BACKGROUND/OBJECTIVES: The results of phase 2 and 3 clinical trials, which justify decisions regarding marketing approval for new drugs, are used for comparison of drugs in the post-marketing phase. A number of meta-analyses of approved antidiabetics have been performed, but the heterogeneity of trials has not been fully examined. The aim of this study was to explore factors that may influence baseline HbA1c in trial samples and treatment outcomes (i.e. HbA1c reductions and effect sizes), with the goal of providing unbiased and fair retrospective comparisons between different antidiabetics. METHOD: We conducted three meta-regression analyses using 78 randomized or non-randomized comparative phase 2 or 3 trials of 24 approved antidiabetics in Japan, conducted from 1987 to 2012. RESULTS: Baseline HbA1c of each arm was higher in phase 2 trials, trials with a greater number of subjects, trials with a lower proportion of male subjects, trials of combination therapy, or trials with longer subject disease duration. Entry criteria were different among drug classes and caused variations in baseline HbA1c. HbA1c reductions were larger in non-randomized trials, trials with a shorter treatment period, or trials with a lower proportion of male subjects. Effect sizes were larger in phase 2 trials, or trials of combination therapy. Larger effect sizes were observed in drugs with later market entry for alpha-glucosidase inhibitors and glinides. CONCLUSION: Baseline HbA1c, an important characteristic of subjects enrolled in trials of antidiabetics, differed significantly across trials. Differences in features of study subjects were caused by explicit stipulations in eligibility criteria of HbA1c and also by other conditions (e.g. trial design, regulatory guidance, treatment guideline) and/or interventions of investigators and pharmaceutical companies that were specific to drugs and trials. Healthcare professionals should carefully consider these heterogeneities in trials used for marketing approval review when making a retrospective comparison to select the best treatment option for patients.