Incretin-Based Therapies in Type 2 Diabetes Mellitus
Chee W. Chia and
Josephine M. Egan
National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825
Context: Glucagon-like peptide-1 (GLP-1) and glucose-dependentinsulinotropic polypeptide are incretins secreted from enteroendocrinecells postprandially in part to regulate glucose homeostasis.Dysregulation of these hormones is evident in type 2 diabetesmellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) andsitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have beenapproved by regulatory agencies for treating T2DM. Liraglutide(GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expectedto arrive on the market soon.
Evidence Acquisition: The background of incretin-based therapyand selected clinical trials of these four drugs are reviewed.A MEDLINE search was conducted for published articles usingthe key words incretin, glucose-dependent insulinotropic polypeptide,GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin,and vildagliptin.
Evidence Synthesis: Exenatide and liraglutide are injectionbased. Three-year follow-up data on exenatide showed a sustainedweight loss and glycosylated hemoglobin (HbA1c) reduction of1%. Nausea and vomiting are common. Results from phase 3 studiesare pending on liraglutide. Sitagliptin and vildagliptin areorally active. In 24-wk studies, sitagliptin reduces HbA1c by0.6–0.8% as monotherapy, 1.8% as initial combination therapywith metformin, and 0.7% as add-on therapy to metformin. Vildagliptinmonotherapy lowered HbA1c by 1.0–1.4% after 24 wk. Theirmajor side effects are urinary tract and nasopharyngeal infectionsand headaches. Exenatide and liraglutide cause weight loss,whereas sitagliptin and vildagliptin do not.
Conclusions: The availability of GLP-1 mimetics and DPP 4 inhibitorshas increased our armamentarium for treating T2DM. Unresolvedissues such as the effects of GLP-1 mimetics and DPP 4 inhibitorson β-cell mass, the mechanism by which GLP-1 mimetics lowersglucagon levels, and exactly how DPP 4 inhibitors lead to adecline in plasma glucose levels without an increase in insulinsecretion, need further research.
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