TY - JOUR

T1 - Separate and combined effects of long-term GIP and GLP-1 receptor activation in patients with type 2 diabetes

T2 - a structured summary of a study protocol for a double-blind, randomised, placebo-controlled clinical trial

AU - Helsted, Mads M.

AU - Gasbjerg, Lærke S.

AU - Vilsbøll, Tina

AU - Nielsen, Casper K.

AU - Forman, Julie L.

AU - Christensen, Mikkel B.

AU - Knop, Filip K.

N1 - Publisher Copyright: © 2023 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023

Y1 - 2023

N2 - Introduction Due to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, tirzepatide, a novel dual incretin receptor agonist (activating the GIP receptor and the glucagon-like peptide 1 (GLP-1) receptor) has demonstrated greater glucose and body weight-lowering properties as compared to GLP-1 receptor agonist therapy. The contribution of GIP receptor activation to effects of tirzepatide remains unknown. We will evaluate the glucose-lowering effect of exogenous GIP in the context of pharmacological GLP-1 receptor activation in patients with T2D. Methods and analysis In this randomised, double-blind, four-arm parallel, placebo-controlled trial, 60 patients with T2D will be included (18-74 of age; on diet and exercise and/or metformin therapy only; glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)). Participants will be randomised to an 8-week run-in period with subcutaneous (s.c.) placebo or semaglutide injections once-weekly (0.5 mg). Participants will then be randomised to 6 weeks' add-on treatment with continuous s.c. placebo or GIP infusion (16 pmol/kg/min). The primary endpoint is change in mean glucose levels (assessed by 14-day continuous glucose monitoring) from the end of the run-in period to end of trial. Ethics and dissemination The present study was approved by the Regional Committee on Health Research Ethics in the Capitol Region of Denmark (identification no. H-20070184) and by the Danish Medicines Agency (EudraCT no. 2020-004774-22). All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals.

AB - Introduction Due to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, tirzepatide, a novel dual incretin receptor agonist (activating the GIP receptor and the glucagon-like peptide 1 (GLP-1) receptor) has demonstrated greater glucose and body weight-lowering properties as compared to GLP-1 receptor agonist therapy. The contribution of GIP receptor activation to effects of tirzepatide remains unknown. We will evaluate the glucose-lowering effect of exogenous GIP in the context of pharmacological GLP-1 receptor activation in patients with T2D. Methods and analysis In this randomised, double-blind, four-arm parallel, placebo-controlled trial, 60 patients with T2D will be included (18-74 of age; on diet and exercise and/or metformin therapy only; glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)). Participants will be randomised to an 8-week run-in period with subcutaneous (s.c.) placebo or semaglutide injections once-weekly (0.5 mg). Participants will then be randomised to 6 weeks' add-on treatment with continuous s.c. placebo or GIP infusion (16 pmol/kg/min). The primary endpoint is change in mean glucose levels (assessed by 14-day continuous glucose monitoring) from the end of the run-in period to end of trial. Ethics and dissemination The present study was approved by the Regional Committee on Health Research Ethics in the Capitol Region of Denmark (identification no. H-20070184) and by the Danish Medicines Agency (EudraCT no. 2020-004774-22). All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals.

KW - diabetes

KW - endocrinology

KW - general diabetes

KW - general endocrinology

KW - lipid disorders

UR - http://www.scopus.com/inward/record.url?scp=85148968936&partnerID=8YFLogxK

U2 - 10.1136/bmjopen-2022-065736

DO - 10.1136/bmjopen-2022-065736

M3 - Journal article

C2 - 36849212

AN - SCOPUS:85148968936

VL - 13

JO - BMJ Open

JF - BMJ Open

SN - 2044-6055

IS - 2

M1 - e065736

ER -