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

April 6, 2020 updated by: Sofie Hædersdal, University Hospital, Gentofte, Copenhagen

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Hellerup, Denmark, DK-2900
        • Center for Diabetes Research, Gentofte Hospital, Copenhagen University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: A1: GRA-placebo + MEAL + DPP4-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo
Procedure: Standardised liquid meal
Drug: LY2403021 placebo
Drug: Linagliptin placebo
Placebo Comparator: A2: GRA-active + MEAL + DPP4-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo
Procedure: Standardised liquid meal
Drug: Linagliptin placebo
Drug: LY2403021
Glucagon receptor antagonist
Active Comparator: A3: GRA-placebo + MEAL + DPP4-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
Procedure: Standardised liquid meal
Drug: LY2403021 placebo
Drug: Linagliptin
DPP-4-inhibitor
Other Names:
  • Trajenta
Active Comparator: A4: GRA-active + MEAL + DPP4-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)
Procedure: Standardised liquid meal
Drug: LY2403021
Glucagon receptor antagonist
Drug: Linagliptin
DPP-4-inhibitor
Other Names:
  • Trajenta
Placebo Comparator: B1: GRA-placebo + MEAL + SGLT2-placebo
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
Procedure: Standardised liquid meal
Drug: LY2403021 placebo
Drug: Empagliflozin placebo
Placebo Comparator: B2: GRA-active + MEAL + SGLT2-placebo
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo
Procedure: Standardised liquid meal
Drug: LY2403021
Glucagon receptor antagonist
Drug: Empagliflozin placebo
Active Comparator: B3: GRA-placebo + MEAL + SGLT2-active
LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
Procedure: Standardised liquid meal
Drug: LY2403021 placebo
Drug: Empagliflozin
SGLT2-inhibitor
Other Names:
  • Jardiance
Active Comparator: B4: GRA-active + MEAL + SGLT2-active
300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)
Procedure: Standardised liquid meal
Drug: LY2403021
Glucagon receptor antagonist
Drug: Empagliflozin
SGLT2-inhibitor
Other Names:
  • Jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in postprandial glucose excursions (linagliptin)
Time Frame: 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).
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
Time Frame: 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
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Endogenous glucose production
Time Frame: 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.
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.
Lipolysis
Time Frame: 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.
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.
Appetite
Time Frame: 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).
VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.
Differences in gastric emptying
Time Frame: -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)
-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1.
Time Frame: : 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes
: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes
Energy intake (kcal/kJ)
Time Frame: 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
At time 240 to 270, the participants will eat an ad libitum meal.
Changes in blood pressure (mmHg)
Time Frame: Measured at time 0 and time 210 minutes.
Measured at time 0 and time 210 minutes.
Changes in pulse rate (beat per minute)
Time Frame: Measured at time 0 and at time 210 minutes.
Measured at time 0 and at time 210 minutes.
Free fatty acids
Time Frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Serum values of free fatty acids
-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Plasma Fibroblast growth factor-21
Time Frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Resting energy expenditure
Time Frame: -60 to -50 and 35 to 45
Resting energy expenditure evaluated by 10 minutes of indirect calorimetry.
-60 to -50 and 35 to 45

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Gentofte, Copenhagen

Collaborators

Eli Lilly and Company

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2016

Primary Completion (Actual)

August 1, 2016

Study Completion (Actual)

July 1, 2018

Study Registration Dates

First Submitted

June 1, 2016

First Submitted That Met QC Criteria

June 6, 2016

First Posted (Estimate)

June 7, 2016

Study Record Updates

Last Update Posted (Actual)

April 8, 2020

Last Update Submitted That Met QC Criteria

April 6, 2020

Last Verified

November 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-15018701

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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