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Diabetes Management DPP-4 Inhibitors
Dipeptidyl Peptidase-4 Inhibitors and the Management of Hyperglycemia
Pamela M Katz, MD
1
and Lawrence A Leiter, MD
2
1. Resident, Division of Endocrinology and Metabolism, University of Toronto;
2. Head, Division of Endocrinology and Metabolism, St Michael’s Hospital, and Professor of Medicine and Nutritional Sciences, University of Toronto
Abstract
Incretin-based therapies, including both glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors, are increasingly
being used for the treatment of type 2 diabetes. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are gut-derived incretin
hormones that regulate glucose through co-ordinated effects on pancreatic alpha and beta cells. DPP-4 inhibitors enhance the effects of
endogenous, active GLP-1 and GIP by inhibiting the enzyme responsible for their degradation. These agents lower glycated hemoglobin (HbA
1c
)
and help patients achieve glycemic targets, yet are weight-neutral and, due to their glucose-dependant mechanism of action, carry minimal risk
of hypoglycemia. Furthermore, incretin-based therapies may alter disease progression through preservation of beta-cell mass and function.
Although initially recommended for use in the early stages of type 2 diabetes, DPP-4 inhibitors appear to maintain their glycemic efficacy across
the continuum of disease. They can be used either as monotherapy or in dual or triple combination therapy with other oral antihyperglycemic
agents, and potentially also in combination with insulin. This review will focus on DPP-4 inhibitors and current clinical trial evidence to support
their use in the management of hyperglycemia in type 2 diabetes.
Keywords
Type 2 diabetes, incretin, DPP-4 inhibitors, dipeptidyl peptidase-4, sitagliptin, vildagliptin, saxagliptin
Disclosures: Pamela M Katz, MD, has no conflicts of interest to declare. Lawrence A Leiter, MD, has received research funding from, provided continuing medical education (CME)
on behalf of, and acted as a consultant to AstraZeneca, BMS, BI, Eli Lilly, GSK, Merck, Novartis, Novo Nordisk, Roche, sanofi-aventis, and Servier.
Received: November 15, 2009 Accepted: December 8, 2009
Correspondence: Lawrence A Leiter, MD, Head, Division of Endocrinology & Metabolism, St Michael's Hospital, 61 Queen St East #6121, Toronto, Ontario, Canada M5C 2T2.
E: leiterl@smh.toronto.on.ca
The global prevalence of diabetes has increased dramatically in recent (not approved in the US at present). Caution must be employed when
years and is predicted to rise substantially further to 440 million by comparing efficacy between trials, as the degree of glucose lowering
2030.
1,2
Patients with type 2 diabetes face an increased risk of achieved depends in large part on baseline glycated hemoglobin (HbA
1c
).
microvascular and macrovascular complications leading to significant
morbidity and mortality and enormous healthcare expenditures. Despite Incretin Physiology
the proven benefits of intensive glycemic control, particularly with The incretin effect refers to the augmentation of glucose-stimulated
respect to microvascular disease,
3
the evidence-based goals are insulin secretion by intestinally derived peptides that are released in the
frequently not achieved.
4
presence of nutrients or glucose in the gut.
12
Two gastrointestinal
peptide hormones mainly mediate this response: glucose-dependent
The progressive nature of type 2 diabetes, largely driven by a relentless insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1).
13,14
decline in beta-cell function, leads to an inevitable need for escalation of
treatment strategies.
5–7
Persistent hyperglycemia may hasten this decline GLP-1 and GIP activate G-protein-coupled receptors on pancreatic
through an effect known as glucotoxicity. Unfortunately, intensification of beta cells to stimulate insulin secretion.
15
GLP-1 also acts on alpha
therapy has often led to undesirable side effects, including hypoglycemia cells to inhibit the secretion of glucagon, thereby decreasing hepatic
and weight gain, and may not adequately control post-prandial glucose glucose production. Effects on alpha and beta cells are glucose-
excursions.
8
These and other factors contribute to clinical inertia, resulting dependent, therefore incretin-based therapies carry minimal risk for
in unnecessary and disadvantageous delays to initiation of appropriate hypoglycemia.
15
Further effects of GLP-1 include inhibition of gastric
therapy.
9–11
Understanding of incretin physiology has led to the emptying and a sense of satiety, which may contribute to reduced
development of novel agents that successfully address several of these caloric intake.
13–15
The incretin effect is impaired in patients with type 2
barriers. In this review, we will present the evidence for three DPP-4 diabetes, mainly due to reduced levels of active GLP-1, as well as
inhibitors currently in clinical use: sitagliptin, saxagliptin, and vildagliptin defective GIP activity despite normal or increased levels.
16–20
© TOUCH BRIEFINGS 2009 63
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