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

Study Overview
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Brief Summary
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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.

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

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: LY2403021
* Drug: LY2403021 placebo
* Procedure: Standardised liquid meal
* Drug: Linagliptin
* Drug: Linagliptin placebo
* Drug: Empagliflozin
* Drug: Empagliflozin placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endogenous glucose production | 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 | 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. | 
| 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 | 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. | 
| Energy intake (kcal/kJ) | 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) |  | Measured at time 0 and time 210 minutes. | 
| Changes in pulse rate (beat per minute) |  | Measured at time 0 and at time 210 minutes. | 
| Differences in gastric emptying | 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 | 
| Free fatty acids | 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 |  | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes | 
| Resting energy expenditure | Resting energy expenditure evaluated by 10 minutes of indirect calorimetry. | -60 to -50 and 35 to 45 |