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.