SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis

Sponsor

The University of Texas Health Science Center at San Antonio (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05960656

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the effect of empagliflozin, with and without pancreatic clamp, on endogenous (hepatic) glucose production (EGP, or 6,6, D2-glucose), gluconeogenesis (D2O), lipolysis (U-2H-glycerol), ketogenesis (13C-palmitate conversion to 3-betahydroxybutyrate), and norepinephrine turnover (3H-NE) in type 2 diabetes subjects.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Type 1 Diabetes	Drug: Empagliflozin 25 MG Other: Placebo	Early Phase 1

Detailed Description

After confirming eligibility, subjects will be randomized to receive empagliflozin (n=20) or placebo (n=10) in 2:1 ratio. Subject stratification will be done according to the following parameters: age (> or < 50 y), BMI (> or < 30 kg/m2), eGFR (> or < 80 ml/min/1.73 m2), HbA1c (> or < 8.5%). Each subject will participate in two studies performed in random order with 10-21 day interval between studies. Background medications (MET and/or SU) will be withheld on the morning of study. In Study 1, EGP will be measured with a prime-continuous 6,6, D2-glucose infusion and lipolysis will be measured with prime-continuous infusion of U-2H-glycerol. The rate of ketogenesis will be determined by infusion of 13C palmitate and quantitating the enrichment of 13C in 3-hydroxybutyrate (b-OHB). Total body NE turnover will be measured with 3H-norepinephrine (3H-NE) infusion before and after empagliflozin administration. Study 2 will be similar to Study 1 with one exception. EGP, lipolysis, and ketogenesis, and NE turnover will be measured under pancreatic clamp conditions.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

A randomized controlled 2 arm clinical trial comprised of two studiesA randomized controlled 2 arm clinical trial comprised of two studies

Masking:

Single (Participant)

Masking Description:

Subjects will be randomly assigned 2:1 active drug:placebo.

Primary Purpose:

Basic Science

Official Title:

SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Jan 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Empagliflozin Administration of Empagliflozin 25mg administered at time zero.	Drug: Empagliflozin 25 MG A medication used in the management and treatment of type 2 diabetes mellitus. It is in the sodium-glucose co-transporter (SGLT-2) class of medications. Other Names: Jardiance
Placebo Comparator: Placebo/Control Group Administration of placebo for empagliflozin 25mg administered at time zero.	Other: Placebo Inert tablet Other Names: Placebo for empagliflozin

Arm

Intervention/Treatment

Experimental: Empagliflozin

Administration of Empagliflozin 25mg administered at time zero.

Drug: Empagliflozin 25 MG

A medication used in the management and treatment of type 2 diabetes mellitus. It is in the sodium-glucose co-transporter (SGLT-2) class of medications.

Other Names:

Jardiance

Placebo Comparator: Placebo/Control Group

Administration of placebo for empagliflozin 25mg administered at time zero.

Other: Placebo

Inert tablet

Other Names:

Placebo for empagliflozin

Outcome Measures

Primary Outcome Measures

Endogenous Glucose Production (EGP) during Study 1 [Baseline to 300 minutes]
Measurement of Endogenous Glucose Production (EGP) during the study using 5 hours of a stable isotope (6,6, D2-glucose infusion). The change in EGP during the last hour of the study (i.e., 240-300 min) from baseline is considered the drug's effect on EGP. Analysis of blood provides the level of EGP in mg/kg.min
Endogenous Glucose Production (EGP) during Study 2 [Baseline to 300 minutes]
Measurement of Endogenous Glucose Production (EGP) during the study using 5 hours of a stable isotope (6,6, D2-glucose infusion). The change in EGP during the last hour of the study (i.e., 240-300 min) from baseline is considered the drug's effect on EGP. Analysis of blood provides the level of EGP in mg/kg.min
Ketone Body Turnover (ketogenesis) during Study 1 [Baseline to 300 minutes]
The rate of ketogenesis will be determined by 5 hours infusion of stable isotope 13C palmitate and quantitating the enrichment of 13C in 3-hydroxybutyrate (b-OHB). The ketone body 3-hydroxybutyrate is a product of acetyl-CoA that is liberated from hepatic fatty acid beta-oxidation and blood levels of 3-OHB reflect hepatic ketogenesis. Thus, the basal rate of ketone appearance, as well as the ketone rate appearance during the last hour of the study, is calculated from the enrichment of 13C in palmitate appearing in 3-OHB.
Ketone Body Turnover (ketogenesis) during Study 2 [Baseline to 300 minutes]
The rate of ketogenesis will be determined by 5 hours infusion of stable isotope 13C palmitate and quantitating the enrichment of 13C in 3-hydroxybutyrate (b-OHB). The ketone body 3-hydroxybutyrate is a product of acetyl-CoA that is liberated from hepatic fatty acid beta-oxidation and blood levels of 3-OHB reflect hepatic ketogenesis. Thus, the basal rate of ketone appearance, as well as the ketone rate appearance during the last hour of the study, is calculated from the enrichment of 13C in palmitate appearing in 3-OHB.

Secondary Outcome Measures

Plasma Insulin Concentration Study 1 [Baseline to 300 minutes]
Change in concentration of plasma insulin during the study
Plasma Insulin Concentration Study 2 [Baseline to 300 minutes]
Change in concentration of plasma insulin during the study
Plasma Free Fatty Acids (FFA) Study 1 [Baseline to 300 minutes]
Change in concentration of free fatty acids during the study
Plasma Free Fatty Acids (FFS) Study 2 [Baseline to 300 minutes]
Change in concentration of free fatty acids during the study

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Ages 30-75 years
Body Mass Index (BMI) 21-45 kg/m2
Hemoglobin A1C (HbA1c) = 7.0-10%
Estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73m2
Blood Pressure (BP) < 145/85 mmHg
Participants must be in general good health based on medical history, physical exam, screening blood chemistries, complete blood chemistry (CBC), thyroid stimulating hormone/thyroxine (TSH/T4), electrocardiogram (EKG), and urinalysis
Stable body weight (±1.5 kg) over the last 3 months and must not participate in an excessively heavy exercise program
Patients treated with diet, sulfonylurea (SU), metformin (MET), or SU/MET
Statin therapy is permissible if the dose has been stable for at least 3 months

Exclusion Criteria:

Patients treated with Glucagon-like peptide 1 receptor agonists (GLP-1 RA), Dipeptidyl Peptidase IV inhibitors (DPP-4i), Thiazolidinediones (TZD), or insulin are excluded
Patients taking medications (other than SU/MET) known to affect glucose metabolism are excluded
Subjects with evidence of proliferative retinopathy or eGFR < 60 are excluded
Women of childbearing potential are excluded unless they are taking/using appropriate contractive medications/devices