SGLTi, Hepatic Glucose Production and Ketogenesis

Not Applicable

Recruiting

• Conditions: Type 2 Diabetes
• Interventions: Drug: Empagliflozin 25 MG; Other: Placebo; Drug: Pioglitazone 30mg + Empagliflozin (25 mg); Drug: Pioglitazone 30mg

• Registration Number: NCT05960656
• Lead Sponsor: The University of Texas Health Science Center at San Antonio

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.

Study Timeline

• Study First Submitted: 2023-07-13
• Study First Submitted QC: 2023-07-21
• Study First Posted: 2023-07-27
• Study Start: 2023-10-05
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-26
• Last Update Posted: 2025-07-01
• Primary Completion: 2027-06-01
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Empagliflozin	Empagliflozin 25 MG	Empagliflozin 25 mg/day
Placebo/Control Group	Placebo	Placebo control
Empagliflozin + pioglitazone	Pioglitazone 30mg + Empagliflozin (25 mg)	Combination of empagliflozin (25 mg/day) plus pioglitazone (30 mg/day)
Placebo/Control Group	Placebo	Placebo control
Empagliflozin	Empagliflozin 25 MG	Empagliflozin 25 mg/day
Pioglitazone	Pioglitazone 30mg	Pioglitazone 30 mg/day

Primary Outcome Measures

Name	Time	Method
Endogenous Glucose Production (EGP)	0 and 300 minutes	Measurement of Endogenous Glucose Production (EGP) using stable isotope (6,6, D2- glucose infusion).

Trial Locations

Locations (1)

Texas Diabetes Institute/UH; 🇺🇸 San Antonio, Texas, United States