SGLT2i, Pioglitazone, and Ketone Production in T2D

NCT ID: NCT07053319

Last Updated: 2025-07-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 64 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-02-01
• Study Completion Date: 2027-06-30

Brief Summary

To examine whether the empagliflozin-induced stimulation of EGP, lipolysis, and ketone production in T2D individuals can be blocked by pioglitazone (which has direct hepatic and adipose tissue effects).

Detailed Description

Participants: 64 T2D subjects with the same inclusion and exclusion criteria as Protocol 1. Subjects with hematuria are excluded.

Study Design: Infusions of 3-3H-glucose and 14C-glycerol are started and continued to study end (2 PM). Baseline blood samples for HbA1c (x2) and for plasma insulin, glucagon, glucose, FFA, BHB, AcAc, glycerol, and plasma 3-3H-glucose and 14C-glycerol specific activities are drawn at -30, -20, -10, -5, and 0 minutes for measurement of lipolysis, ketone production (plasma ketone levels), and EGP. Empagliflozin (25 mg) is ingested at time zero (9AM) and plasma samples for the above are obtained every 10-20 minutes.

Following completion of the above study, subjects will be randomized to one of four groups (16 per group) for 10 weeks: (1) empagliflozin, 25 mg/day, plus pioglitazone placebo; (2) pioglitazone, 15 mg/day, increased to 30 mg after 2 weeks plus empagliflozin placebo; (3) empagliflozin (25 mg/d) plus pioglitazone (15/30 mg/d); (4) empa placebo plus pio placebo. Subjects will return to the CRC every 1-2 weeks for interim medical history, to check medication compliance, and to measure plasma insulin, glucagon, glucose, FFA, glycerol, BHB, and AcAc levels. At week 10, subjects will return to the CRC at 6AM and the baseline study will be repeated. HbA1c will be measured twice during week 10.

Conditions

Type 2 Diabetes

Study Design

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

Study Groups

Empagliflozin plus Pioglitazone placebo

Empagliflozin 25 mg/day plus pioglitazone placebo

Group Type: EXPERIMENTAL

Empagliflozin 25 MG plus Pioglitazone placebo

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.

Pioglitazone plus Empagliflozin Placebo

Pioglitazone, 15 mg/day, increased to 30 mg after 2 weeks plus empagliflozin placebo

Group Type: PLACEBO_COMPARATOR

Pioglitazone 15 mg increased to 30 mg after 2 weeks plus Empagliflozin Placebo

Intervention Type: DRUG

Placebo-Inert tablet

Empagliflozin plus Pioglitazone

Empagliflozin(25mg/day) plus pioglitazone (15/30 mg/d)

Group Type: EXPERIMENTAL

Empagliflozin 25 mg/d plus Pioglitazone (15/30 mg/d)

Intervention Type: DRUG

Pioglitazone, a medication used in the management and treatment of type 2 diabetes mellitus. It is in the thiazolidinedione class of medications

Empagliflozin placebo + pioglitazone placebo

empagliflozin placebo plus pioglitazone placebo

Group Type: EXPERIMENTAL

Pioglitazone placebo + Empagliflozin placebo

Intervention Type: DRUG

Placebo-Inert tablet

Interventions

Empagliflozin 25 MG plus Pioglitazone placebo

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

Pioglitazone 15 mg increased to 30 mg after 2 weeks plus Empagliflozin Placebo

Placebo-Inert tablet

Intervention Type: DRUG

Empagliflozin 25 mg/d plus Pioglitazone (15/30 mg/d)

Pioglitazone, a medication used in the management and treatment of type 2 diabetes mellitus. It is in the thiazolidinedione class of medications

Intervention Type: DRUG

Pioglitazone placebo + Empagliflozin placebo

Placebo-Inert tablet

Intervention Type: DRUG

Other Intervention Names

Empagliflozin; Placebo-Inert tablet; Placebo for empagliflozin; Pioglitazone, a medication used in the management and treatment of type 2 diabetes mellitus. It is in the thiazolidinedione class of medications; Empagliflozin/Pioglitazone; Empagliflozin, 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/Placebo

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) < 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

• 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

20230457HU-504077

Identifier Type: -

Identifier Source: org_study_id