SGLT2i, Pioglitazone, and Ketone Production in T2D

Purpose

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).

Condition

  • Type 2 Diabetes

Eligibility

Eligible Ages
Between 30 Years and 75 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
A randomized controlled 4 arm clinical trial
Primary Purpose
Basic Science
Masking
Triple (Participant, Care Provider, Investigator)
Masking Description
Subjects will be randomly assigned 1:1:1:1 ratio

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Empagliflozin plus Pioglitazone placebo 		Empagliflozin 25 mg/day plus pioglitazone placebo
  • Drug: 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.
    Other names:
    • Empagliflozin
    • Placebo-Inert tablet
Placebo Comparator
Pioglitazone plus Empagliflozin Placebo 		Pioglitazone, 15 mg/day, increased to 30 mg after 2 weeks plus empagliflozin placebo
  • Drug: Pioglitazone 15 mg increased to 30 mg after 2 weeks plus Empagliflozin Placebo
    Placebo-Inert tablet
    Other names:
    • 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
Experimental
Empagliflozin plus Pioglitazone 		Empagliflozin(25mg/day) plus pioglitazone (15/30 mg/d)
  • Drug: 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.
    Other names:
    • Empagliflozin
    • Placebo-Inert tablet
  • 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
    Other names:
    • 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.
Experimental
Empagliflozin placebo + pioglitazone placebo 		empagliflozin placebo plus pioglitazone placebo
  • Drug: Pioglitazone placebo + Empagliflozin placebo
    Placebo-Inert tablet
    Other names:
    • Placebo/Placebo

Recruiting Locations

Texas Diabetes Institute/UH
San Antonio, Texas 78229-3900
Contact:
Ralph DeFronzo, MD
210-358-7200
defronzo@uthscsa.edu

More Details

Status
Recruiting
Sponsor
The University of Texas Health Science Center at San Antonio

Study Contact

Ralph DeFronzo, MD
210-567-6691
defronzo@uthscsa.edu

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.