Clinical trial NCT03193684: Empagliflozin and Hepatic Glucose Metabolism
Official title: Effect of Empagliflozin on Hepatic Glucose Metabolism: Role of Autonomic Nervous System
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hepatic Glucose Metabolism
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2017-06-21
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: subjects will receive in parallel a treatment with empagliflozin or placebo for 3 months hepatic glucose metabolism and norepinephrine turnover will be studied before and after treatment
Primary purpose: BASIC_SCIENCE

Brief summary: 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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Effect of Empagliflozin on Autonomic Nervous System
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Hepatic Glucose Production
timeFrame: Baseline and 12 weeks
Other outcomes:
measure: Absolute Percentage Change From Baseline to 12 Weeks in Hepatic Fat Content
timeFrame: Baseline and12 weeks
Locations:
city: San Antonio
country: United States
facility: Diabetes Division, UTHSCSA
state: Texas
Study officials:
affiliation: Diabetes Division, UTHSCSA
name: Muhammad Abdul-Ghani, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: