SGLTi, Hepatic Glucose Production and Ketogenesis

Protocol l: SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis

In this study, we will test the hypothesis that distinct mechanisms account for the SGLT2i-induced stimulation of ketogenesis and lipolysis versus endogenous (hepatic) glucose production in patients with type 2 diabetes (T2D) and type 1 diabetes (T1D), and that the increases in ketone production and lipolysis can be prevented by concomitant administration of the thiazolidinedione pioglitazone. We will conduct five distinct experiments to test this hypothesis in patients with T2D and T1D.

MAIN STUDY: To examine the effect of empagliflozin versus empagliflozin/pancreatic clamp on EGP (6,6, D2-glucose), gluconeogenesis (D2O), lipolysis (U-2H-glycerol), ketogenesis (13C-palmitate conversion to 3-betahydroxybuyrate), and norepinephrine turnover (3H-NE) in type 2 diabetes subjects.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Empagliflozin 25 MG; Other: Placebo

Detailed Description

MAIN STUDY

Participants: 30 T2D subjects, age = 30-75 y, BMI = 23-38 kg/m2, HbA1c = 7.0-11%, eGFR > 60 ml/min/1.73m2, BP < 160/90 mmHg. Participants must be in general good health based on medical history, physical exam, screening blood chemistries, CBC, TSH/T4, EKG, and urinalysis. Patients must have 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, SU, metformin, or SU/MET are eligible. Patients treated with GLP-1 RA, DPP-4i, TZD, or insulin are excluded. Patients taking medications (other than SU/MET) known to affect glucose metabolism are excluded. Statin therapy is permissible if the dose has been stable for at least 3 months. 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.

Protocol: 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 7-10 day interval between studies. In Study 1a, 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 (BHB). Total body NE turnover will be measured with 3H-norepinephrine (3H-NE) infusion before and after empagliflozin administration. Study 1b will be similar to Study 1a with one exception. EGP, lipolysis, and ketogenesis, and NE turnover will be measured under pancreatic clamp conditions.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ralph Defronzo, MD; Phone Number: 210-567-6691; Email: defronzo@uthscsa.edu
• Study Contact Backup: Name: Aurora Merovci, MD; Phone Number: 210-567-6691; Email: merovci@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229-3900
      • Recruiting
      • Texas Diabetes Institute/UH
      • Contact: Ralph DeFronzo, MD; Phone Number: 210-358-7200; Email: defronzo@uthscsa.edu
      • Principal Investigator: Ralph DeFronzo, MD
      • Contact: Aurora Merovci, MD; Phone Number: 210-567-6691; Email: merovci@uthscsa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Patients with T2D

Inclusion Criteria:

• Ages 30-75
• BMI (Body Mass Index) 21-45 kg/m2
• HbA1c = 7.0-11%
• eGFR (estimated glomerular filtration rate)> 60 ml/min/1.73m2
• Blood Pressure (BP)≤160/90 mmHg
• Participants must be in general good health based on medical history, physical exam, screening blood chemistries, CBC (Complete Blood Count), TSH/T4 (thyroid/thyroxine hormone), EKG (electrocardiogram), and urinalysis (UA)
• 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, Sulfonylureas, Metformin, or Sulfonylureas/Metformin (Sulfo/MET)
• Participants receiving a Glucagon like peptide -1 receptor agonist (GLP1-RA) must be on a stable dose for at least three months prior to study enrollment.
• Participants receiving a Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitor) must be on a stable dose for at least two months prior to study enrollment.
• SGLT2 inhibitors must be discontinued at least two months prior to study enrollment.
• Statin therapy is permissible if the dose has been stable for at least 3 months

EXCLUSION CRITERIA

An individual who meets any of the following criteria will be excluded from participation in this study:

• Patients treated with Thiazolidinediones (TZDs), or Insulin are excluded.
• Patients taking medications other than Sulfonylureas/Metformin (SU/MET), stable dose of GLP1-RA and DPP4i known to affect glucose metabolism are excluded. Patients taking SGLT2i within 2 months of screening visit will be excluded from participating in this study, however they may be asked whether they would agree to discontinue the medication for two months to become eligible. (Please see clarification below.) *
• Subjects with evidence of proliferative retinopathy or estimated glomerular filtration rate (eGFR) < 60 are excluded
• Women of childbearing potential are excluded unless they are taking/using appropriate contractive medications/devices * Only participants who are taking SGLT2 inhibitors during the prescreening period will be asked to discontinue the medication at least two months prior to the screening visit. If they agree, they will return for an HbA1c measurement four weeks after stopping the SGLT2 inhibitor.

If their HbA1c rises to greater than 10%, treatment will be initiated with either metformin, a DPP-4 inhibitor, or a sulfonylurea. We do not anticipate any adverse effects during this initial period, provided the HbA1c remains below 10%.

HbA1c will be measured using a fingerstick test, which requires only a minimal amount of blood. No compensation will be provided during this phase.

After two months of medication discontinuation, participants will return for a screening visit. If they meet all eligibility criteria, they will be enrolled in the study and payment done by protocol.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin; Empagliflozin 25 mg/day	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; Placebo control	Other: Placebo; Inert tablet; Other Names: Placebo for empagliflozin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous Glucose Production (EGP)	Measurement of Endogenous Glucose Production (EGP) using stable isotope (6,6, D2- glucose infusion).	0 and 300 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Insulin Concentration	Change in concentration of plasma insulin during the study	0 and 300 minutes
Plasma Free Fatty Acids (FFA)	Change in concentration of free fatty acids during the study	0 and 300 minutes
Plasma glucose concentrations	Change in concentration of plasma glucsoe during the study	baseline and week 10 (Study 4 and Study 5)

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: Ralph DeFronzo, MD, The University of Texas Health Science Center at San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: July 13, 2023
• First Submitted That Met QC Criteria: July 21, 2023
• First Posted (Actual): July 27, 2023

Study Record Updates

• Last Update Posted (Actual): July 17, 2026
• Last Update Submitted That Met QC Criteria: July 15, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Gluconeogenesis; Lipolysis; Endogenous glucose production; Pancreatic clamp; Ketogenesis; Norepinephrine turnover
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; empagliflozin
• Other Study ID Numbers: HSC20230457H - 440509; R01DK024092 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

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.: No