Preclinical and Clinical Data on Extraglycemic Effects of GLP-1 Receptor Agonists

Abstract

The diverse actions of the incretin hormone glucagon-like peptide (GLP)-1 include insulinotropic, beta-cell preservative, cardioprotective and vasodilatory effects. This spectrum makes GLP-1 an appealing therapeutic option for patients with type 2 diabetes. However, its rapid metabolism by the enzyme dipeptidyl peptidase (DPP)-4 renders it impractical. Incretin-based analogues have been developed to extend endogenous GLP-1 action (GLP-1 receptor agonists) and to hamper its degradation (DPP-4 inhibitors). Evidence suggests that GLP-1 receptor agonists and DPP-4 inhibitors have different pharmacodynamic and pharmacokinetic effects. For example, GLP-1 receptor agonists deliver supraphysiologic levels of GLP-1 analogues designed to resist inactivation by DPP-4, whereas DPP-4 inhibition conserves native GLP-1 resulting in concentrations within the physiologic range. Furthermore, GLP-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. In contrast, DPP-4 inhibitors are weight neutral and have modest effects on glucose control. DPP-4 inhibition is dependent on the availability of endogenous GLP-1, which appears to be adversely affected by type 2 diabetes and its progression. Therefore, DPP-4 inhibitors may be better suited for patients with mild hyperglycemia without comorbidities. This review examines the present understanding of the pancreatic effects of endogenous GLP-1, and the extrapancreatic actions it exerts on human bodily systems. Also, it analyzes available preclinical and clinical data on incretin therapies with respect to glycemia, lipids, blood pressure, and weight.

Figure 1. Glucagon-like peptide-1: pancreatic and extrapancreatic actions

The various organs or organ systems affected by GLP-1 actions are depicted in the figure. In the pancreas, GLP-1 action causes short term effects that result in increased glucose-dependent insulin- and somatostatin secretion, increased insulin synthesis, and inhibition of glucagon secretion. Long-term effects of GLP-1 action on the pancreas include increased expression of genes that modify beta-cell function and survival in a beneficial way by inhibiting beta-cell apoptosis and stimulating beta-cell replication. In the stomach and intestine, GLP-1 slows motility resulting in delayed gastric emptying and a retardation of intestinal motility. In the CNS, GLP-1 is an important neurotransmitter for regulating appetite and eating behavior. GLP-1 promotes satiety and leads to reduced food intake. Additional long-term effects of GLP-1 on the CNS comprise an improvement of learning and memory, as well as a stimulation of neuronal cell survival and replication. In liver, adipose tissue and muscle, GLP-1 action causes increased glycogen synthesis and liogenesis. These effects are mainly mediated by the increase in insulin secretion and suppression of glucagon secretion mediated by GLP-1. In the heart GLP-1 improves left ventricular function and has preventive effects on ischemic damage of the heart muscle. Reproduced from Best Pract Res Clin Endocrinol Metab, Vol 18, Baggio LL, Drucker DJ, Clinical endocrinology. Glucagon-like peptide-1 and glucagon-like peptide-2, 531-554, 2004, with permission from Elsevier [63].