SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis

Conditions
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Type 2 Diabetes, Type 1 Diabetes

Intervention / Treatment
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* Drug: Empagliflozin 25 MG
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized controlled 2 arm clinical trial comprised of two studies
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Administration of Empagliflozin 25mg administered at time zero. | Drug: Empagliflozin 25 MG<br>* 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.<br>* Other names: Jardiance;|
| Placebo Comparator: Placebo/Control Group<br>Administration of placebo for empagliflozin 25mg administered at time zero. | Other: Placebo<br>* Inert tablet<br>* Other names: Placebo for empagliflozin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endogenous Glucose Production (EGP) during Study 1 | Measurement of Endogenous Glucose Production (EGP) during the study using 5 hours of a stable isotope (6,6, D2-glucose infusion). The change in EGP during the last hour of the study (i.e., 240-300 min) from baseline is considered the drug's effect on EGP. Analysis of blood provides the level of EGP in mg/kg.min | Baseline to 300 minutes | 
| Endogenous Glucose Production (EGP) during Study 2 | Measurement of Endogenous Glucose Production (EGP) during the study using 5 hours of a stable isotope (6,6, D2-glucose infusion). The change in EGP during the last hour of the study (i.e., 240-300 min) from baseline is considered the drug's effect on EGP. Analysis of blood provides the level of EGP in mg/kg.min | Baseline to 300 minutes | 
| Ketone Body Turnover (ketogenesis) during Study 1 | The rate of ketogenesis will be determined by 5 hours infusion of stable isotope 13C palmitate and quantitating the enrichment of 13C in 3-hydroxybutyrate (b-OHB). The ketone body 3-hydroxybutyrate is a product of acetyl-CoA that is liberated from hepatic fatty acid beta-oxidation and blood levels of 3-OHB reflect hepatic ketogenesis. Thus, the basal rate of ketone appearance, as well as the ketone rate appearance during the last hour of the study, is calculated from the enrichment of 13C in palmitate appearing in 3-OHB. | Baseline to 300 minutes | 
| Ketone Body Turnover (ketogenesis) during Study 2 | The rate of ketogenesis will be determined by 5 hours infusion of stable isotope 13C palmitate and quantitating the enrichment of 13C in 3-hydroxybutyrate (b-OHB). The ketone body 3-hydroxybutyrate is a product of acetyl-CoA that is liberated from hepatic fatty acid beta-oxidation and blood levels of 3-OHB reflect hepatic ketogenesis. Thus, the basal rate of ketone appearance, as well as the ketone rate appearance during the last hour of the study, is calculated from the enrichment of 13C in palmitate appearing in 3-OHB. | Baseline to 300 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Insulin Concentration Study 1 | Change in concentration of plasma insulin during the study | Baseline to 300 minutes | 
| Plasma Insulin Concentration Study 2 | Change in concentration of plasma insulin during the study | Baseline to 300 minutes | 
| Plasma Free Fatty Acids (FFA) Study 1 | Change in concentration of free fatty acids during the study | Baseline to 300 minutes | 
| Plasma Free Fatty Acids (FFS) Study 2 | Change in concentration of free fatty acids during the study | Baseline to 300 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic clamp, Endogenous glucose production, Ketogenesis, Gluconeogenesis, Lipolysis, Norepinephrine turnover