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Investigational glucagon receptor antagonists in Phase I and II clinical trials for diabetes

André J Scheen1,2, Nicolas Paquot2, Pierre J Lefèbvre2

  • 1a Division of Clinical Pharmacology , Center for Interdisciplinary Research on Medicines (CIRM), University of Liège , Belgium.

Expert Opinion on Investigational Drugs
|October 21, 2017
PubMed
Abstract

Insights

Targeting glucagon receptor (GCGr) antagonists shows promise for type 2 diabetes (T2D) management. While early trials faced challenges, newer approaches offer potential benefits for glucose control.

Area of Science:

  • Endocrinology
  • Pharmacology
  • Metabolic Diseases

Background:

  • Type 2 diabetes (T2D) is a bihormonal pancreatic disease, yet therapies primarily target insulin.
  • Glucagon's role in T2D has been historically overlooked, but glucagon receptor (GCGr) antagonists are now under investigation.

Purpose of the Study:

  • To review the rationale and development of GCGr antagonists for T2D.
  • To summarize clinical trial results and discuss future directions for GCGr antagonism.

Main Methods:

  • Review of preclinical data from GCGr knock-out mice.
  • Analysis of pharmacological strategies to antagonize GCGr.
  • Examination of Phase I-II clinical trial data for GCGr antagonists.

Main Results:

  • Proof-of-concept for improved glucose control with GCGr antagonism in humans confirmed.
  • Development of some small molecule GCGr antagonists was halted due to adverse events.
  • Innovative approaches like monoclonal antibodies and antisense oligonucleotides are emerging.

Conclusions:

  • GCGr antagonists demonstrate potential for T2D therapy, but benefit/risk profiles require careful consideration.
  • Newer therapeutic strategies show promise, though none have reached Phase III trials.
  • GCGr antagonists must offer clear advantages over existing T2D medications to gain clinical acceptance.
Keywords:
Antisense oligonucleotidesglucagon inhibitionglucagon receptormonoclonal antibodiessmall-moleculestype 2 diabetes

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