الفهرس 
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Abstract
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.
Results: By transient elastography, 12 (20%) T1DM patients with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher) and 48 (80%) patients had steatosis stage S2 or higher. Baseline MMP-14 levels were significantly higher among all T1DM patients with NASH compared with healthy controls; median (IQR), 194.05 (138.5 – 336.7) versus 46.70 (41.64 – 52.23) (p<0.001). Baseline MMP-14 was positively correlated to insulin dose (p = 0.016), alanine transferase (ALT), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p<0.001 for all). Both vildagliptin and control groups were well-matched as regards baseline clinical, laboratory and radiological characteristics (p<0.05). After six months, T1DM patients with NASH on vildagliptin therapy had significantly lower systolic and diastolic blood pressure as well as insulin dose (p<0.001). Blood glucose levels, HbA1c, liver enzymes, triglycerides, total cholesterol, hepatic steatosis index and TyG index as well as MMP-14 were significantly lower after vildagliptin therapy (p<0.001). CIMT, liver stiffness and CAP were also significantly decreased post-therapy compared with baseline levels and compared with the control group (p<0.001). Vildagliptin was safe and well-tolerated without reported side effects.
Conclusions: Administration of DDP-4 inhibitor, vildagliptin, in a once daily dose of 50 mg orally for six months as an add-on therapy for adolescents with T1DM and NASH improved glycemic control, dyslipidemia, MMP-14 levels and decreased CIMT; hence, reducing subclinical atherosclerosis. Vildagliptin prevented the progression of NASH as evidenced by decreased liver stiffness and CAP levels.