Review
Incretin-based therapies: mimetics versus protease inhibitors

https://doi.org/10.1016/j.tem.2007.06.005Get rights and content

The physiological incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), lower blood glucose levels through multiple mechanisms, including enhancement of glucose-stimulated insulin secretion. Although of demonstrated benefit to glycemic control in patients with type 2 diabetes, particularly for GLP-1, the half-lives of these peptides are too short for practical therapeutic utility. Here, we discuss recent approaches to incretin-based therapy, including the use of long-acting GLP-1 receptor agonists, degradation-resistant GLP-1 analogs, GLP-1 analogs conjugated to albumin, non-peptide small molecules that bind to the GLP-1 receptor, and inhibitors of dipeptidyl peptidase IV, the enzyme that degrades both GIP and GLP-1.

Introduction

The incretin concept was first developed based on observations that insulin release was enhanced by oral ingestion of glucose as compared with isoglycemic loads that were administered intravenously. It was therefore hypothesized that, in response to nutrient ingestion, the gastrointestinal tract released one or more hormones that augmented glucose-dependent insulin secretion [1]. The existence of such hormones has now been well established, and the two main incretins have been identified as glucose-dependent insulinotropic polypeptide (GIP; formerly known as gastric-inhibitory polypeptide) and glucagon-like peptide-17–36NH2 (GLP-1) 2, 3, 4. Together, these hormones account for ∼50% of the total insulin response following a meal, and each peptide is believed to contribute equally to the incretin effect [5]. The discovery of the incretins has engendered tremendous interest in their potential for therapeutic use in patients with type 2 diabetes mellitus (T2DM). Indeed, both a GLP-1 receptor agonist and a GLP-1-degradation inhibitor have recently been approved for clinical use, and several related compounds are currently undergoing clinical trials. Here, I consider the advantages and potential disadvantages of the use of such agents in the treatment of patients with T2DM.

Section snippets

Physiology of the incretin system

Both GIP and GLP-1 are secreted by specialized enteroendocrine cells within the epithelial layer of the intestinal tract. However, the GIP-producing K cells are localized proximally, mainly within the duodenum, whereas the L cells that release GLP-1 are distributed primarily in the distal ileum and colon [6]. Release of both hormones is stimulated by nutrient ingestion, and by carbohydrate and fat in particular 7, 8. The circulating levels of GIP rise rapidly following enteral nutrition,

Incretin mimetics

Several different approaches are currently being taken to develop GLP-1 mimetics, including the use of GLP-1 receptor agonists (e.g. exenatide), structurally modified peptides (e.g. liraglutide), conjugated analogs [e.g. ConjuChem-1134-preformed conjugate (CJC-1134-PC) and naliglutide (also known as albugon)] and non-peptide small molecules. The advantages and potential disadvantages of each of these approaches will be discussed in turn.

DP IV inhibitors

One DP IV inhibitor, sitagliptin (Januvia™), has recently been approved for clinical use in the USA. Importantly, both sitagliptin and a related inhibitor, vildagliptin, have been tested extensively for their selectivity for DP IV, as compared with other members of the dipeptidyl peptidase enzyme family 57, 58. Studies on both of these agents in poorly-controlled patients with T2DM have demonstrated a reduction in HbA1c levels of ∼1% over 18–52-week trials but only modest or no decreases in

Clinical value of incretin-based therapies

Although clinical trials on various incretin-based therapies to date have reported only a modest reduction in HbA1c levels (of ∼1%), the true clinical effectiveness of this approach might still remain to be fully realized. For example, the effects of exenatide in patients with poor glycemic control are greater for those individuals with higher initial HbA1c levels (i.e. ≥9% versus <9%) 42, 43, 45. Sitagliptin has similarly been reported to be more effective in patients with higher baseline HbA1c

Conclusions

Over the past decade, novel incretin mimetics and DP IV inhibitors have been developed based upon our current understanding of incretin physiology. The majority of these agents have been demonstrated to lower glycemia in patients, with relatively few side effects and good safety profiles. However, each of these agents demonstrates a unique set of potential disadvantages, all of which must be balanced in consideration of their use. Nonetheless, it is clear that incretin-based therapy shows great

Disclosure statement

The author has served as a consultant in the past 12 months to Johnson & Johnson Pharmaceutical Research & Development, Merck & Co., Inc., Merck Frosst, and Metabolex, Inc.

Acknowledgements

I thank Daniel Drucker and Roman Iakoubov, University of Toronto, for critical reading of the manuscript. P.L.B. is supported by grants from the Canadian Institutes of Health Research and the Canadian Diabetes Association, and by the Canada Research Chair Program.

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