Empagliflozin and Hepatic Glucose Metabolism

Phase 4

Completed

Conditions: Hepatic Glucose Metabolism

Interventions: Drug: Control
Drug: Empagliflozin 25 MG

Registration Number: NCT03193684

Lead Sponsor: The University of Texas Health Science Center at San Antonio

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 72

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
control	Control	matching placebo 1 pill per day
Treatment	Empagliflozin 25 MG	empagliflozin 25 mg per day

Primary Outcome Measures

Name	Time	Method
Effect of Empagliflozin on Autonomic Nervous System	Baseline and 12 weeks	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

Secondary Outcome Measures