Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial

Abstract

Background & aims: Uncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin vs. the efficacy of a placebo 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 prediabetes or early diabetes randomized to sitagliptin orally 100mg/day or placebo for 24weeks. Primary outcome was liver fat change measured by MRI-PDFF in colocalized 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 magnetic resonance 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 alanine aminotransferase, 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 r(2)=0.96 to r(2)=0.99 (p<0.0001), demonstrating the strong internal validity of the findings. 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.

Lay summary: In a randomized, double-blind, placebo-controlled study, the anti-diabetic drug sitagliptin was no more effective than placebo for improving liver fat and liver fibrosis in patients with non-alcoholic fatty liver disease. This study demonstrates that non-invasive magnetic resonance imaging techniques, including magnetic resonance imaging-proton density-fat fraction and magnetic resonance elastography, can be used to assess treatment response in non-alcoholic fatty liver disease clinical trials.

Keywords: Biomarker; Fat mapping; Fibrosis; Hepatic steatosis; Imaging; Lipid lowering therapy; MRI-proton-density-fat-fraction (PDFF); Magnetic resonance elastography; NAFLD; Non-alcoholic steatohepatitis; Non-invasive assessment; Sitagliptin.

Figure 1

Percentage change in liver fat relative to baseline as assessed by MRI-PDFF and stratified by treatment group. The sitagliptin group is on the left in red and the placebo group is on the right in blue. There was no significant difference in the change in liver fat between the two groups (p=0.585).

Figure 2

MRI-PDFF fat mapping throughout the whole liver of a representative study patient. The upper panels show MRI-PDFF measurements in the superior liver (regions 1, 2, 4a, 7, and 8) and the lower panels show MRI-PDFF in the inferior liver (regions 3, 4b, 5, and 6). The left column shows MRI-PDFF values at week 0 and the right column shows MRI-PDFF values at week 24. The patient's calculated liver fat fraction (averaged from the nine liver segments) decreased from 55.3% (Week 0) to 38.1% (Week 24).

Figure 3

MRE (60 Hz) elastograms depicting of hepatic stiffness throughout the entire liver of a representative patient at week 0 (left panel) and week 24 (right panel).