Diabetes Mellitus, Type 2
Conditions
Brief summary
Purpose/Objectives: Examining the effect of SGLT2 inhibition on EGP and plasma glucose concentration in diabetic and non-diabetic subjects after kidney transplantation (i.e. renal denervation) or in subjects after renal sympathectomy (63) can add insight about the possible role of a neural arc which mediates the changes in plasma glucagon and/or insulin concentration in response to glucosuria.
Detailed description
Purpose/Objectives: Examining the effect of SGLT2 inhibition on EGP and plasma glucose concentration in diabetic and non-diabetic subjects after kidney transplantation (i.e. renal denervation) or in subjects after renal sympathectomy (63) can add insight about the possible role of a neural arc which mediates the changes in plasma glucagon and/or insulin concentration in response to glucosuria. Research Design/Plan: After screening, eligible subjects will receive 2 measurements of endogenous glucose production with a prime-continuous infusion of 3-3H-glucose. Each measurement will be performed on a separate day in random order after a 10-12 hour overnight fast and will last 8 hours (from 6 AM to 2 PM). After a 3-hour tracer equilibration period, each subject will receive one of the following medications in random order: (i) placebo and (ii) dapagliflozin 10 mg. Following the test medication at 9 AM, blood samples will be drawn every 20 minutes for an additional 5 hours and plasma glucose, insulin, C-peptide, glucagon, catecholamine concentrations and tritiated glucose sp act will be measured. Methods: Visit 1: Screening Visit 2: Endogenous Glucose Production Measurement (EGP) Visit 3: After completing the first EGP measurement, subjects will return to the Diabetes Research Unit for the second study.
Interventions
DRUGDapagliflozin 10mg then Placebo Oral Tablet
SGLT2 inhibitor - Dapagliflozin then Placebo
DRUGPlacebo Oral Tablet then Dapagliflozin 10mg
Placebo then SGLT2 inhibitor - Dapagliflozin
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Post renal transplant type 2 diabetes mellitus patients and non-diabetic mellitus patients after renal transplant with a control group of type 2 diabetes mellitus who have not undergone renal transplant
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* age = 18-70 years * BMI = 18.5-40 kg/m2 * HbA1c ≥ 7.0% and ≤10.0% for type 2 diabetics * males or females * Must be at least 3 months post renal transplantation and be on a stable dose of prednisone (≤5 mg/day), tacrolimus, and mycophenolate mofetil * Not taking any antidiabetic medications or who are treated with metformin, sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor, thiazolidinedione or some combination * Must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis
Exclusion criteria
* Subjects who are taking insulin or SGLT2 inhibitor are excluded * Only subjects whose body weight has not been stable (± 3 lbs) over the preceding three months and/or who participate in an excessively heavy exercise program will be excluded. * Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine \>1.4 females or \>1.5 males (and eGFR \<45ml/min.1.73m2), or 24-hour urine albumin excretion \> 300 mg will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Endogenous Glucose Production (EGP) | baseline and 240-300 minutes | Renal transplant subjects with native kidneys intact underwent measurement of EGP with an 8 hour infusion of 3-3H-glucose on 2 separate days with the administration in random order of either dapagliflozin 10mg or placebo after 3 hours of the tracer equilibration period. The equilibration at 3 hours was considered the baseline measurement. Measurement of change in endogenous glucose production was obtained for all subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose | baseline and 240-300 minutes | Change in Fasting Plasma Glucose in Type 2 Diabetes Mellitus subjects only |
| Change in Fasting Plasma Insulin | baseline and 240-300 minutes | Change in Fasting Plasma Insulin in Type 2 Diabetes Mellitus subjects in diabetic subjects only |
Countries
United States
Participant flow
Pre-assignment details
Diabetic and non-diabetic subjects were assigned to both interventions after randomization, either dapagliflozin first with placebo second, or placebo first and then dapagliflozin next.
Participants by arm
| Arm | Count |
|---|---|
| Diabetic Subjects Diabetic renal transplant subjects with native kidneys intact who were Type 2 diabetics | 6 |
| Non-diabetic Subjects Non-diabetic subjects after renal transplant with intact native kidneys | 8 |
| Control Group Type 2 diabetic subjects who did not under go renal transplant | 20 |
| Total | 34 |
Baseline characteristics
| Characteristic | Total | Control Group | Non-diabetic Subjects | Diabetic Subjects |
|---|---|---|---|---|
| A1C (average blood glucose level over 3 months) | 6.4 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.1 | 7.5 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.2 | 5.6 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.1 | 7.2 Percentage of glycated hemoglobin STANDARD_DEVIATION 0.1 |
| Age, Customized Subjects between 18 and 70 years | 34 Participants | 20 Participants | 8 Participants | 6 Participants |
| Race/Ethnicity, Customized Black Non-Hispanic | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 22 Participants | 12 Participants | 5 Participants | 5 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 10 Participants | 8 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 34 participants | 20 participants | 8 participants | 6 participants |
| Sex: Female, Male Female | 17 Participants | 8 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 17 Participants | 12 Participants | 5 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 20 |
| other Total, other adverse events | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 20 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 20 |
Outcome results
Primary
Change in Endogenous Glucose Production (EGP)
Renal transplant subjects with native kidneys intact underwent measurement of EGP with an 8 hour infusion of 3-3H-glucose on 2 separate days with the administration in random order of either dapagliflozin 10mg or placebo after 3 hours of the tracer equilibration period. The equilibration at 3 hours was considered the baseline measurement. Measurement of change in endogenous glucose production was obtained for all subjects.
