Until recently, the pathogenesis of
type 2 diabetes mellitus (T2DM) has been conceptualized in terms of the predominant defects in insulin secretion and
insulin action. It is now recognized that abnormalities in other
hormones also contribute to the development of
hyperglycemia. For example, the
incretin effect, mediated by
glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic peptide (GIP), is attenuated in T2DM.
Intravenous administration of
GLP-1 ameliorates
hyperglycemia in patients with T2DM, but an extremely short half-life limits its utility as a therapeutic agent. Strategies to leverage the beneficial effects of
GLP-1 include
GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous
GLP-1 and GIP. The
GLP-1 agonist
exenatide has been shown to improve HbA1c and decrease
body weight. However,
exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of
antibodies. Studies of a long-acting
exenatide formulation suggest that it has improved efficacy and also promotes
weight loss. Another prospect is
liraglutide, a once-daily human
GLP-1 analog. In phase 2 studies,
liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than
exenatide.
DPP-4 inhibitors such as
sitagliptin and
vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the
incretin system with a focus on the role of
GLP-1 receptor agonists and
DPP-4 inhibitors.