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

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Abstract

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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    Disclosure: Research support from Novartis and Merck. Otherwise, the author declares no conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria.

    Acknowledgment: AdelphiEden Health Communications and Jacki Gordon, PhD for medical editorial services.

    Funding: Publication of the supplement to JAPhA made possible through an educational grant from Novo Nordisk Inc.

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