Recent studies suggested that reduced hepatic insulin clearance (HIC) after mixed meal ingestion was associated with amelioration of postprandial hyperglycemia by supplying sufficient insulin throughout the body and that HIC might be regulated by increases in serum incretins. Despite broad use in practice, the effects of DPP-4i on HIC are little known. Thus, we aimed to clarify the effect of a DPP-4i, anagliptin (ANA), on HIC in type 2 diabetes mellitus (T2DM) patients. Analyzed were 977 T2DM patients (72% male, mean age: 58 y, HbA1c: 8.0%, BMI: 25 kg/m2, HOMA-β: 26.4, HOMA-IR: 2.7) on diet and exercise therapy who received ANA or a placebo as initial monotherapy and add-on therapy in five phase 2 and 3 randomized controlled trials (ANA: 706, placebo: 271). Postprandial HIC (P-HIC) from the meal tolerance test was calculated as the ratio: C-peptide AUC0-120min to insulin AUC0-120min. Differences in variables between ANA and placebo were analyzed by an ANCOVA model, with the treatment group as a fixed effect and the baseline value as a covariate. Multivariate analysis was done to clarify possible independent factors associated with HbA1c. After taking ANA for 12 weeks, HbA1c was significantly reduced (-0.65%, p<0.01 vs. baseline) and C-peptide AUC0-120min and insulin AUC0-120min were significantly increased (+0.25 ng·h/mL and +3.36 µU·h/mL, p<0.001 vs. baseline). Conversely, in the ANA group, P-HIC levels decreased significantly from baseline (least squares [LS] mean: -0.0ng·h/mL / μU·h/mL, p<0.001). Furthermore, decreased P-HIC by ANA negatively correlated with P-HIC levels at baseline (r=-0.32, p<0.001). Multivariate analysis showed that higher baseline P-HIC levels produced greater reductions in HbA1c. Our results indicated that ANA reduced P-HIC and that the reduction might contribute to improvements in postprandial hyperglycemia. DPP-4i may improve hyperglycemia partially by the regulation of P-HIC. Disclosure Y. Matsubayashi: None. T. Abe: None. S. Muragishi: Employee; Self; Kowa Pharmaceutical Co., Ltd. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd. K. Furusawa: Employee; Self; Sanwakagakukenkyusho Co.,LTD. T. Yamada: None. K. Fujihara: None. S. Tanaka: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..