Incretin-based therapies in type 2 diabetes mellitus

Abstract

Context: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon.

Evidence acquisition: The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin.

Evidence synthesis: Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA(1c)) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA(1c) by 0.6-0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA(1c) by 1.0-1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not.

Conclusions: The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on beta-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.

Figure 1

Structure of native GLP-1, exenatide, liraglutide, sitagliptin, and vildagliptin. The N-terminal dipeptide “HA” of GLP-1 is cleaved by DPP 4, and the remaining fragment does not increase insulin secretion. For exenatide the substitution of glycine for alanine at position 8 prevents the degradation by DPP 4. The free-fatty acid derivative that is attached to liraglutide is thought to promote noncovalent binding of liraglutide to albumin.

Figure 2

Mechanism of action of sitagliptin, vildagliptin, and exenatide. GLP-1 is released from L cells (stained red) of the gut, and is subject to DPP 4 (stained green on endothelial cells of blood vessels of the gut) degradation in both gut and blood. Sitagliptin and vildagliptin inhibit DPP 4 action in blood and on endothelial cells. Metformin, orlistat, and α-glucosidase inhibitors increase GLP-1 secretion. Exenatide, a GLP-1R agonist, increases insulin secretion from β-cells (stained green) in islets of Langerhans. The α-cells in islets are stained red.