NCT05729282

Glycemic Effect of Diazoxide in NAFLD

Role of Hyperinsulinemia in Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis: Diazoxide Pilot & Feasibility Study

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (actual)
• Sponsor: Columbia University · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

The goal of this clinical trial is to compare a two-week course of diazoxide (at two different doses) and placebo in people with overweight/obesity and insulin resistance (IR) with, or at high risk for, non-alcoholic fatty liver disease (NAFLD). The main questions it aims to answer are how mitigation of compensatory hyperinsulinemia with diazoxide affects parameters of glucose and lipid metabolism (how people with IR and NAFLD respond to lowering high insulin levels so that the investigators can see what happens to how the liver handles fat and sugar). Participants will: * Take 27 doses of diazoxide (at 1 mg per kg of body weight per dose \[mpk\] or 2 mpk) or of placebo, over 14 days * Take 32 doses of heavy (deuterated) water (50 mL each) over 14 days * Have blood drawn and saliva collected after an overnight fast on four mornings over the two-week study period * Consume their total calculated daily caloric needs as divided into three meals per day * Wear a continuous glucose monitor for the two-week study period Researchers will compare fasting blood tests at intervals during the study period in participants randomized (like the flip of a coin) to diazoxide 1 mpk, diazoxide 2 mpk, or placebo, to see how the drug treatment affects plasma glucose, serum insulin, and serum lipid parameters (triglycerides, free fatty acids, and apolipoprotein B). They will also consume heavy (deuterated) water to assess de novo lipogenesis (building of new fatty acids by the liver).

Detailed description

Non-alcoholic fatty liver disease (NAFLD) is an under-appreciated complication of lipid dysmetabolism in type 2 diabetes (T2DM). Although it appears that insulin resistance (IR) is a mechanism common to both, the pathophysiology of its connection to unhealthy fat accumulation in the liver remains unclear. The investigators propose that the hyperinsulinemia that accompanies IR drives the excess hepatic de novo lipogenesis (DNL) that characterizes IR-associated NAFLD (IR-NAFLD). As such, despite its potential impact on glucose tolerance, lowering insulin levels might attenuate the pro-steatotic drive in patients with IR. The investigators' long-term objective, therefore, is to blunt endogenous insulin secretion using the insulin anti-secretagogue diazoxide in order to assess the impact on DNL. However, in order to optimize diazoxide treatment conditions, the investigators must first perform a pilot \& feasibility study. This is a single-center, randomized, double blinded, placebo-controlled clinical trial to provide pilot and feasibility data on the use of diazoxide oral suspension to ameliorate hyperinsulinemia in participants with overweight/obesity and insulin resistance (prediabetic state or elevated Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score, + fasting hyperinsulinemia) who are diagnosed with, or clinically judged to be at high risk of, NAFLD. Participants will be randomized to one of three parallel arms: placebo, diazoxide at 1 mg per kg of body weight (mpk) per dose, or diazoxide at 2 mpk per dose, for a total of 27 doses over 14 days. They will also consume heavy (deuterated) water for a total of 32 doses of 50 ml over 14 days to measure de novo lipogenesis, an exploratory endpoint. They will present for outpatient blood draws and saliva collections after an overnight fast at four time points during the study course. Additionally, participants will follow a weight-maintaining diet and wear a professional continuous glucose monitor (CGM) throughout.

Conditions

• Hyperinsulinemia
• Insulin Resistance
• Non-Alcoholic Fatty Liver Disease
• Prediabetic State

Interventions

Type	Name	Description
DRUG	Diazoxide oral suspension, 1 mg per kg per dose	Diazoxide oral suspension provided in label-obscured single-use oral syringes at 1 mg per kg per dose (total of 27 doses over 14 days).
DRUG	Diazoxide oral suspension, 2 mg per kg per dose	Diazoxide oral suspension provided in label-obscured single-use oral syringes at 2 mg per kg per dose (total of 27 doses over 14 days).
DRUG	Placebo	Flavor-approximate placebo consisting of peppermint extract in diet tonic water, thickened with xanthan gum, provided in label-obscured single-use oral syringes at 2 mg per kg per dose (total of 27 doses over 14 days).
DEVICE	FreeStyle Libre Pro	All participants will wear a FreeStyle Libre Pro continuous glucose monitor (CGM) to track glycemic trends in response to study treatments. Investigators and participants will be blinded to CGM readings until after each participant has completed the trial.
DRUG	Deuterated water (2H2O/D2O)	All participants will consume 32 aliquots of deuterated water (2H2O/D2O) 50 mL over 14 days to assess hepatic de novo lipogenesis. Tracer enrichment will be determined in blood and saliva.

Timeline

• Start date: 2023-08-01
• Primary completion: 2025-09-10
• Completion: 2025-09-10
• First posted: 2023-02-15
• Last updated: 2026-01-07

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study
• FDA-regulated device study