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
Masaru Kitazawa, Takashi Katagiri, Hiromi Suzuki, Mayuko Yamada, Mariko Hatta, Hiroki Takizawa, Koshiro Murai, Takaaki Sato, Yasuhiro Matsubayashi, Takaho Yamada, Shiro Tanaka, Hirohito Sone ABSTRACT
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.