noticeably. There were no significant differences in rates of adverse events between the two groups.ConclusionsPioglitazone/metformin FDC was superior to uptitrated metformin among patients with T2DM without adequate glycemic control.Trial Registration NumberThis trial is registered with the Chinese Clinical Trial Registry (ChiCTR1900028606).