SGLT2i, Pioglitazone, and Ketone Production in T2D

The University of Texas System (UT)

Status and phase: Enrolling; Phase 1

Conditions: Type 2 Diabetes

Treatments: Drug: Empagliflozin 25 MG plus Pioglitazone placebo; Drug: Pioglitazone 15 mg increased to 30 mg after 2 weeks plus Empagliflozin Placebo; Drug: Pioglitazone placebo + Empagliflozin placebo; Drug: Empagliflozin 25 mg/d plus Pioglitazone (15/30 mg/d)

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT07053319

20230457HU-504077

R01DK024092 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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).

Full 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.

Enrollment: 64 estimated patients

Sex: All

Ages: 30 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

---

64 participants in 4 patient groups, including a placebo group

Empagliflozin plus Pioglitazone placebo

Experimental group

Description:

Empagliflozin 25 mg/day plus pioglitazone placebo

Treatment:

Drug: Empagliflozin 25 MG plus Pioglitazone placebo

Pioglitazone plus Empagliflozin Placebo

Placebo Comparator group

Description:

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

Treatment:

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

Empagliflozin plus Pioglitazone

Experimental group

Description:

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

Treatment:

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

Empagliflozin placebo + pioglitazone placebo

Experimental group

Description:

empagliflozin placebo plus pioglitazone placebo

Treatment:

Drug: Pioglitazone placebo + Empagliflozin placebo