Time frame: baseline and 240-300 minutes
Population: The control group did not have renal surgery and were only administered the dapagliflozin, not the placebo, so no participants show for baseline or 240 to 300 minutes for placebo measurements, only for dapagliflozin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Diabetic Subjects | Change in Endogenous Glucose Production (EGP) | Baseline Measurement Placebo | 2.03 mg/kg.min | Standard Deviation 0.2 |
| Diabetic Subjects | Change in Endogenous Glucose Production (EGP) | Baseline Measurement Dapagliflozin | 2.21 mg/kg.min | Standard Deviation 0.19 |
| Diabetic Subjects | Change in Endogenous Glucose Production (EGP) | 240-300 minute measurement Dapagliflozin | 1.96 mg/kg.min | Standard Deviation 0.14 |
| Diabetic Subjects | Change in Endogenous Glucose Production (EGP) | 240-300 minute measurement Placebo | 1.55 mg/kg.min | Standard Deviation 0.09 |
| Non-diabetic Subjects | Change in Endogenous Glucose Production (EGP) | Baseline Measurement Dapagliflozin | 1.85 mg/kg.min | Standard Deviation 0.1 |
| Non-diabetic Subjects | Change in Endogenous Glucose Production (EGP) | Baseline Measurement Placebo | 1.92 mg/kg.min | Standard Deviation 0.1 |
| Non-diabetic Subjects | Change in Endogenous Glucose Production (EGP) | 240-300 minute measurement Placebo | 1.68 mg/kg.min | Standard Deviation 0.1 |
| Non-diabetic Subjects | Change in Endogenous Glucose Production (EGP) | 240-300 minute measurement Dapagliflozin | 1.78 mg/kg.min | Standard Deviation 0.1 |
| Control Group | Change in Endogenous Glucose Production (EGP) | 240-300 minute measurement Dapagliflozin | 2.6 mg/kg.min | Standard Deviation 0.1 |
| Control Group | Change in Endogenous Glucose Production (EGP) | Baseline Measurement Dapagliflozin | 2.5 mg/kg.min | Standard Deviation 0.1 |
Secondary
Change in Fasting Plasma Glucose
Change in Fasting Plasma Glucose in Type 2 Diabetes Mellitus subjects only
Time frame: baseline and 240-300 minutes
Population: Only type 2 diabetic subjects were included in this group, so the 8 non-diabetic renal transplant subjects were not included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Diabetic Subjects | Change in Fasting Plasma Glucose | Baseline Measurement Placebo | 143 mg/dL | Standard Deviation 14 |
| Diabetic Subjects | Change in Fasting Plasma Glucose | 240-300 minute measurement Placebo | 124 mg/dL | Standard Deviation 10 |
| Diabetic Subjects | Change in Fasting Plasma Glucose | Baseline Measurement Dapagliflozin | 143 mg/dL | Standard Deviation 15 |
| Diabetic Subjects | Change in Fasting Plasma Glucose | 240-300 minute measurement Dapagliflozin | 112 mg/dL | Standard Deviation 9 |
| Non-diabetic Subjects | Change in Fasting Plasma Glucose | Baseline Measurement Dapagliflozin | 135.7 mg/dL | Standard Deviation 2.6 |
| Non-diabetic Subjects | Change in Fasting Plasma Glucose | 240-300 minute measurement Dapagliflozin | 106.6 mg/dL | Standard Deviation 1.3 |
Secondary
Change in Fasting Plasma Insulin
Change in Fasting Plasma Insulin in Type 2 Diabetes Mellitus subjects in diabetic subjects only
Time frame: baseline and 240-300 minutes
Population: Only type 2 diabetic subjects were included in this group, so the 8 subjects who were non-diabetic who had renal transplant were not included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Diabetic Subjects | Change in Fasting Plasma Insulin | 240-300 minute measurement Placebo | 10 U/ml | Standard Deviation 1.1 |
| Diabetic Subjects | Change in Fasting Plasma Insulin | Baseline Measurement Dapagliflozin | 14 U/ml | Standard Deviation 3 |
| Diabetic Subjects | Change in Fasting Plasma Insulin | 240-300 minute measurement Dapagliflozin | 11 U/ml | Standard Deviation 2 |
| Diabetic Subjects | Change in Fasting Plasma Insulin | Baseline Measurement Placebo | 12 U/ml | Standard Deviation 2 |
| Non-diabetic Subjects | Change in Fasting Plasma Insulin | Baseline Measurement Dapagliflozin | 15.2 U/ml | Standard Deviation 1.9 |
| Non-diabetic Subjects | Change in Fasting Plasma Insulin | 240-300 minute measurement Dapagliflozin | 9.9 U/ml | Standard Deviation 1.2 |