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

March 30, 2024 updated by: Nancy Samir Elbarbary, Ain Shams University

Effect of Dipeptidyl Peptidase- 4 Inhibitors Supplementation on Non-Alcoholic Steatohepatitis in Adolescents With Type 1 Diabetes Mellitus

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
60

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Cairo, Egypt, 11361
        • Nancy Elbarbary

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Dipeptidyl peptidase-4 inhibitors supplementation
Intervention group receiving Dipeptidyl peptidase-4 inhibitors supplementation
Drug: Dipeptidyl peptidase 4 (DPP-4) inhibitor
Intervention group received Dipeptidyl peptidase-4 (DPP-4) inhibitors supplementation in a dose of 50 mg with main meal for 6 months.
Other Names:
  • Dipeptidyl peptidase-4 inhibitors
No Intervention: Control group
Control group not receiving Dipeptidyl peptidase-4 inhibitors supplementation

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of participants with treatment-related effect on NASH status in adolescents with type 1 diabetes mellitus
Time Frame: 6 months
Effect of DPP-4 inhibitors on NASH in adolescents with type 1 diabetes mellitus measured by Doppler ultrasound and transient elastography with controlled attenuation parameter (CAP) to assess liver stiffness and steatosis stage.
6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of participants with treatment-related Matrix metalloproteinase-14 (MMP-14) level change
Time Frame: 6 months
Effect of (DPP-4) inhibitors supplementation on Matrix metalloproteinase-14 (MMP-14, (ng/mL) level
6 months
Number of participants with treatment-related Glycemic control (HbA1c%) level change
Time Frame: 6 months
Effect of Dipeptidyl peptidase-4 (DPP-4) inhibitors on glycemic control (HbA1c%)
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Ain Shams University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 10, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 15, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 25, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 30, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 5, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 5, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 30, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • Ain Shams University25032024

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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