Introduction✩✩✩

Type 2 diabetes mellitus, with its rapid increase in prevalence worldwide and continued management challenges, poses a major ongoing problem in clinical practice. Although several new therapies have become available in the past 2 decades, use of these treatments has not made it possible to achieve a normal blood sugar level in a large proportion of patients without risks of side effects or of other deleterious results. Indeed, the only major clinical trial to attempt to achieve a normal hemoglobin A1c (HbA1c) level, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), reported a surprising increase in mortality associated with intensive therapy that targeted an HbA1c level <6%. In addition, side effects of diabetes medications, including hypoglycemia, weight gain, and potential cardiovascular problems, have resulted in repeated calls for the evaluation of safety and adverse events over the long term, as opposed to what may be observed in short-term clinical trials, which are much more suitable for drug approval. Thus, large trials, with longer durations, focusing on clinical outcomes and safety, are going to be needed to determine the appropriate place of new therapies in clinical practice.

The limitations of older therapies for diabetes have intensified the quest for new medications and a better understanding of both the physiology and pathophysiology of glucose metabolism. Consequently, there has been much interest in the role of gut hormones in the regulation of blood glucose through modulation of pancreatic function. This has led to an explosion of reports in the literature on the physiologic role of the so-called incretin hormones and incretin effect, how the activity of these hormones might be impaired in diabetes, and what the effects of that impairment might be.

The task of this supplement jointly published in The American Journal of Medicine and The European Journal of Internal Medicine is to review and summarize what is known today about incretin physiology and the pathophysiologic impairment of these hormones, particularly in the context of diabetes. This supplement also discusses and reviews the clinical applications of treatments based on these hormones. Indeed, this field has advanced significantly in that several new medications related to the incretin system have either already been approved for clinical use or are in late stages of development. We therefore review the clinical data currently available on these medications and put them into the context of both the abnormalities of incretin pathophysiology and the unmet needs (instanced above) of patients with type 2 diabetes.

In the first article, Dr. Michael A. Nauck reviews the science of incretin biology, outlines the importance of looking beyond just glucose and insulin, and discusses the physiology of the incretin system and its role in glucose regulation. In this context, the importance of the secretion of glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide and their effects on glucose-dependent secretion of insulin by the pancreatic β-cells are noted and discussed. GLP-1 also has an important effect on the pancreatic α-cells, helping to regulate glucagon secretion—a previously neglected aspect of the pathophysiology of diabetes. Suppression of glucagon, coupled with stimulation of insulin in response to a meal, is normally mediated by GLP-1, but these effects appear to be suboptimal in patients with impaired glucose tolerance and diabetes. There is much to be learned from investigation into the gastrointestinal peptides and their roles in the physiology of not only pancreatic regulation but also appetite regulation and effects on other body systems. For example, there are positive, though not yet definitive, indications (based on clinical trial evidence) that the incretins may help protect β-cell “health” and preserve β-cell functionality, and that consequently therapies based on those hormones could hold out the promise of delaying the progression of type 2 diabetes, particularly if initiated early on in the disease process.

A number of incretin-based agents have been approved for use, including exenatide, a GLP-1 receptor agonist, and sitagliptin, a dipeptidyl peptidase–4 (DPP-4) inhibitor. Moreover, there now is a large body of evidence demonstrating the efficacy and safety of incretin-based therapies. Exenatide has now been available for a few years and has the unique advantage of causing weight loss while improving glycemic control. A number of other GLP-1 analogs are in development, including a long-acting version of exenatide and liraglutide, a GLP-1 analog with 97% human homology. Because native GLP-1 is rapidly deactivated by the enzyme DPP-4, an alternative strategy has been the development of drugs that inhibit this enzyme and thus promote higher levels in circulation of naturally secreted GLP-1, an approach that may be more physiological. On the other hand, such a physiologic approach may lack some of the pharmacologic effects of GLP-1 analogs on gastric emptying and appetite suppression. In the second article, Dr. Matthew P. Gilbert and Dr. Richard E. Pratley discuss the results and implications of a large number of clinical trials involving GLP-1 receptor agonists and DPP-4 inhibitors used as monotherapy as well as in combination with a range of oral antidiabetic agents and insulin.

Experimental evidence suggests that, in addition to the pancreas, the incretin hormones have receptors in many other tissues, and, therefore, potentially have activity that extends beyond known effects on glucose metabolism and glycemic control. For example, GLP-1 receptors are known to be present in the heart and vascular tissue; activation of those receptors may result in vascular protection, as well as beneficial changes in blood pressure and other cardiovascular risk markers. A range of experimental and clinical findings, including in vitro studies, animal data, and clinical marker data from human trials, suggests the exciting possibility that the effects of incretin-based therapies may extend beyond insulin stimulation and glucagon regulation to include the potential to prevent or reverse the progressive loss of β-cell function that is characteristic of type 2 diabetes. Of course, these suggestions and possibilities will require additional clinical investigation in substantial human trials. The potential range of GLP-1 activity may even extend to the central nervous system, the endothelium, and bones, although, again, the clinical relevance of these interactions will require additional investigation. In the third article, Dr. Sunder Mudaliar and Dr. Robert R. Henry move beyond glycemic regulation to discuss all of the potential effects of the incretins.

Finally, when any new class of agents appears, it becomes challenging to determine its true role in clinical practice within existing guidelines and algorithms. It is important to attempt to determine the appropriate patient for any new therapy and then to assess the potential for therapeutic drug synergies or harmful drug–drug interactions. Clinical trials must be developed to determine the true place of new therapies in clinical practice over the long term. In their article on the clinical application of incretin-based therapies, Dr. David M. Kendall and colleagues remind us that although current antidiabetic therapies work, they do leave something to be desired: many patients never get to goal, even on therapy, while others are unable to maintain glycemic control. Part of the problem may be that most current antidiabetic therapies do not target the core pathophysiologic defects of type 2 diabetes, particularly progressive β-cell dysfunction. The new incretin-based therapies could play an important role here, if their promise of β-cell protection and preserved functionality continues to be borne out. Another important aspect of these new therapies is their beneficial (or at least neutral) effect on common comorbidities associated with diabetes, such as overweight/obesity and hypertension. The authors approach these issues in an attempt to find a place for incretin-based therapies within the current paradigm of care.

Ultimately, the goals of the reviews in this supplement are to help the practitioner understand advances in the pathophysiology of type 2 diabetes and to demonstrate how new incretin-based therapies may help not only to control glycemia but perhaps also to address some of the hitherto stubbornly treatment-resistant aspects of this disease.

Author Disclosures 

The author of this article has disclosed the following industry relationships:

Vivian A. Fonseca, MD, has served on the Speakers' Bureau for Daiichi-Sankyo Co. Ltd., Eli Lilly & Co., GlaxoSmithKline, Novartis Pharmaceuticals Corp., Novo Nordisk A/S, sanofi-aventis, and Takeda Pharmaceuticals North America, Inc.; has worked as a consultant to Daiichi-Sankyo Co. Ltd., Eli Lilly & Co., GlaxoSmithKline, Novartis Pharmaceuticals Corp., Novo Nordisk A/S, sanofi-aventis, and Takeda Pharmaceuticals North America, Inc.; and has received research/grant support (to Tulane University) from AstraZeneca, Daiichi-Sankyo Co. Ltd., Eli Lilly & Co., GlaxoSmithKline, Novartis Pharmaceuticals Corp., Novo Nordisk A/S, Pfizer Inc, sanofi-aventis, and Takeda Pharmaceuticals North America, Inc.