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Literature Compendium |
Current Concepts in Type 2 Diabetes
Volume 2
The Appropriate Application of Oral Pharmacological Therapy, Non-Insulin Injectable Agents, and Insulin in the Management of Type 2 Diabetes
Chapter 3
Antihyperglycaemic Agents: Incretin Hormone Therapies
The failure to achieve adequate glycaemic control has led to further study of the pathogenesis of the disease as well as to new drug discovery. This section highlights the actions and clinical effects of incretin-based therapies.
The islet response to a glucose challenge is regulated not only by the direct effects of blood glucose concentration, but by other factors, including the autonomic nervous system and incretin hormones. Both neural signals and incretins act on pancreatic islet cells in the presence of glucose to increase insulin secretion and decrease glucagon secretion. In humans, the major incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP are released from the intestine in response to nutrient uptake and augment insulin secretion from pancreatic β-cells in a glucose-dependent manner by stimulating all steps of insulin biosynthesis. GLP-1 also suppresses glucagon secretion from α-cells in a glucose-dependent manner.
Recognition of the importance of incretins to the maintenance of glucose homeostasis led to the development of incretin-based therapies, which include inhibitors of dipeptidyl peptidase-4 (DPP-4)—the enzyme responsible for the degradation and rapid inactivation of GLP-1 and GIP—and GLP-1 receptor agonists (also called incretin mimetics)—agents that work by binding and activating the GLP-1 receptor. Hence, both DPP-4 inhibitors and GLP-1 receptor agonists increase active levels of endogenous incretin hormones.
The Drucker and Nauck paper1 is an excellent review of the physiology of the incretin system and the anti-diabetic actions of GLP-1 and GIP. It presents an overview of major clinical trial results for the GLP-1 receptor agonists exenatide and liraglutide, the long-acting GLP-1 receptor agonist exenatide long-acting release (LAR), and the DPP-4 inhibitors sitagliptin and vildagliptin. Finally, there is an informative comparison of GLP-1 receptor agonists and DPP-4 inhibitors that summarizes clinically relevant differences between these drug classes with regard to administration, tolerability, and adverse events.
Rosenstock and Zinman2 provide a superb review of DPP-4 inhibitors in the management of Type 2 diabetes, including a thorough summary of proof-of-concept studies, mechanistic studies, pharmacokinetic studies, preclinical trials, and clinical trials in individuals with Type 2 diabetes treated with sitagliptin or vildagliptin alone or in combination with other agents. The authors state that oral DPP-4 inhibitors improve islet function by increasing α- and β-cell responsiveness to glucose, resulting in improved glucose-dependent insulin secretion and reduced inappropriate glucagon secretion. They also state that DPP-4 inhibitors appear to have physiologically based anti-hyperglycaemic effects and may modify the progressive nature of Type 2 diabetes.
Ratner and colleagues3 performed an 82-week interim analysis of an uncontrolled, open-label extension of a pivotal 30-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy and safety of exenatide in individuals with Type 2 diabetes. Mean change from baseline in HbA1c among individuals treated with exenatide who completed the original 30-week trial (n=183) was –1.0 %, and that among individuals who completed 82 weeks (n=92) was –1.3 %. A total of 46% and 59% of individuals at 30 and 82 weeks, respectively, achieved an HbA1c ≤7.0 %. Mean change from baseline in weight among exenatide-treated individuals who completed the original 30-week trial was –3.0 kg, and that in individuals who completed 82 weeks was –5.3 kg. Hence, the reductions in glycaemia and body weight achieved with exenatide therapy were durable and progressive. Hypoglycaemia was rare. The results of this study are important because they are the first to demonstrate a long-term effect of exenatide therapy.
As these investigations demonstrate, incretin-based therapies represent a new and exciting development in the treatment of Type 2 diabetes. DPP-4 inhibitors and incretin mimetics work by increasing active levels of endogenous incretin hormones and enhance glucose homeostasis via mechanisms involving both α-cells and β-cells. Hence, they fit well into the increasingly recognized paradigm of treating Type 2 diabetes by targeting multiple pathogenic mechanisms. Moreover, studies have demonstrated that they can be used effectively and safely in combination with other classes of anti-diabetic drugs, thereby addressing additional pathogenic pathways and potentially increasing the likelihood of achieving blood glucose and HbA1c targets.
References
3. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419-428.
Click to proceed to Chapter 4.
Click to proceed to Programme Evaluation and Post-test.
Click to return to Opening Page.
Click to return to Table of Contents.
Click to return to Introduction.
Click to return to Chapter 1.
Click to return to Chapter 2.
The Literature Compendium is funded by an educational grant from Pfizer Inc.
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