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

Sponsor
University Hospital, Gentofte, Copenhagen (Other)
Overall Status
Completed
CT.gov ID
NCT02792400
Collaborator
Eli Lilly and Company (Industry)
24
Enrollment
1
Location
8
Arms
26
Duration (Months)
0.9
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
N/A

Study Design

Study Type:
Interventional
Actual Enrollment :
24 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Basic Science
Official Title:
The Role of Glucagon in the Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-glucose Co-transporter-2 Inhibitors
Study Start Date :
May 1, 2016
Actual Primary Completion Date :
Aug 1, 2016
Actual Study Completion Date :
Jul 1, 2018

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: A1: GRA-placebo + MEAL + DPP4-placebo

LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo

Drug: LY2403021 placebo

Procedure: Standardised liquid meal

Drug: Linagliptin placebo
Placebo Comparator: A2: GRA-active + MEAL + DPP4-placebo

300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo

Drug: LY2403021
Glucagon receptor antagonist

Procedure: Standardised liquid meal

Drug: Linagliptin placebo
Active Comparator: A3: GRA-placebo + MEAL + DPP4-active

LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta)

Drug: LY2403021 placebo

Procedure: Standardised liquid meal

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)

    Drug: LY2403021
    Glucagon receptor antagonist

    Procedure: Standardised liquid meal

    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

    Drug: LY2403021 placebo

    Procedure: Standardised liquid meal

    Drug: Empagliflozin placebo
    Placebo Comparator: B2: GRA-active + MEAL + SGLT2-placebo

    300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo

    Drug: LY2403021
    Glucagon receptor antagonist

    Procedure: Standardised liquid meal

    Drug: Empagliflozin placebo
    Active Comparator: B3: GRA-placebo + MEAL + SGLT2-active

    LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance)

    Drug: LY2403021 placebo

    Procedure: Standardised liquid meal

    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)

    Drug: LY2403021
    Glucagon receptor antagonist

    Procedure: Standardised liquid meal

    Drug: Empagliflozin
    SGLT2-inhibitor
    Other Names:
  • Jardiance

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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).

    2. 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

    1. 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.

    2. 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.

    3. 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]

    4. 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).

    5. 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

    6. Changes in blood pressure (mmHg) [Measured at time 0 and time 210 minutes.]

    7. Changes in pulse rate (beat per minute) [Measured at time 0 and at time 210 minutes.]

    8. 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)

    9. Free fatty acids [-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes]

      Serum values of free fatty acids

    10. Plasma Fibroblast growth factor-21 [-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes]

    11. Resting energy expenditure [-60 to -50 and 35 to 45]

      Resting energy expenditure evaluated by 10 minutes of indirect calorimetry.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    30 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Center for Diabetes Research, Gentofte Hospital, Copenhagen University Hellerup Denmark DK-2900

    Sponsors and Collaborators

    • University Hospital, Gentofte, Copenhagen
    • Eli Lilly and Company

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Sofie Hædersdal, MD, PhD student, University Hospital, Gentofte, Copenhagen
    ClinicalTrials.gov Identifier:
    NCT02792400
    Other Study ID Numbers:
    • H-15018701
    First Posted:
    Jun 7, 2016
    Last Update Posted:
    Apr 8, 2020
    Last Verified:
    Nov 1, 2017
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Additional relevant MeSH terms:
    Empagliflozin
    Linagliptin

    Study Results

    No Results Posted as of Apr 8, 2020