Empagliflozin and Hepatic Glucose Metabolism

Effect of Empagliflozin on Hepatic Glucose Metabolism: Role of Autonomic Nervous System

the aim of this study is to examine the role of autonomic nervous system in the increase in hepatic glucose production in response to glucosuria caused by inhibition of renal glucose uptake

Study Overview

• Status: Completed
• Conditions: Hepatic Glucose Metabolism
• Intervention / Treatment: Drug: Empagliflozin 25 MG; Drug: Control

Detailed Description

Purpose/Objectives: To investigate the effect of empagliflozin, an SGLT2 inhibitor on hepatic glucose production and the role of autonomic nervous system in mediating the increase in hepatic glucose production in response glucosuria Research Design/Plan: the role of autonomic nervous system in the increase in hepatic glucose production caused by empagliflozin will be examined with norepinephrine (NE) turnover in two protocols. The first protocol is cross sectional, in which 36 T2DM patients will receive hepatic glucose production (HGP) and NE turnover will be measured before and after empagliflozin or placebo administration. In protocol 2, diabetic and non-diabetic subjects will receive baseline HGP, NE turnover, hepatic glucose uptake (HGU) and liver fat measurement before at 2 days after the start and 12 weeks after empagliflozin or placebo treatment.

Methods: the following techniques will be employed (1) Measurement of hepatic glucose production with 3H-glucose infusion, with and without glucose clamp, (2) substrate oxidation with indirect calorimetry and plasma ketone/lactate/insulin/glucagon concentrations; (3) Measurement of HGU with Oral-IV double tracer infusion; (4) Measurement of whole body norepinephrine turnover with 3H-norepinephrine infusion; (5) Measurement of heart rate variability; (6) Measurement of liver fat content with 1H-MRS Clinical Relevance: The results of the present studies will help identify the mechanism responsible for the increase in HGP caused by empagliflozin and the increase in ketone production. The first action of the drug ameliorates its clinical efficacy while the second increases the risk of adverse events (ketoacidosis). Identifying the mechanisms underlying these actions will help developing therapeutic strategies which increase the drug clinical efficacy and mitigates its adverse events.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Diabetes Division, UTHSCSA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• eGFR>60 ml/min healthy volunteers type 2 diabetes patients who otherwise healthy

Exclusion Criteria:

• eGFR <60 T2DM patients on insulin, GLP-1 RA or SGLT2 treatment Major organ disease type 1 diabetes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; empagliflozin 25 mg per day	Drug: Empagliflozin 25 MG; subjects will receive daily dose of 25mg of empagliflozin for 3 months
Placebo Comparator: control; matching placebo 1 pill per day	Drug: Control; Placebo; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Empagliflozin on Autonomic Nervous System	autonomic activity will be measured with as NE turnover rate. Total-body NE turnover rate was measured with 3H-NE infusion. A prime (3.8 µCi)-continuous (0.38 µCi/min) infusion of 3H-NE was started and continued for 60 minutes. Arterialized blood samples were collected before the start and between the 40-60 minute time period after the start of 3H-NE infusion. Total body NE turnover rate was calculated as the 3H-NE infusion rate (dpm/min) divided by the steady state plasma 3H-NE specific activity (dpm/pg) after 30 minutes	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic Glucose Production	HGP will be measured with tracer dilution technique	Baseline and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Percentage Change From Baseline to 12 Weeks in Hepatic Fat Content	the effect of treatment on hepatic fat content will be measured with MRS.	Baseline and12 weeks

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Muhammad Abdul-Ghani, MD, PhD, Diabetes Division, UTHSCSA

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2018
• Primary Completion (Actual): January 30, 2023
• Study Completion (Actual): January 30, 2024

Study Registration Dates

• First Submitted: June 17, 2017
• First Submitted That Met QC Criteria: June 17, 2017
• First Posted (Actual): June 21, 2017

Study Record Updates

• Last Update Posted (Actual): August 28, 2024
• Last Update Submitted That Met QC Criteria: August 7, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: HSC20170214H; 2R01DK097554-06 (U.S. NIH Grant/Contract)

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
• product manufactured in and exported from the U.S.: Yes