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Incretin-based therapies for type 2 diabetes mellitus

Abstract

Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.

Key Points

  • Incretins exert antidiabetic actions in a glucose-dependent manner

  • Glucagon-like peptide 1 receptor (GLP-1R) agonists, but not dipeptidyl peptidase-4 (DPP-4) inhibitors, inhibit gastric emptying and might cause weight loss

  • DPP-4 inhibitors can be administered orally and are well tolerated

  • GLP-1R agonists must be administered by subcutaneous injection and commonly cause nausea

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Figure 1: GLP-1 receptor agonists exert diverse actions on distinct target tissues, which lead to reduction of blood glucose level and body weight in humans.
Figure 2: Mechanism of action of DPP-4 inhibitors.

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Correspondence to Daniel J. Drucker.

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Competing interests

D. Drucker declared associations with the following companies: Amylin Pharmaceuticals, Arena Pharmaceuticals Inc., Arisaph Pharmaceuticals Inc, Conjuchem Inc., Eli Lilly Inc., Emisphere Technologies Inc., GlaxoSmithKline, Glenmark Pharmaceuticals, Hoffman LaRoche Inc., Isis Pharmaceuticals Inc., Mannkind Inc., Merck Research Laboratories, Metabolex Inc., Novartis Pharmaceuticals, Novo Nordisk Inc., Phenomix Inc., Takeda, Transition Pharmaceuticals (advisor/consultant); Arena Pharmaceuticals Inc, Merck Research Laboratories, Metabolex Inc. and Novo Nordisk Inc (advisor/consultant and research/grant support). J. Lovshin declared no competing interests.

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Lovshin, J., Drucker, D. Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 5, 262–269 (2009). https://doi.org/10.1038/nrendo.2009.48

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