Jeffrey Cui1, Len Philo2, Phirum Nguyen1, Heather Hofflich3, Carolyn Hernandez1, Ricki Bettencourt4, Lisa Richards5, Joanie Salotti5, Archana Bhatt1, Jonathan Hooker6, William Haufe6, Catherine Hooker6, David A Brenner7, Claude B Sirlin6, Rohit Loomba8. 1. NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, United States. 2. Naval Medical Center San Diego, San Diego, CA, United States. 3. Division of General Internal Medicine, Department of Medicine, University of California at San Diego, La Jolla, CA, United States. 4. NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, United States; Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA, United States. 5. NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, United States; Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, United States. 6. Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, United States. 7. Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, United States. 8. NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, United States; Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA, United States; Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, United States; San Diego Integrated NAFLD Research Consortium (SINC), United States. Electronic address: roloomba@ucsd.edu.
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 tositagliptin 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.
RCT Entities:
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 NAFLDpatients 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 diabeticpatients 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.
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