PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria

The University of Texas System (UT)

Status and phase: Completed; Phase 4

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: Placebo Oral Tablet then Dapagliflozin 10mg; Drug: Dapagliflozin 10mg then Placebo Oral Tablet

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03168295

R01DK107680 (U.S. NIH Grant/Contract)

HSC20160042H

Details and patient eligibility

About

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.

Full 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.

Enrollment: 34 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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34 participants in 3 patient groups

Placebo first and then dapagliflozin

Experimental group

Description:

Renal transplant subjects with intact native kidneys with Type 2 Diabetes Mellitus receive dapagliflozin then placebo

Treatment:

Drug: Dapagliflozin 10mg then Placebo Oral Tablet

Drug: Placebo Oral Tablet then Dapagliflozin 10mg

Dapagliflozin first then placebo

Active Comparator group

Description:

Renal transplant subjects with intact native kidneys who are non-diabetic receive placebo then dapagliflozin

Treatment:

Drug: Dapagliflozin 10mg then Placebo Oral Tablet

Drug: Placebo Oral Tablet then Dapagliflozin 10mg

Control Group

Other group

Description:

Subjects who are type 2 diabetes mellitus who have not undergone renal transplant.

Treatment:

Drug: Dapagliflozin 10mg then Placebo Oral Tablet