Effect of Dipeptidyl Peptidase- 4 Inhibitors on Non-Alcoholic Steatohepatitis and Type 1 Diabetes

Summary

Background: Non-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD) that can precipitate to advanced fibrosis and leads to cardiovascular morbidity and mortality. Many patients with type 1 diabetes mellitus (T1DM) had histological evidence of steatosis and met the histological criteria for NASH. Matrix metalloproteinase-14 (MMP-14) is a type 1 transmembrane proteinase expressed in liver fibrosis and is involved in the development of atherosclerosis and cardiovascular disease. Hepatic dipeptidyl peptidase-4 (DPP-4) expression in NAFLD may be directly associated with hepatic lipogenesis and liver injury. Some studies showed the beneficial effect of dipeptidyl peptidase-4 (DDP-4) inhibitors in NAFLD/NASH for their role in improving hepatic glucose metabolism. Vildagliptin, a DPP-4 inhibitor, could be promising therapeutic agents for NAFLD/NASH. To the best of our knowledge, no previous study assessed the role of DPP-4 inhibitors in adolescent patients with T1DM and NASH. Objectives: This randomized-controlled clinical trial assessed the impact of the oral DPP-4 inhibitor, vildagliptin, as an add-on therapy on NASH in adolescents with T1DM as well as its effect on glycemic control, lipid profile, MMP-14 levels and CIMT as a marker for subclinical atherosclerosis. Methods: This study included 60 adolescents with T1DM and NASH with a mean age 15.6 ± 2.08 years and disease duration ≥ 5 years. Forty age- and sex-matched healthy subjects with a mean age 14.9 ± 3.2 years were enrolled as healthy controls to compare MMP-14 levels. T1DM patients were randomly assigned to receive oral vildagliptin (50 mg daily) with lunch meal for six months or not. Fasting and 2 hours post-prandial blood glucose levels, HbA1c, liver function tests, fasting lipid profile, hepatic steatosis index and triglyceride glucose (TyG) index were assessed. MMP-14 levels were measured by enzyme-linked immunosorbent assay among all patients and healthy controls. CIMT was assessed using Doppler ultrasound and transient elastography with controlled attenuation parameter (CAP) was performed to assess liver stiffness and steatosis stage.

Timeline

Start

2022-11-10

Primary completion

2023-12-01

Completion

2024-01-15

Publications

• Results Temple JL, Cordero P, Li J, Nguyen V, Oben JA. A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence. Int J Mol Sci. 2016 Jun 15;17(6):947. doi: 10.3390/ijms17060947.
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• Results Geervliet E, Moreno S, Baiamonte L, Booijink R, Boye S, Wang P, Voit B, Lederer A, Appelhans D, Bansal R. Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis. J Control Release. 2021 Apr 10;332:594-607. doi: 10.1016/j.jconrel.2021.03.016. Epub 2021 Mar 15.
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• Results Wang Q, Long M, Qu H, Shen R, Zhang R, Xu J, Xiong X, Wang H, Zheng H. DPP-4 Inhibitors as Treatments for Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Diabetes Res. 2018 Jan 8;2018:5308582. doi: 10.1155/2018/5308582. eCollection 2018.
• Results Hussain M, Majeed Babar MZ, Hussain MS, Akhtar L. Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease. Pak J Med Sci. 2016 Nov-Dec;32(6):1396-1401. doi: 10.12669/pjms.326.11133.

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