Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin

NCT02984644 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: HSC20160586H
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

To determine the role of plasma glucagon and insulin in the rise of endogenous glucose production (EGP) following the SGLT2 inhibition.

Conditions

Type II; Diabetes

Outcome Measures

Primary Outcomes (6)

• Measurement of the Change in Plasma Glucose (mg/dL): Study 1

  Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration

  Baseline to 240-300 minutes

• Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2

  Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)

  Baseline to 240-300 minutes

• Change in Plasma Glucose Using a Pancreatic Clamp: Study 3

  Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.

  Baseline to 240-300 minutes

• Change in EGP: Study 1

  Change from baseline to the last hour of the study (240-300 minutes) in EGP

  Baseline to 240-300 minutes

• Change in EGP With Glucose Clamp: Study 2

  Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)

  Baseline to 240-300 minutes

• Change in EGP With Pancreatic Clamp: Study 3

  Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.

  Baseline to 240-300 minutes

Secondary Outcomes (6)

• Change in Plasma Insulin Concentrations: Study 1

  Baseline to 240-300 minutes

• Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2

  Baseline to 240-300 minutes

• Change in Plasma Insulin While Using Pancreatic Clamp: Study 3

  Baseline to last hour of the study

• Change in Glucagon: Study 1

  Baseline to 240-300 minutes

• Change in Glucagon Using Glucose Clamp: Study 2

  Baseline to 240-300 minutes

Study Arms (2)

Dapagliflozin

ACTIVE COMPARATOR

32 subjects will receive dapagliflozin 10mg

Drug: Dapagliflozin

Placebo

PLACEBO COMPARATOR

16 subjects will receive placebo

Drug: Placebo

Interventions

Dapagliflozin DRUG

Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.

Also known as: Farxiga

Dapagliflozin

Placebo DRUG

Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.

Also known as: Placebo for Dapagliflozin

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• T2DM according to ADA criteria-HbA1C \< 8.0%
• BMI = 25-35 kg/m2
• Subjects must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis
• Body weight has been stable (± 3 lbs) over the preceding three months
• Do not participate in an excessively heavy exercise program
• Taking stable dose (more than 3 months) of monotherapy or combination therapy with metformin and/or a sulfonylurea

You may not qualify if:

• Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea) will be excluded
• Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine \>1.4 females or \>1.5 males, or 24-hour urine albumin excretion \> 300 mg will be excluded

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead

Study Sites (1)

University of Texas Health Science Center

San Antonio, Texas, 78229, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Dr. Eugenio Cersosimo
• Organization: University of Texas Health Science Center at San Antonio

cersosimo@uthscsa.edu

210-358-7200

Study Officials

• Eugenio Cersosimo, MD,PhD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2016
• First Posted: December 7, 2016
• Study Start: September 6, 2017
• Primary Completion: November 16, 2018
• Study Completion: November 16, 2019
• Last Updated: December 18, 2019
• Results First Posted: December 18, 2019

Record last verified: 2019-11

Locations

US (1)