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

SGLT2 INHIBITION AND STIMULATIION OF ENDOGENOUS GLUCOSE PRODUCTION Significance - PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Dapagliflozin 10mg then Placebo Oral Tablet; Drug: Placebo Oral Tablet then Dapagliflozin 10mg

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.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • The University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo first and then dapagliflozin; Renal transplant subjects with intact native kidneys with Type 2 Diabetes Mellitus receive dapagliflozin then placebo	Drug: Dapagliflozin 10mg then Placebo Oral Tablet; SGLT2 inhibitor - Dapagliflozin then Placebo; Other Names: Farxiga then placebo; Drug: Placebo Oral Tablet then Dapagliflozin 10mg; Placebo then SGLT2 inhibitor - Dapagliflozin; Other Names: Placebo then Farxiga
Active Comparator: Dapagliflozin first then placebo; Renal transplant subjects with intact native kidneys who are non-diabetic receive placebo then dapagliflozin	Drug: Dapagliflozin 10mg then Placebo Oral Tablet; SGLT2 inhibitor - Dapagliflozin then Placebo; Other Names: Farxiga then placebo; Drug: Placebo Oral Tablet then Dapagliflozin 10mg; Placebo then SGLT2 inhibitor - Dapagliflozin; Other Names: Placebo then Farxiga
Other: Control Group; Subjects who are type 2 diabetes mellitus who have not undergone renal transplant.	Drug: Dapagliflozin 10mg then Placebo Oral Tablet; SGLT2 inhibitor - Dapagliflozin then Placebo; Other Names: Farxiga then placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	baseline and 240-300 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fasting Plasma Glucose	Change in Fasting Plasma Glucose in Type 2 Diabetes Mellitus subjects only	baseline and 240-300 minutes
Change in Fasting Plasma Insulin	Change in Fasting Plasma Insulin in Type 2 Diabetes Mellitus subjects in diabetic subjects only	baseline and 240-300 minutes

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Ralph A DeFronzo, MD, The University of Texas Health Science at San Antonio

Publications and helpful links

General Publications

• Daniele G, Solis-Herrera C, Dardano A, Mari A, Tura A, Giusti L, Kurumthodathu JJ, Campi B, Saba A, Bianchi AM, Tregnaghi C, Egidi MF, Abdul-Ghani M, DeFronzo R, Del Prato S. Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy. Diabetologia. 2020 Nov;63(11):2423-2433. doi: 10.1007/s00125-020-05254-w. Epub 2020 Aug 22.
• Solis-Herrera C, Daniele G, Alatrach M, Agyin C, Triplitt C, Adams J, Patel R, Gastaldelli A, Honka H, Chen X, Abdul-Ghani M, Cersosimo E, Del Prato S, DeFronzo R. Increase in Endogenous Glucose Production With SGLT2 Inhibition Is Unchanged by Renal Denervation and Correlates Strongly With the Increase in Urinary Glucose Excretion. Diabetes Care. 2020 May;43(5):1065-1069. doi: 10.2337/dc19-2177. Epub 2020 Mar 6.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): May 15, 2019

Study Registration Dates

• First Submitted: May 24, 2017
• First Submitted That Met QC Criteria: May 24, 2017
• First Posted (Actual): May 30, 2017

Study Record Updates

• Last Update Posted (Actual): September 17, 2020
• Last Update Submitted That Met QC Criteria: September 15, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: HSC20160042H; R01DK107680 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No