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

ABSTRACT

Introduction: Despite type 2 diabetes (T2D) being recognized as a bihormonal pancreatic disease, current therapies are mainly focusing on insulin, while targeting glucagon has been long dismissed. However, glucagon receptor (GCGr) antagonists are currently investigated in clinical trials.

Area covered: Following a brief description of the rationale for antagonizing GCGr in T2D, lessons from GCGr knock-out mice and pharmacological means to antagonize GCGr, a detailed description of the main results obtained with GCGr antagonists in Phase I-II clinical trials is provided. The development of several small molecules has been discontinued, while new ones are currently considered as well as innovative approaches such as monoclonal antibodies or antisense oligonucleotides inhibiting GCGr gene expression. Their potential benefits but also limitations are discussed.

Expert opinion: The proof-of-concept that antagonizing GCGr improves glucose control in T2D has been confirmed in humans. Nevertheless, some adverse events led to stopping the development of some of these GCGr antagonists. New approaches seem to have a better benefit/risk balance, although none has progressed to Phase III clinical trials so far. Pharmacotherapy of T2D is becoming a highly competitive field so that GCGr antagonists should provide clear advantages over numerous existing glucose-lowering medications before eventually reaching clinical practice.

KEYWORDS:

• Antisense oligonucleotides
• glucagon inhibition
• glucagon receptor
• monoclonal antibodies
• small-molecules
• type 2 diabetes

Article highlights

• Glucagon plays a major role in glucose homeostasis, mainly by stimulating hepatic glucose production

• Increased glucagon levels are observed in patients with type 2 diabetes (T2D), which contribute to fasting hyperglycemia and, although to a lesser extent, to postprandial hyperglycemia

• Glucagon receptor (GCGr) knock-out mice are resistant to develop diabetes, a condition at least partially replicated by the use of pharmacological GCGr antagonists in various animal models, but only in conditions with sufficient levels of basal insulin.

• Several small molecules have been developed to antagonize the GCGr, but some of the compounds initially tested in humans have been discontinued because of the occurrence of adverse effects that potentially hinder a favorable benefit-risk ratio

• Novel small-molecule agents and selective monoclonal antibodies targeting the GCGr as well as antisense oligonucleotides that reduce the expression of the GCGr gene are currently investigated in Phase I-II clinical trials, with more promising results, although some increases in liver enzymes and high circulating glucagon levels have also been reported

• The benefit/risk ratio of GCGr antagonists should be better evaluated in further Phase III clinical trials, especially in comparison with classical and more recently accepted glucose-lowering agents, before considering their use in clinical practice for the management of T2D

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Declaration of Interest

The authors would like to state that no conflicts of interest are directly relevant to the content of this manuscript. A. J. Scheen has received lecturer/advisor, clinical investigation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, and Sanofi. N. Paquot has received lecturer/advisor, clinical investigation fees from Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, NovoNordisk and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.