Fatty Liver Index and Differential Glycemic Responses to Ipragliflozin Versus Sitagliptin Over 52 Weeks: An Exploratory Post Hoc Analysis of the Niigata Ipragliflozin and Sitagliptin With Metformin (N‐ ISM ) Study

AIMS: To explore whether fatty liver index (FLI) stratification is associated with differential glycemic responses to sodium-glucose co-transporter-2 (SGLT2) versus dipeptidyl peptidase-4 (DPP-4) inhibitors as second-line therapy in type 2 diabetes without established atherosclerotic cardiovascular disease (ASCVD). MATERIALS AND METHODS: In this exploratory post hoc analysis of a previous 52-week randomised trial of ipragliflozin versus sitagliptin added to metformin in Japanese patients with type 2 diabetes, 91 patients were stratified by median FLI into low (< 51; n = 44) and high (≥ 51; n = 47) groups. The outcome was the 52-week change in glycated haemoglobin A1c (HbA1c). The treatment-by-FLI interaction was tested by baseline-HbA1c-adjusted analysis of covariance; FLI was also modelled continuously and parallel analyses used body mass index (BMI) and alanine aminotransferase (ALT). RESULTS: The baseline-HbA1c-adjusted treatment-by-FLI interaction was significant at 52 weeks (p = 0.013): ipragliflozin was associated with a greater HbA1c reduction than sitagliptin in the high FLI group (-0.41%, 95% confidence interval -0.77, -0.06; p = 0.023), with no significant difference in the low FLI group (+0.24%; p = 0.194). The interaction was also significant with FLI modelled continuously (p = 0.013) and in mixed-model and multiple-imputation sensitivity analyses (p = 0.010 and 0.003). BMI and ALT showed similar significant interactions (p = 0.028 and 0.032), favouring ipragliflozin in the high-value subgroup. FLI provided the clearest signal but was not the only effect modifier. CONCLUSIONS: FLI-based stratification was associated with differential glycemic responses to ipragliflozin versus sitagliptin. These findings are hypothesis-generating, given the small, complete-case sample and the sample-derived cut-off. Prospective studies are warranted before FLI can inform antidiabetic drug selection.