Back to resultsSGLT2 Inhibitors, Ketogenesis, and Ketoacidosis
Primary Purpose
Type 2 Diabetes, Type 1 Diabetes
Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Empagliflozin 25 MG
Placebo
Sponsored by
About this trial
This is an interventional basic science trial for Type 2 Diabetes focused on measuring Pancreatic clamp, Endogenous glucose production, Ketogenesis, Gluconeogenesis, Lipolysis, Norepinephrine turnover
Eligibility Criteria
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
Sites / Locations
- Texas Diabetes Institute/UHRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Empagliflozin
Placebo/Control Group
Arm Description
Administration of Empagliflozin 25mg administered at time zero.
Administration of placebo for empagliflozin 25mg administered at time zero.
Outcomes
Primary Outcome Measures
Endogenous Glucose Production (EGP) during Study 1
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
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
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
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
Change in concentration of plasma insulin during the study
Plasma Insulin Concentration Study 2
Change in concentration of plasma insulin during the study
Plasma Free Fatty Acids (FFA) Study 1
Change in concentration of free fatty acids during the study
Plasma Free Fatty Acids (FFS) Study 2
Change in concentration of free fatty acids during the study
Full Information
NCT ID
NCT05960656
First Posted
July 13, 2023
Last Updated
October 18, 2023
Sponsor
The University of Texas Health Science Center at San Antonio
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1. Study Identification
Unique Protocol Identification Number
NCT05960656
Brief Title
SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis
Official Title
SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 5, 2023 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
January 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Texas Health Science Center at San Antonio
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
4. Oversight
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.
No
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes, Type 1 Diabetes
Keywords
Pancreatic clamp, Endogenous glucose production, Ketogenesis, Gluconeogenesis, Lipolysis, Norepinephrine turnover
7. Study Design
Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
A randomized controlled 2 arm clinical trial comprised of two studies
Masking
Participant
Masking Description
Subjects will be randomly assigned 2:1 active drug:placebo.
Allocation
Randomized
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Empagliflozin
Arm Type
Experimental
Arm Description
Administration of Empagliflozin 25mg administered at time zero.
Arm Title
Placebo/Control Group
Arm Type
Placebo Comparator
Arm Description
Administration of placebo for empagliflozin 25mg administered at time zero.
Intervention Type
Drug
Intervention Name(s)
Empagliflozin 25 MG
Other Intervention Name(s)
Jardiance
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo for empagliflozin
Intervention Description
Inert tablet
Primary Outcome Measure Information:
Title
Endogenous Glucose Production (EGP) during Study 1
Description
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
Time Frame
Baseline to 300 minutes
Title
Endogenous Glucose Production (EGP) during Study 2
Description
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
Time Frame
Baseline to 300 minutes
Title
Ketone Body Turnover (ketogenesis) during Study 1
Description
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.
Time Frame
Baseline to 300 minutes
Title
Ketone Body Turnover (ketogenesis) during Study 2
Description
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.
Time Frame
Baseline to 300 minutes
Secondary Outcome Measure Information:
Title
Plasma Insulin Concentration Study 1
Description
Change in concentration of plasma insulin during the study
Time Frame
Baseline to 300 minutes
Title
Plasma Insulin Concentration Study 2
Description
Change in concentration of plasma insulin during the study
Time Frame
Baseline to 300 minutes
Title
Plasma Free Fatty Acids (FFA) Study 1
Description
Change in concentration of free fatty acids during the study
Time Frame
Baseline to 300 minutes
Title
Plasma Free Fatty Acids (FFS) Study 2
Description
Change in concentration of free fatty acids during the study
Time Frame
Baseline to 300 minutes
10. Eligibility
Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ralph DeFronzo, MD
Phone
210-567-6691
Email
defronzo@uthscsa.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Aurora Merovci, MD
Phone
210-567-6691
Email
merovci@uthscsa.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ralph DeFronzo, MD
Organizational Affiliation
University of Texas Health Science Center San Antonio
Official's Role
Principal Investigator
Facility Information:
Facility Name
Texas Diabetes Institute/UH
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229-3900
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ralph DeFronzo, MD
Phone
210-358-7200
Email
defronzo@uthscsa.edu
First Name & Middle Initial & Last Name & Degree
Aurora Merovci, MD
Phone
210-567-6691
Email
merovci@uthscsa.edu
First Name & Middle Initial & Last Name & Degree
Ralph DeFronzo, MD
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Deidentified data will be shared with NIH and as a publication in a peer reviewed journal once data are published.
IPD Sharing Time Frame
At study end after analysis of data.
Learn more about this trial
SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis
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