Incretin therapies: The new frontier in diabetes management

Marketplace has spoken to needs of diabetic patients.

Issue: November 2006

ByAlan J. Garber, MD, PhD, MACE

Alan J. Garber, MD, PhD [photo]
Alan J. Garber

Diabetes has always been regarded as a disease of two defects, namely of defective insulin secretion and defective insulin sensitivity. Therapies to overcome the resistance to insulin action have proliferated in recent years with the arrival of rosiglitazone and pioglitizone. They have had an enormous impact upon diabetes practice, although they have not fully displaced metformin as first line therapy for overweight type 2 diabetic patients. They have diminished enthusiasm somewhat for sulfonylureas in these patients; thus, we have good therapies to deal with one of the two fundamental defects. To deal with the other defect of insulin secretion, sulfonylureas have generally been inadequate, and we have had to resort to insulin therapy in such patients. Now, however, we have a new era of diabetes management upon us in which use of the incretin-islet axis can be made to augment insulin secretion and suppress the hyperglucangonemia of type 2 diabetes.

Incretins include the enteric hormones GLP-1 and GIP. Both increase and augment glucose-induced insulin secretion, particularly early insulin secretion. Both of these are defective early in the course of type 2 diabetes. GLP-1 also suppresses glucagon independently of insulin. Hyperglucagonemia is a clear concomitant of diabetes as well. In particular, nonsuppressable glucagons in the immediate postprandial state account for much of the postprandial hyperglycemia noted early in the course of type 2 diabetes. GLP-1 is diminished in IGT and even further in type 2 diabetes. Administration of GLP-1 but not GIP augments glucose induced insulin secretion in patients with diabetes. Additionally, incretins inhibit gastric emptying and have appetite suppressive properties as well. Although these discoveries are less than 20 years old, they have rapidly led to the appearance of a whole new therapeutic focus for diabetic patients.

The unprecedented success of exenetide (Byetta, Amylin) therapy for patients with type 2 diabetes underscores the importance of this therapeutic approach. Exenetide is a mimetic or analog of GLP-1 with about 53% homology with native GLP-1. Although it is administered twice daily by injection, it has had an amazing impact upon the diabetes marketplace and revolutionized thinking about diabetes therapies. Previously, it was thought that injectable therapies such as insulin would be refused by most patients. This is definitely not true of exenetide — many patients actively seek its use and ask their physicians about it. The reason for this is the collateral benefit of weight loss with exenetide, which is now of obvious importance to diabetic patients. Many have never successfully lost weight prior to receiving exenetide.

Now the same approach of replacement GLP-1 therapy is available with the recent approval of DPP-IV inhibitors, the first being sitagliptin (Januvia, Merck). This agent will be shortly followed by the approval of a second DPP-IV inhibitor vildagliptin (Galvus, Novartis) within a month or so. Both agents are potent inhibitors of the endoprotease that specifically inactivates GLP-1 (DPP-IV) which is an alanine directed dipeptidyl peptidase that also functions in the immunomodulation system as CD-26. Both of these inhibitors improve postprandial glucagon, insulin and glucose levels. They have a lesser effect on fasting glucose and on HbA1c reductions than do conventional first-line agents such as metformin, thiazolidinediones and sulfonylureas.

Nevertheless, these new DPP-IV inhibitors are not associated with any weight gain, in marked contradistinction with the thiazolidinediones and sulfonylureas, which both increase weight. Furthermore, unlike sulfonylureas there is no tendency for hypoglycemia with DPP-IV inhibitors unless combined with sulfonylureas or with insulin. This profile of weight neutrality and freedom from hypoglycemia makes the new DPP-IV inhibitors likely successors to sulfonylureas for those patients unwilling or unable to take injectable incretin therapies such as exenetide or longer-acting versions such as liraglutide (fatty acylated GLP-1) or the LAR form of exenetide, both of which will be available in two years or so.

Thus, it seems clear that even before the introduction of weight-specific therapies for type 2 diabetes such as rimonabant, the marketplace has clearly spoken to the needs of diabetic patients and provided a much desired form of antihyperglycemic therapy with collateral benefits highly prized by patients who have been harassed for years to lose weight and exercise, only to be given medicines that produce weight gain and defensive eating to stave off the hypoglycemic side effects of our medications. For these reasons, new approaches to diabetes management will always have a weight aspect to the choices being made. This began with the widespread acceptance of metformin, a weight neutral drug for hyperglycemia, and now extends to the DPP-IV category of oral agents.

Even newer insulins have a weight focus to their development plan. Insulin detemir has little or no weight gain in patients with type 1 diabetes and half the weight gain in patients with type 2 when compared to other basal insulins, even newer basal analogs. Patients will readily take twice daily Byetta injections with no fear of the needle when they learn of the potential for weight loss with this agent. We should all hope for even more agents with weight-neutral or weight-beneficial properties for our populations with exploding obesity, rampant type 2 diabetes and consequential cardiovascular disease. After all, it couldn’t hurt and maybe it will even help a great deal.

For more information:

Alan J. Garber, MD, PhD, is Professor, Departments of Medicine, Biochemistry and Molecular Biology and Cellular and Molecular Biology at Baylor College of Medicine. He is also the Chief Medical Editor of Endocrine Today.