Vigabatrin and Insulin Sensitivity

The Effect of Vigabatrin on Insulin Sensitivity

Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity and is associated with an increased risk of developing type 2 diabetes. The hallmark feature of NAFLD is an increase in intrahepatic triglyceride (IHTG) content. Data from studies conducted in rodent models suggest increased IHTG content can alter hepatic vagal afferent nerve (HVAN) activity. In rodent models of obesity and NAFLD, HVAN activity is reduced leading to impaired insulin sensitivity and glucose control. The reduction in HVAN activity is likely due to increased hepatic release of GABA, an inhibitory neurotransmitter, attributable to increased expression of GABA-Transaminase (GABA-T). Pharmacological inhibition of GABA-T in obese mice by treatment with vigabatrin, an irreversible inhibitor of GABA-T improves glucose tolerance and reduces hyperinsulinemia, hyperglycemia, and insulin resistance. It is not known if vigabatrin can also improve metabolic function in people. We propose to conduct a 3-week, single-arm trial to assess the effect size of treatment with vigabatrin on the following specific aims with the larger goal of determining whether a large, randomized controlled trial investigating the effect of vigabatrin is warranted.

Study Overview

• Status: Completed
• Conditions: Obesity; NAFLD
• Intervention / Treatment: Drug: Vigabatrin

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age 25-60 years old
• BMI 30.0-49.9 kg/m2
• IHTG content ≥5.6
• Homeostatic Model of Insulin Resistance (HOMA-IR) Score>2.5.

Exclusion Criteria:

• previous bariatric surgery
• structured exercise ≥250 min per week (e.g., brisk walking)
• unstable weight (>4% change during the last 2 months before entering the study)
• significant organ system dysfunction (e.g., diabetes, severe pulmonary, kidney or cardiovascular disease)
• cancer
• polycystic ovary syndrome
• major psychiatric illness (including suicidal ideation or previous suicide attempts)
• conditions that render subject unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders)
• regular use of tobacco products
• excessive consumption of alcohol (≥3 drinks/day for men and ≥2 drinks/day for women)
• use of medications that are known to affect the study outcome measures or increase the risk of study procedures and that cannot be temporarily discontinued for this study
• pre-existing visual field deficits; or those at high risk of irreversible vision loss, including patients with retinopathy or glaucoma
• pregnant or lactating women
• conditions that render subject unable to complete all testing procedures (e.g. aversion to needles, metal implants that prevent magnetic resonance imaging
• persons who are unable or unwilling to follow the study protocol
• persons who are not able to grant voluntary informed consent
• patients at risk for severe anemia (hemoglobin < 14 g/dL (men) or <12.0 g/dL (women) and/or hematocrit <40% in men or < 37% in women)
• patients with history of lower limb edema (risk of heart failure)
• patients with mild or more severe renal insufficiency (CrCl <100 mL/min (men) or <80 mL/min (women))
• patients with existing peripheral neuropathy
• women who have active menstrual cycles but are not using birth control (acceptable contraception includes barrier/hormonal/IUD)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vigabatrin	Drug: Vigabatrin; Vigabatrin - Pill, 500 mg twice daily for 7 days (days 0-6), 1000 mg twice daily for 7 days (days 7-13), 1500 mg twice daily for 10 days (days 14-23), 1000 mg twice daily for 7 days (days 24-30), 500 mg twice daily for 7 days (days 31-37) and will discontinue treatment on day 38.; Other Names: sabril

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity	Measured by hyperglycemic euglycemic clamp	3 weeks after initiation of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oral Glucose Tolerance	Measured by 75 gram oral glucose tolerance test	3 weeks after initiation of treatment
Oral Glucose Insulin Sensitivity	Insulin sensitivity based on oral glucose tolerance. Values are calculated using glucose and insulin from a 3-hour 75 gram oral glucose tolerance test at 0, 2, and 3 hours. Higher values are indicate better insulin sensitivity.	After 3 weeks on drug

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Samuel Klein, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2021
• Primary Completion (Actual): December 30, 2023
• Study Completion (Actual): May 15, 2024

Study Registration Dates

• First Submitted: March 23, 2020
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (Actual): March 25, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Insulin Resistance; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neurotransmitter Agents; GABA Agents; Anticonvulsants; Vigabatrin
• Other Study ID Numbers: 202006177

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No