Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

Abstract

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.

Figure 1. Physiology of GLP-1 secretion and action on GLP-1 receptors in different organs and tissues

GLP-1 is produced postprandially by intestinal L-cells. Through activation of insulin receptors on beta-cells GLP-1 (like GIP) stimulates insulin biosynthesis and secretion and inhibits glucagon secretion in the pancreas, which in turn reduces hepatic gluconeogenesis. GLP-1 release also exerts protective effects on heart and brain. Insulin sensitivity in the periphery is increased by improved insulin signaling and reduced gluconeogenesis. Figure modified with permission from Cell Metabolism [3].

Figure 2. Diminished incretin effect in type 2 diabetes

Differences in C-peptide responses between oral and i.v. glucose challenges are attributed to the incretin effect that takes place in the intestine. This effect is not present in parenteral glucose administration (turquoise curves). In healthy individuals (left panel) the difference is significant (^* p ≤ 0.05). In type 2 diabetes patients (right panel) the incretin effect is smaller or almost diminished compared with normal healthy individuals. Figure reproduced with permission from Journal of Clinical Endocrinology and Metabolism [16].

Figure 3

Clinical effects of GLP-1 receptor agonists (exenatide, exenatide LAR, liraglutide) and DPP-4 inhibitors (sitagliptin, vildagliptin) on HBA1c (A), change in body weight (B) and hypoglycemia (C) [19, 43-45, 49, 51, 71, 74, 96-106]. DPP-4: dipeptidyl peptidase-4. TZD: thiazolidinedione. OAD: oral antidiabetic drug. ^* p < 0.05. Reproduced with permission from Lancet [19].