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

Not Applicable

Completed

• Conditions: Type 2 Diabetes
• Interventions: Drug: LY2403021 placebo; Drug: LY2403021; Procedure: Standardised liquid meal; Drug: Linagliptin placebo; Drug: Linagliptin; Drug: Empagliflozin placebo; Drug: Empagliflozin

• Registration Number: NCT02792400
• Lead Sponsor: University Hospital, Gentofte, Copenhagen

Brief 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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-05
• Study First Submitted: 2016-06-01
• Study First Submitted QC: 2016-06-06
• Study First Posted: 2016-06-07
• Primary Completion: 2016-08
• Status Verified: 2017-11
• Study Completion: 2018-07
• Last Update Submitted: 2020-04-06
• Last Update Posted: 2020-04-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

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

Read More

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

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
A3: GRA-placebo + MEAL + DPP4-active	LY2403021 placebo	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
B4: GRA-active + MEAL + SGLT2-active	LY2403021	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
B4: GRA-active + MEAL + SGLT2-active	Standardised liquid meal	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
A1: GRA-placebo + MEAL + DPP4-placebo	LY2403021 placebo	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo
A1: GRA-placebo + MEAL + DPP4-placebo	Standardised liquid meal	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo
A1: GRA-placebo + MEAL + DPP4-placebo	Linagliptin placebo	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo
A2: GRA-active + MEAL + DPP4-placebo	LY2403021	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo
A2: GRA-active + MEAL + DPP4-placebo	Standardised liquid meal	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo
A2: GRA-active + MEAL + DPP4-placebo	Linagliptin placebo	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo
A3: GRA-placebo + MEAL + DPP4-active	Standardised liquid meal	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
A3: GRA-placebo + MEAL + DPP4-active	Linagliptin	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
A4: GRA-active + MEAL + DPP4-active	LY2403021	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
A4: GRA-active + MEAL + DPP4-active	Standardised liquid meal	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
A4: GRA-active + MEAL + DPP4-active	Linagliptin	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
B1: GRA-placebo + MEAL + SGLT2-placebo	LY2403021 placebo	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
B1: GRA-placebo + MEAL + SGLT2-placebo	Standardised liquid meal	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
B1: GRA-placebo + MEAL + SGLT2-placebo	Empagliflozin placebo	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
B2: GRA-active + MEAL + SGLT2-placebo	LY2403021	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
B2: GRA-active + MEAL + SGLT2-placebo	Standardised liquid meal	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
B2: GRA-active + MEAL + SGLT2-placebo	Empagliflozin placebo	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
B3: GRA-placebo + MEAL + SGLT2-active	LY2403021 placebo	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
B3: GRA-placebo + MEAL + SGLT2-active	Standardised liquid meal	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
B3: GRA-placebo + MEAL + SGLT2-active	Empagliflozin	LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
B4: GRA-active + MEAL + SGLT2-active	Empagliflozin	300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)

Primary Outcome Measures

Name	Time	Method
Difference in postprandial glucose excursions (linagliptin)	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)	Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values).
Difference in postprandial glucose excursions	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)	Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve

Secondary Outcome Measures

Name	Time	Method
Lipolysis	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.	Glycerol disappearance will be calculated by the non-steady state equation using double tracer technique.
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
Energy intake (kcal/kJ)	At time 240 to 270, the participants will eat an ad libitum meal.	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
Changes in blood pressure (mmHg)	Measured at time 0 and time 210 minutes.
Differences in gastric emptying	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes	Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC)
Free fatty acids	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes	Serum values of free fatty acids
Plasma Fibroblast growth factor-21	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Resting energy expenditure	-60 to -50 and 35 to 45	Resting energy expenditure evaluated by 10 minutes of indirect calorimetry.
Endogenous glucose production	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.	Glucose rate of appearance will be calculated by the non-steady state equation using double tracer technique.
Appetite	VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.	Appetite will be evaluated with a visual analogue scale (VAS).
Changes in pulse rate (beat per minute)	Measured at time 0 and at time 210 minutes.

Trial Locations

Locations (1)

Center for Diabetes Research, Gentofte Hospital, Copenhagen University; 🇩🇰 Hellerup, Denmark