NCT02792400

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
24

participants targeted

Target at below P25 for not_applicable type-2-diabetes

Timeline
Completed

Started May 2016

Typical duration for not_applicable type-2-diabetes

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

May 1, 2016

Completed
1 month until next milestone

First Submitted

Initial submission to the registry

June 1, 2016

Completed
6 days until next milestone

First Posted

Study publicly available on registry

June 7, 2016

Completed
2 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 1, 2016

Completed
1.9 years until next milestone

Study Completion

Last participant's last visit for all outcomes

July 1, 2018

Completed
Last Updated

April 8, 2020

Status Verified

November 1, 2017

Enrollment Period

3 months

First QC Date

June 1, 2016

Last Update Submit

April 6, 2020

Conditions

Type 2 Diabetes

Outcome Measures

Primary Outcomes (2)

  • 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)

  • 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 Outcomes (11)

  • 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.

  • 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.

  • 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

  • Appetite

    VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.

  • Energy intake (kcal/kJ)

    At time 240 to 270, the participants will eat an ad libitum meal.

  • +6 more secondary outcomes

Study Arms (8)

A1: GRA-placebo + MEAL + DPP4-placebo

PLACEBO COMPARATOR

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

Drug: LY2403021 placeboProcedure: Standardised liquid mealDrug: Linagliptin placebo

A2: GRA-active + MEAL + DPP4-placebo

PLACEBO COMPARATOR

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

Drug: LY2403021Procedure: Standardised liquid mealDrug: Linagliptin placebo

A3: GRA-placebo + MEAL + DPP4-active

ACTIVE COMPARATOR

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

Drug: LY2403021 placeboProcedure: Standardised liquid mealDrug: Linagliptin

A4: GRA-active + MEAL + DPP4-active

ACTIVE COMPARATOR

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

Drug: LY2403021Procedure: Standardised liquid mealDrug: Linagliptin

B1: GRA-placebo + MEAL + SGLT2-placebo

PLACEBO COMPARATOR

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

Drug: LY2403021 placeboProcedure: Standardised liquid mealDrug: Empagliflozin placebo

B2: GRA-active + MEAL + SGLT2-placebo

PLACEBO COMPARATOR

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

Drug: LY2403021Procedure: Standardised liquid mealDrug: Empagliflozin placebo

B3: GRA-placebo + MEAL + SGLT2-active

ACTIVE COMPARATOR

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

Drug: LY2403021 placeboProcedure: Standardised liquid mealDrug: Empagliflozin

B4: GRA-active + MEAL + SGLT2-active

ACTIVE COMPARATOR

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

Drug: LY2403021Procedure: Standardised liquid mealDrug: Empagliflozin

Interventions

LY2403021DRUG

Glucagon receptor antagonist

A2: GRA-active + MEAL + DPP4-placeboA4: GRA-active + MEAL + DPP4-activeB2: GRA-active + MEAL + SGLT2-placeboB4: GRA-active + MEAL + SGLT2-active
LY2403021 placeboDRUG
A1: GRA-placebo + MEAL + DPP4-placeboA3: GRA-placebo + MEAL + DPP4-activeB1: GRA-placebo + MEAL + SGLT2-placeboB3: GRA-placebo + MEAL + SGLT2-active
Standardised liquid mealPROCEDURE
A1: GRA-placebo + MEAL + DPP4-placeboA2: GRA-active + MEAL + DPP4-placeboA3: GRA-placebo + MEAL + DPP4-activeA4: GRA-active + MEAL + DPP4-activeB1: GRA-placebo + MEAL + SGLT2-placeboB2: GRA-active + MEAL + SGLT2-placeboB3: GRA-placebo + MEAL + SGLT2-activeB4: GRA-active + MEAL + SGLT2-active
LinagliptinDRUG

DPP-4-inhibitor

Also known as: Trajenta
A3: GRA-placebo + MEAL + DPP4-activeA4: GRA-active + MEAL + DPP4-active
Linagliptin placeboDRUG
A1: GRA-placebo + MEAL + DPP4-placeboA2: GRA-active + MEAL + DPP4-placebo
EmpagliflozinDRUG

SGLT2-inhibitor

Also known as: Jardiance
B3: GRA-placebo + MEAL + SGLT2-activeB4: GRA-active + MEAL + SGLT2-active
Empagliflozin placeboDRUG
B1: GRA-placebo + MEAL + SGLT2-placeboB2: GRA-active + MEAL + SGLT2-placebo

Eligibility Criteria

Age30 Years - 75 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Center for Diabetes Research, Gentofte Hospital, Copenhagen University

Hellerup, DK-2900, Denmark

Location

Related Publications (2)

  • Haedersdal S, Lund A, Nielsen-Hannerup E, Maagensen H, van Hall G, Holst JJ, Knop FK, Vilsboll T. The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition. Diabetes. 2020 Dec;69(12):2619-2629. doi: 10.2337/db20-0369. Epub 2020 Oct 1.

    PMID: 33004472DERIVED

  • Cox AR, Chernis N, Bader DA, Saha PK, Masschelin PM, Felix JB, Sharp R, Lian Z, Putluri V, Rajapakshe K, Kim KH, Villareal DT, Armamento-Villareal R, Wu H, Coarfa C, Putluri N, Hartig SM. STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity. Diabetes. 2020 Dec;69(12):2630-2641. doi: 10.2337/db20-0384. Epub 2020 Sep 29.

    PMID: 32994273DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Linagliptinempagliflozin

Condition Hierarchy (Ancestors)

Diabetes MellitusGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System Diseases

Intervention Hierarchy (Ancestors)

PurinesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-RingHeterocyclic CompoundsQuinazolines

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, INVESTIGATOR
Purpose
BASIC SCIENCE
Intervention Model
CROSSOVER
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
MD, PhD student

Study Record Dates

First Submitted

June 1, 2016

First Posted

June 7, 2016

Study Start

May 1, 2016

Primary Completion

August 1, 2016

Study Completion

July 1, 2018

Last Updated

April 8, 2020

Record last verified: 2017-11

Locations

DK(1)