Empagliflozin and pioglitazone effects on ketone production in type 2 diabetes

Protocol lV: SGLT2 Inhibitors, Pioglitazone and Ketone Production in Type 2 Diabetes Mellitus

This test will see if adding pioglitazone blocks empagliflozin's increase in glucose production, fat breakdown, and ketone production in adults with type 2 diabetes.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 64 (estimated)
• Ages: 30 Years to 75 Years
• Sex: All
• Sponsor: The University of Texas Health Science Center at San Antonio (Academic / other)
• Locations: 1 site (San Antonio, Texas)
• Trial ID: NCT07053319 on ClinicalTrials.gov

What this trial studies

This is a mechanistic Phase 1 study in 64 adults with type 2 diabetes that combines acute tracer-based metabolic testing with a 10-week randomized drug phase. At baseline participants undergo infusion of 3-3H-glucose and 14C-glycerol and serial blood sampling around a single 25 mg dose of empagliflozin to measure endogenous glucose production, lipolysis, and ketone production. Subjects are then randomized to one of four 10-week arms (empagliflozin, pioglitazone, both drugs, or double placebo) with clinic visits every 1–2 weeks for safety and metabolic labs. The baseline metabolic protocol is repeated at week 10 and HbA1c is measured twice during that final week to compare changes across groups.

Who should consider this trial

Good fit: Adults 30–75 years old with type 2 diabetes, BMI 21–45 kg/m2, HbA1c 7.0–11%, eGFR >60 ml/min/1.73m2, controlled BP, and treated with diet, sulfonylurea, metformin, or their combination are ideal candidates.

Not a fit: Patients treated with insulin, GLP-1 receptor agonists, DPP-4 inhibitors, thiazolidinediones, those with hematuria or reduced kidney function, or with unstable medical conditions would be excluded and unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, adding pioglitazone could blunt excessive ketone production and lipolysis caused by empagliflozin while preserving glucose-lowering effects.

How similar studies have performed: Prior work shows SGLT2 inhibitors raise ketone levels and pioglitazone has known hepatic and adipose effects, but using pioglitazone specifically to block SGLT2i-induced ketogenesis is a novel, not yet proven, approach.

Eligibility criteria

Patients with T2D

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

Where this trial is running

San Antonio, Texas

• Texas Diabetes Institute/UH — San Antonio, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Ralph DeFronzo, MD — The University of Texas Health Science Center at San Antonio
• Study coordinator: Ralph DeFronzo, MD

Conditions Type 2 Diabetes; Endogenous glucose production; Ketogenesis; Gluconeogenesis; Lipolysis