Background & Aims Uncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase (ALT) and liver histology in nonalcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin versus placebo's efficacy in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF). Methods This randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with pre-diabetes or early diabetes randomized to sitagliptin orally 100 mg/day or placebo for 24 weeks. Primary outcome was liver fat change measured by MRI-PDFF in co-localized regions of interest within each of nine liver segments. Additional advanced assessments included MR spectroscopy (MRS) for internal validation of MRI-PDFF's accuracy, and MR elastography (MRE) and FIBROSpect® II to assess liver fibrosis. Results Sitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF (mean difference between sitagliptin and placebo arms: −1.3%, p=0.4). Compared to baseline, there were no significant differences in end-of-treatment MRI-PDFF for sitagliptin (18.1% to 16.9%, p=0.27) or placebo (16.6% to 14.0%, p=0.07). The groups had no significant differences for changes in ALT, aspartate aminotransferase, low-density lipoprotein, homeostatic model assessment insulin resistance, and MRE-derived liver stiffness. In both groups at baseline and post-treatment, MRI-PDFF and MRS showed robust correlation coefficients ranging from r2=0.96 to r2=0.99 (p<0.0001), demonstrating the findings’ strong internal validity. FIBROSpect® II showed no changes in the sitagliptin group but was significantly increased in the placebo group (p=0.03). Conclusions Sitagliptin was safe but not better than placebo in reducing liver fat in prediabetic or diabetic patients with NAFLD.

No abstract