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Glucagon antagonism

Glucagon plays a central role in glucose homeostasis, namely by in-
creasing hepatic glucose production and raising blood glucose levels.
Blunting the effects of has long been considered a means of reduc-
ing hyperglycaemia in T2DM. There are two ways in which to limit the
activity of glucagon. Firstly, immuno-neutralisers effectively reduce the
amount of glucagon in the body, but the development of such com-
pounds for use in humans has not progressed because of limitations im-
posed by the delivery methods necessary to achieve significant levels
of exposure for the peptide agents. 77

Secondly, and more promisingly, are small molecules that inhibit the
glucagon receptor. Several examples of these are in early Phase 2 clini-
cal development. They act by preventing glucagon binding to its re-
ceptor and triggering the increased production of glucose. Blocking
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the action of glucagon is predicted to be an effective means of con-
trolling hepatic glucose production, thereby lowering fasting and post-
prandial hyperglycaemia in T2DM. Table 7 presents a ‘SWOT’ analysis
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of glucagon receptor antagonists.

Table 7. Glucagon receptor antagonists – Strengths, Weaknesses, Opportunities and Threats.

Strengths Weaknesses

z Novel mode of action z Still in the early stages of development
z Orally active z Not yet supported by a large body of late phase
clinical data
z Offers the control of hepatic glucose production
z No data on long-term antagonism of glucagon
receptors
z Glucagon receptor antagonists are an unknown
quantity in T2DM management
z Unknown how glucagon receptor antagonists could
fit in combination therapy
z Glucagon receptors widely expressed throughout
the body
Opportunities Threats

z T2DM management is moving beyond simple z Emergence of other agents with a more familiar
glycaemic parameters mode of action
z The position of many OADs is being eroded by
safety concerns (e.g. SUs, TZDs)
z Patient-centric treatment is increasingly important

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