SGLTi, Hepatic Glucose Production and Ketogenesis

NCT ID: NCT05960656

Last Updated: 2025-07-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-05
• Study Completion Date: 2027-06-30

Brief Summary

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.

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.

Conditions

Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Empagliflozin

Empagliflozin 25 mg/day

Group Type: EXPERIMENTAL

Empagliflozin 25 MG

Intervention Type: DRUG

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.

Placebo/Control Group

Placebo control

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Inert tablet

Interventions

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.

Intervention Type: DRUG

Placebo

Inert tablet

Intervention Type: OTHER

Other Intervention Names

Jardiance; Placebo for empagliflozin

Eligibility Criteria

Inclusion Criteria

• Ages 30-75 years
• Body Mass Index (BMI) 21-45 kg/m2
• Hemoglobin A1C (HbA1c) = 7.0-11%
• Estimated glomerular filtration rate (eGFR) > 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, 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

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

NIH

Sponsor Role: collaborator

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ralph DeFronzo, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas Health Science Center San Antonio

Locations

Texas Diabetes Institute/UH

San Antonio, Texas, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Ralph DeFronzo, MD

Role: CONTACT

defronzo@uthscsa.edu

210-567-6691

Aurora Merovci, MD

Role: CONTACT

merovci@uthscsa.edu

210-567-6691

Facility Contacts

Ralph DeFronzo, MD

Role: primary

defronzo@uthscsa.edu

210-358-7200

Aurora Merovci, MD

Role: backup

merovci@uthscsa.edu

210-567-6691

Other Identifiers

R01DK024092

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HSC20230457H - 440509

Identifier Type: -

Identifier Source: org_study_id