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Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus

Authors
Kathleen Dungan, MD
Anthony DeSantis, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

Current pharmacologic treatments for type 2 diabetes are based upon increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion. Glucagon-like peptide-1 (GLP-1)-based therapies (eg, dipeptidyl peptidase 4 [DPP-4] inhibitors, GLP-1 receptor agonists) affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and of food intake (table 1).

This topic will review the mechanism of action and therapeutic utility of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. GLP-1 receptor agonists are discussed separately. A general discussion of the initial management of blood glucose and the management of persistent hyperglycemia in adults with type 2 diabetes is also presented separately. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus" and "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

MECHANISM OF ACTION

Glucagon-like peptide-1 (GLP-1) is produced from the proglucagon gene in L-cells of the small intestine and is secreted in response to nutrients (figure 1) [1]. GLP-1 exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islets [2]. It has also been shown to slow gastric emptying [3], inhibit inappropriate post-meal glucagon release [1,4], and reduce food intake (table 1). GLP-1-based therapies, including the dipeptidyl peptidase 4 (DPP-4) inhibitors, do not usually cause hypoglycemia unless combined with therapies that can cause hypoglycemia [5]. GLP-1 is considered an incretin and is one of a family of naturally occurring gut hormones that is released in the setting of a meal, but not with intravenous carbohydrate, and stimulates insulin synthesis and secretion. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Glucagon-like peptide-1'.)

DPP-4 inhibitors are a class of oral diabetes drugs that inhibit the enzyme DPP-4 [6]. DPP-4 is a ubiquitous enzyme expressed on the surface of most cell types that deactivates a variety of other bioactive peptides, including glucose-dependent insulinotropic polypeptide (GIP) and GLP-1; therefore, its inhibition could potentially affect glucose regulation through multiple effects. However, DPP-4 inhibitors have a modest effect on GLP-1 levels, compared with giving GLP-1 agonists. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus".)

CANDIDATES

Dipeptidyl peptidase 4 (DPP-4) inhibitors are not considered as initial therapy for the majority of patients with type 2 diabetes. Initial therapy in most patients with type 2 diabetes should begin with diet, weight reduction, exercise, and metformin (in the absence of contraindications). DPP-4 inhibitors can be considered as monotherapy in patients who are intolerant of or have contraindications to metformin, sulfonylureas, or thiazolidinediones, such as patients with chronic kidney disease or who are at particularly high risk for hypoglycemia. DPP-4 inhibitors can be considered as add-on drug therapy for patients who are inadequately controlled on metformin, a thiazolidinedione, or a sulfonylurea. However, the modest glucose-lowering effectiveness, expense, and limited clinical experience temper our enthusiasm for these drugs. Therapeutic options for initial and subsequent therapy are reviewed in detail separately. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus", section on 'Choice of initial therapy' and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Treatment options'.)

                

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Literature review current through: Nov 2016. | This topic last updated: Tue Oct 18 00:00:00 GMT+00:00 2016.
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