SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis
Purpose
The purpose of this study is to examine the effect of empagliflozin, with and without pancreatic clamp, on endogenous (hepatic) glucose production (EGP, or 6,6, D2-glucose), gluconeogenesis (D2O), lipolysis (U-2H-glycerol), ketogenesis (13C-palmitate conversion to 3-betahydroxybutyrate), and norepinephrine turnover (3H-NE) in type 2 diabetes subjects.
Conditions
- Type 2 Diabetes
- Type 1 Diabetes
Eligibility
- Eligible Ages
- Between 30 Years and 75 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Ages 30-75 years - Body Mass Index (BMI) 21-45 kg/m2 - Hemoglobin A1C (HbA1c) = 7.0-10% - 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
- Early Phase 1
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Intervention Model Description
- A randomized controlled 2 arm clinical trial comprised of two studies
- Primary Purpose
- Basic Science
- Masking
- Single (Participant)
- Masking Description
- Subjects will be randomly assigned 2:1 active drug:placebo.
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Empagliflozin |
Administration of Empagliflozin 25mg administered at time zero. |
|
|
Placebo Comparator Placebo/Control Group |
Administration of placebo for empagliflozin 25mg administered at time zero. |
|
Recruiting Locations
San Antonio, Texas 78229-3900
More Details
- Status
- Recruiting
- Sponsor
- The University of Texas Health Science Center at San Antonio
Detailed Description
After confirming eligibility, subjects will be randomized to receive empagliflozin (n=20) or placebo (n=10) in 2:1 ratio. Subject stratification will be done according to the following parameters: age (> or < 50 y), BMI (> or < 30 kg/m2), eGFR (> or < 80 ml/min/1.73 m2), HbA1c (> or < 8.5%). Each subject will participate in two studies performed in random order with 10-21 day interval between studies. Background medications (MET and/or SU) will be withheld on the morning of study. In Study 1, EGP will be measured with a prime-continuous 6,6, D2-glucose infusion and lipolysis will be measured with prime-continuous infusion of U-2H-glycerol. The rate of ketogenesis will be determined by infusion of 13C palmitate and quantitating the enrichment of 13C in 3-hydroxybutyrate (b-OHB). Total body NE turnover will be measured with 3H-norepinephrine (3H-NE) infusion before and after empagliflozin administration. Study 2 will be similar to Study 1 with one exception. EGP, lipolysis, and ketogenesis, and NE turnover will be measured under pancreatic clamp conditions.