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Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus

Nature Reviews Endocrinology volume 16, pages 642–653 (2020)Cite this article

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Abstract

Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.

Key points

  • Dipeptidyl peptidase 4 inhibitors (DPP4i) were rationally designed based on the prior knowledge of the physiology of glucagon-like peptide 1 and an understanding of the role of DPP4 in its metabolism.

  • DPP4i are all small molecules that inhibit the catalytic activity of the enzyme without affecting any of the other known functions of the DPP4 protein.

  • The DPP4i class comprises a heterogeneous group of unrelated compounds with differing pharmacokinetic profiles.

  • Potential risks and benefits of DPP4i can be divided into class effects, occurring directly as a consequence of the inhibition of DPP4 activity, and compound-specific effects, related to the individual chemical entities.

  • DPP4i have a favourable therapeutic profile and are proven not to increase cardiovascular risk; they are safe and effective in the majority of patients with type 2 diabetes mellitus.

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Fig. 1: Anti-diabetic actions of GLP1.
Fig. 2: Mechanism of action of DPP4i.

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    Carolyn F. Deacon

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No writing assistance or financial support was used in the preparation of this article. C.F.D. has received consultancy and/or lecture fees from companies with an interest in developing and marketing incretin-based therapies for treatment of type 2 diabetes mellitus (Boehringer Ingelheim, Lilly, Merck/MSD and Novo Nordisk). C.F.D.’s spouse is employed by, and holds stock in, Merck/MSD.

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Deacon, C.F. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 16, 642–653 (2020). https://doi.org/10.1038/s41574-020-0399-8

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