Incretin-Based Therapies in Type 2 Diabetes Mellitus

• Published in: The journal of clinical endocrinology and metabolism 2008-10, Vol.93 (10), p.3703-3716
• Main Authors: Chia, Chee W., Egan, Josephine M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biological and medical sciences; Clinical Review; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - therapeutic use; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Glucagon-Like Peptide 1 - adverse effects; Glucagon-Like Peptide 1 - analogs & derivatives; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Incretins - adverse effects; Incretins - therapeutic use; Medical sciences; Models, Biological; Molecular Sequence Data; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2007-2109

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 (HbA1c) 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 HbA1c 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 HbA1c 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 β-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.