Type 2 Diabetes
Conditions
Keywords
Endogenous glucose production, Ketogenesis, Gluconeogenesis, Lipolysis
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.
Interventions
DRUGEmpagliflozin 25 MG
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.
DRUGPioglitazone 15 mg increased to 30 mg after 2 weeks plus Empagliflozin Placebo
Placebo-Inert tablet
DRUGEmpagliflozin 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
Sponsors
The University of Texas Health Science Center at San Antonio
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Subjects will be randomly assigned 1:1:1 ratio
Intervention model description
A randomized controlled 3 arm clinical trial
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Ages 30-75 * BMI (Body Mass Index) 21-45 kg/m2 * HbA1c = 7.0-11% * eGFR (estimated glomerular filtration rate)\> 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, CBC (Complete Blood Count), TSH/T4 (thyroid/thyroxine hormone), EKG (electrocardiogram), and urinalysis (UA) * 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, Sulfonylureas, Metformin, or Sulfonylureas/Metformin (Sulfo/MET) * Participants receiving a Glucagon like peptide -1 receptor agonist (GLP1-RA) must be on a stable dose for at least three months prior to study enrollment. * Participants receiving a Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitor) must be on a stable dose for at least two months prior to study enrollment. * SGLT2 inhibitors must be discontinued at least two months prior to study enrollment. * Statin therapy is permissible if the dose has been stable for at least 3 months
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: * Patients treated with Thiazolidinediones (TZDs), or Insulin are excluded. * Patients taking medications other than Sulfonylureas/Metformin (SU/MET), stable dose of GLP1-RA and DPP4i known to affect glucose metabolism are excluded. Patients taking SGLT2i within 2 months of screening visit will be excluded from participating in this study, however they may be asked whether they would agree to discontinue the medication for two months to become eligible. (Please see clarification below.) \* * Subjects with evidence of proliferative retinopathy or estimated glomerular filtration rate (eGFR) \< 60 are excluded * Women of childbearing potential are excluded unless they are taking/using appropriate contractive medications/devices \* Only participants who are taking SGLT2 inhibitors during the prescreening period will be asked to discontinue the medication at least two months prior to the screening visit. If they agree, they will return for an HbA1c measurement four weeks after stopping the SGLT2 inhibitor. If their HbA1c rises to greater than 10%, treatment will be initiated with either metformin, a DPP-4 inhibitor, or a sulfonylurea. We do not anticipate any adverse effects during this initial period, provided the HbA1c remains below 10%. HbA1c will be measured using a fingerstick test, which requires only a minimal amount of blood. No compensation will be provided during this phase. After two months of medication discontinuation, participants will return for a screening visit. If they meet all eligibility criteria, they will be enrolled in the study and payment done by protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous Glucose Production (EGP) | 0 and 300 minutes | Measurement of Endogenous Glucose Production (EGP) using stable isotope (6,6, D2- glucose infusion). |
Countries
United States
Contacts
CONTACTRalph DeFronzo, MD
CONTACTAurora Merovci, MD
PRINCIPAL_INVESTIGATORRalph DeFronzo, MD
The University of Texas Health Science Center at San Antonio
Outcome results
None listed