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

Non-Alcoholic Fatty Liver Disease (NAFLD) is characterised by excessive hepatic fat accumulation (steatosis) in the absence of significant alcohol consumption, occurring with or without hepatic inflammation and fibrosis. Steatosis may progress to a more advanced form of the disease, non-alcoholic steatohepatitis (NASH), which can precipitate to advanced fibrosis, leading to cirrhosis and/or hepatocellular carcinoma (HCC) and can result in the need for liver transplantation or death as well as cardiovascular morbidity and mortality.

It was demonstrated that 53.1% of patients with type 1 diabetes mellitus (T1DM) had histological evidence of steatosis and 20.4% met the histological criteria for NASH. Patients with T1DM onset at an earlier age have an increased incidence of cardiovascular disease (CVD) events and increased CVD mortality.

Matrix metalloproteinases (MMPs) are found to have multiple biological activities including diseases like angiogenesis and cirrhosis. They are expressed in atherosclerotic plaques, promoting vascular remodelling, contributing to atherothrombosis, and plaque disruption. MMP-14 is involved in the development of atherosclerosis and CVD. MMP-14 is also noticed to be expressed in highly invasive hepatocellular carcinoma and expressed in liver fibrosis.

Carotid ultrasound is easily available, a cost effective and non-invasive tool for evaluating carotid artery intima-media thickness (CIMT) to assess CVD as carotid atherosclerosis. CIMT was higher for individuals with NASH than for those with simple steatosis.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of oral diabetes drugs with a glucose-lowering effect. DPP-4 inhibitors exert their glucose-lowering effects primarily by blocking the enzyme DPP-4, which is involved in the degradation of incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors are widely used for the treatment of type 2 diabetes since 2006. Although DPP-4 inhibitors may be beneficial for T1DM, existing studies do not strongly support these positive effects in clinical practice.

Vildagliptin, an oral antihyperglycemic agent that competitively inhibits DPP-4. A few trials have demonstrated that vildagliptin has an effect on NAFLD. In 44 patients with T2DM and hepatic steatosis, vildagliptin treatment for 6 months decreased liver enzymes and intrahepatic triglyceride content, as assessed by MRI. In a study conducted in Pakistan, vildagliptin for 12 weeks improved liver enzymes and steatosis grading, as assessed by ultrasound.

Aim: To assess the effect of Dipeptidyl peptidase-4 (DPP-4) inhibitors supplementation as an add on therapy on NASH in adolescents with type 1 diabetes mellitus as well as its effect on glycemic control, lipid profile, MMP-14 levels and CIMT as a marker for subclinical atherosclerosis.

Inclusion criteria

• Adolescents diagnosed with type 1 diabetes according to ISPAD guidelines .
• Patients aged 12-18 years with NASH.
• Patients on regular visit to clinic.
• Patients on regular insulin therapy.

Exclusion criteria

• Patients with renal impairment due to cause other than diabetes.
• Patients with hypertension.
• Hyper- or hypo-thyroidism.
• Hepatitis virus infection (B or C) or any evidence of infection.
• History of liver disease other than NASH such as cholestasis and Wilson disease.
• Patients with autoimmune hepatitis.
• Recurrent diabetic ketoacidosis (more than 2 episodes in the previous 12 months)
• Patients were already on anti-hypertensive drugs or any antioxidant therapy such as vitamin supplements.
• Taking any vitamins or food supplements one month before study.
• Participation in a previous investigational drug study within 3 months preceding screening.