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

University Hospital, Gentofte, Copenhagen

Status: Completed

Conditions: Type 2 Diabetes

Treatments: Drug: LY2403021; Drug: Empagliflozin placebo; Procedure: Standardised liquid meal; Drug: LY2403021 placebo; Drug: Linagliptin placebo; Drug: Empagliflozin; Drug: Linagliptin

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02792400

H-15018701

Details and patient eligibility

About

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.

Enrollment: 24 patients

Sex: All

Ages: 30 to 75 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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24 participants in 8 patient groups, including a placebo group

A1: GRA-placebo + MEAL + DPP4-placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: Linagliptin placebo

Drug: LY2403021 placebo

A2: GRA-active + MEAL + DPP4-placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: Linagliptin placebo

Drug: LY2403021

A3: GRA-placebo + MEAL + DPP4-active

Active Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: Linagliptin

Drug: LY2403021 placebo

A4: GRA-active + MEAL + DPP4-active

Active Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: Linagliptin

Drug: LY2403021

B1: GRA-placebo + MEAL + SGLT2-placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: LY2403021 placebo

Drug: Empagliflozin placebo

B2: GRA-active + MEAL + SGLT2-placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: LY2403021

Drug: Empagliflozin placebo

B3: GRA-placebo + MEAL + SGLT2-active

Active Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: Empagliflozin

Drug: LY2403021 placebo

B4: GRA-active + MEAL + SGLT2-active

Active Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: Empagliflozin

Drug: LY2403021