The Role of Glucagon in the Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-glucose Co-transporter-2 Inhibitors

Type 2 Diabetes Clinical Trial

Official title:

The Role of Glucagon in the Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-glucose Co-transporter-2 Inhibitors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02792400
• Other study ID #: H-15018701
• Status: Completed
• Phase: N/A
• Start date: May 2016
• Est. completion date: July 2018

Study information

• Verified date: November 2017
• Source: University Hospital, Gentofte, Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and in response to ingestion of glucose or a mixed meal.glucagon, glucagon concentrations fail to decrease appropriately and may even increase. This diabetic hyperglucagonaemia may therefore contribute importantly to the hyperglycaemia of the patients.

Several glucose-lowering treatment modalities have been shown to affect glucagon levels in patients with type 2 diabetes, but the role of glucagon in the glucose-lowering effects of these treatment modalities has been difficult to discern. By using a glucagon receptor antagonist (GRA) the investigators will exploit glucagon receptor antagonism to delineate the role of glucagon during treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to increase and decrease plasma glucagon levels, respectively.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: July 2018
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 75 Years

Eligibility

Inclusion Criteria:

• Caucasians above 30 years of age with diet or metformin treated type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization)

• Normal haemoglobin

• Informed consent

Exclusion Criteria:

• Inflammatory bowel disease

• Intestinal resections

• Nephropathy (serum creatinine above normal range and/or albuminuria)

• Liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2×normal values)

• Treatment with medicine that cannot be paused for 12 hours

• Pregnancy and/or breastfeeding

• Family history of pancreatic islet tumours

• Age above 75 years

• Treatment with loop-diuretics (applies only to arms with empagliflozin or empagliflozin placebo)

• Chronic heart failure

Related Conditions & MeSH terms

• Type 2 Diabetes

Intervention

Drug:
• LY2403021
Glucagon receptor antagonist
• LY2403021 placebo

Procedure:
• Standardised liquid meal

Drug:
• Linagliptin
DPP-4-inhibitor
• Linagliptin placebo

• Empagliflozin
SGLT2-inhibitor
• Empagliflozin placebo

Locations

Country	Name	City	State
Denmark	Center for Diabetes Research, Gentofte Hospital, Copenhagen University	Hellerup

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Gentofte, Copenhagen	Eli Lilly and Company

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in postprandial glucose excursions (linagliptin)	Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values).	Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with linagliptin (A1, A2, A3, A4)
Primary	Difference in postprandial glucose excursions	Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve	Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with empagliflozin (B1, B2, B3, B4)
Secondary	Endogenous glucose production	Glucose rate of appearance will be calculated by the non-steady state equation using double tracer technique.	Plasma concentration of 6,6^2 H2-glucose and U-13C^6-glucose at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.
Secondary	Lipolysis	Glycerol disappearance will be calculated by the non-steady state equation using double tracer technique.	Plasma concentration of 1,1,2,3,3-^2-H5 - glycerol measured at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.
Secondary	Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1.		: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes
Secondary	Appetite	Appetite will be evaluated with a visual analogue scale (VAS).	VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.
Secondary	Energy intake (kcal/kJ)	At the end of the standardised liquid meal test, food intake will be examined with an ad libitum meal. The weight of the food will be measured in grams and calculated to the energy intake in kcal/kJ	At time 240 to 270, the participants will eat an ad libitum meal.
Secondary	Changes in blood pressure (mmHg)		Measured at time 0 and time 210 minutes.
Secondary	Changes in pulse rate (beat per minute)		Measured at time 0 and at time 210 minutes.
Secondary	Differences in gastric emptying	Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC)	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Secondary	Free fatty acids	Serum values of free fatty acids	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Secondary	Plasma Fibroblast growth factor-21		-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Secondary	Resting energy expenditure	Resting energy expenditure evaluated by 10 minutes of indirect calorimetry.	-60 to -50 and 35 to 45