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Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors

Joshua J Neumiller
Journal of the American Pharmacists Association: JAPhA 2009, 49 Suppl 1: S16-29
19801361

OBJECTIVE: To review the pharmacology (absorption, metabolism, distribution, elimination, and contraindications) of incretin-based agents currently available and in regulatory review for the treatment of patients with type 2 diabetes.

DATA SOURCES: Medline search of all relevant clinical and review articles.

STUDY SELECTION: English-language articles pertinent to the pharmacology, pharmacodynamics, pharmacokinetics, efficacy, and safety of glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors were reviewed for relevance.

DATA EXTRACTION: Data pertinent to the pharmacology, pharmacodynamics, pharmacokinetics, efficacy, and safety of GLP-1 agonists and DPP-4 inhibitors were extracted and used.

DATA SYNTHESIS: Incretin hormones are secreted from the gastrointestinal tract following meal ingestion, the two most important of which are glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. Patients with type 2 diabetes have an impaired response to GIP, while intravenous GLP-1 has been shown to increase insulin secretion in response to elevated glucose levels. Incretin-based agents include GLP-1 receptor agonists, which mimic endogenous GLP-1, and DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, alogliptin), which inhibit the breakdown of endogenous incretin hormones. GLP-1 receptor agonists stimulate insulin secretion in a glucose-dependent manner and suppress glucagon secretion with a low risk of hypoglycemia. The GLP-1 receptor agonists are further differentiated as either human analogues (e.g., liraglutide) or synthetic exendin-based mimetics (e.g., exenatide). These agents delay gastric emptying and may beneficially affect satiety and are thus associated with weight reduction.

CONCLUSION: GLP-1 receptor agonists and DPP-4 inhibitors facilitate therapy intensification and achievement of established glycemic goals. They enhance postprandial and fasting glycemic control, and use may improve beta-cell function and possibly preserve beta-cell mass. GLP-1 receptor agonists may also have favorable effects on blood pressure. They may be introduced as adjuncts to ongoing therapy with conventional agents with a potential benefit of slowing the progression of type 2 diabetes.

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