Trial Outcomes & Findings for Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (NCT NCT02984644)

NCT ID: NCT02984644

Last Updated: 2019-12-18

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 30 participants
• Primary outcome timeframe: Baseline to 240-300 minutes
• Results posted on: 2019-12-18

Participant Flow

Participant milestones

Measure	Dapagliflozin Subjects will receive dapagliflozin 10mg Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.	Placebo Subjects will receive placebo Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
Overall Study STARTED	20	10
Overall Study COMPLETED	20	10
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study

Baseline characteristics by cohort

Measure	Dapagliflozin n=20 Participants Subjects will receive dapagliflozin 10mg Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.	Placebo n=10 Participants Subjects will receive placebo Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.	Total n=30 Participants Total of all reporting groups
Age, Continuous	55 Years STANDARD_DEVIATION 2 • n=5 Participants	53 Years STANDARD_DEVIATION 2 • n=7 Participants	54 Years STANDARD_DEVIATION 2 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants • 30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study	3 Participants n=7 Participants • 30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study	11 Participants n=5 Participants • 30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study
Sex: Female, Male Male	12 Participants n=5 Participants • 30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study	7 Participants n=7 Participants • 30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study	19 Participants n=5 Participants • 30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study
Ethnicity (NIH/OMB) Hispanic or Latino	13 Participants n=5 Participants	5 Participants n=7 Participants	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	5 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	12 Participants n=5 Participants	4 Participants n=7 Participants	16 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	7 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized African American	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment United States	20 participants n=5 Participants	10 participants n=7 Participants	30 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to 240-300 minutes

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

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Measurement of the Change in Plasma Glucose (mg/dL): Study 1	-29 mg/dl Standard Deviation 4	-17 mg/dl Standard Deviation 3

PRIMARY outcome

Timeframe: Baseline to 240-300 minutes

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)

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2	3 mg/dl Standard Deviation 1	1 mg/dl Standard Deviation 1

PRIMARY outcome

Timeframe: Baseline to 240-300 minutes

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.

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in Plasma Glucose Using a Pancreatic Clamp: Study 3	-30 mg/dl Standard Deviation 4	-7 mg/dl Standard Deviation 5

PRIMARY outcome

Timeframe: Baseline to 240-300 minutes

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

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in EGP: Study 1	0.10 mg/kg.min Standard Deviation 0.1	-0.56 mg/kg.min Standard Deviation 0.11

PRIMARY outcome

Timeframe: Baseline to 240-300 minutes

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)

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in EGP With Glucose Clamp: Study 2	-0.57 mg/kg.min Standard Deviation 0.12	-1.28 mg/kg.min Standard Deviation 0.172

PRIMARY outcome

Timeframe: Baseline to 240-300 minutes

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.

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in EGP With Pancreatic Clamp: Study 3	-0.23 mg/kg.min Standard Deviation 0.09	-0.48 mg/kg.min Standard Deviation 0.05

SECONDARY outcome

Timeframe: Baseline to 240-300 minutes

Plasma insulin concentrations during measurement of EGP

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in Plasma Insulin Concentrations: Study 1	5 microUnits/mL Standard Deviation 1	3 microUnits/mL Standard Deviation 1

SECONDARY outcome

Timeframe: Baseline to 240-300 minutes

Plasma insulin concentration is measured from baseline to the last hour of the study while 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)

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2	0 microUnits/mL Standard Deviation 1	0 microUnits/mL Standard Deviation 1

SECONDARY outcome

Timeframe: Baseline to last hour of the study

Plasma insulin concentration during measurement of EGP while using 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.

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in Plasma Insulin While Using Pancreatic Clamp: Study 3	2 microUnits/mL Standard Deviation 1	0 microUnits/mL Standard Deviation 1

SECONDARY outcome

Timeframe: Baseline to 240-300 minutes

Change in glucagon concentrations during measurement of EGP

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in Glucagon: Study 1	5 ng/ml Standard Deviation 2	-1 ng/ml Standard Deviation 2

SECONDARY outcome

Timeframe: Baseline to 240-300 minutes

Plasma glucagon concentration during measurement of 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.

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in Glucagon Using Glucose Clamp: Study 2	-6 ng/ml Standard Deviation 2	-7 ng/ml Standard Deviation 3

SECONDARY outcome

Timeframe: Baseline to 240-300 minutes

Measurement of change in plasma glucagon from baseline to one hour prior to end of study while 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.

Outcome measures

Measure	Dapagliflozin 10mg n=20 Participants Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Placebo n=10 Participants Change in plasma glucose concentration after placebo administration
Change in Glucagon Using Pancreatic Clamp: Study 3	-1 ng/ml Standard Deviation 1	-2 ng/ml Standard Deviation 2

Adverse Events

Dapagliflozin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Eugenio Cersosimo

University of Texas Health Science Center at San Antonio

Phone: 210-358-7200

Email: cersosimo@uthscsa.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place