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Completed

NCT Number: NCT02792400

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

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.

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Key information

Conditions

Type 2 Diabetes Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

30 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Center for Diabetes Research, Gentofte Hospital, Copenhagen University

Hellerup, DK-2900, Denmark

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

LY2403021

Drug

Glucagon receptor antagonist

LY2403021 placebo

Drug

Standardised liquid meal

Procedure

Linagliptin

Drug

DPP-4-inhibitor

Other names: Trajenta

linagliptin placebo

Drug

Empagliflozin

Drug

SGLT2-inhibitor

Other names: Jardiance

Empagliflozin placebo

Drug

Primary outcomes

  1. 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).

  2. 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

Secondary outcomes

  1. 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.

  2. 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.

  3. 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

  4. 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).

  5. 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

  6. Changes in blood pressure (mmHg)

    Time frame: Measured at time 0 and time 210 minutes.

  7. Changes in pulse rate (beat per minute)

    Time frame: Measured at time 0 and at time 210 minutes.

  8. 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)

  9. 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

  10. Plasma Fibroblast growth factor-21

    Time frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes

  11. Resting energy expenditure

    Time frame: -60 to -50 and 35 to 45

    Resting energy expenditure evaluated by 10 minutes of indirect calorimetry.

Sponsors and collaborators

Lead sponsor

University Hospital, Gentofte, Copenhagen

Other

Collaborators

  • Eli Lilly and Company

Registry information

Important dates

Study start
2016
Primary completion
2016
Study completion
2018
First posted
Jun 7, 2016
Registry last updated
Apr 8, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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