Incretin Therapy and Islet Pathology: A Time for Caution

  1. Steven E. Kahn
  1. Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington
  1. Corresponding author: Steven E. Kahn, skahn{at}u.washington.edu.

The past 25 years have seen the introduction of a number of new classes of medications for treating type 2 diabetes. The primary goal of these drugs is to safely lower plasma glucose in order to simultaneously reduce vascular complications and improve quality of life.

It is equally critical to demonstrate an agent’s therapeutic effectiveness as it is to prove its safety. Frequently, this determination of safety occurs in the very early stages of drug development. However, in some instances, it is only after sufficient clinical experience has been obtained that the potential for harm becomes apparent. Recent examples include two therapeutically effective thiazolidinediones: troglitazone, which increased the risk of hepatic injury (1), and rosiglitazone, which a meta-analysis suggested increased the risk of cardiovascular events (2).

Two recently introduced classes of glucose-lowering agents increase incretin action. One is the glucagon-like peptide-1 (GLP-1) receptor agonists. In 2005, exenatide was the first of these agents to be introduced (3). The other is the dipeptidyl peptidase-4 (DPP-4) inhibitors, of which sitagliptin was initially approved in 2006 (3). These medications are widely used, and are associated with a reduced risk of hypoglycemia and weight gain. This, despite the fact that they may increase the risk of pancreatitis (4,5), a condition that is known to be more common in type 2 diabetes (6).

In this issue of Diabetes, authors from Florida and California together report pancreatic morphology from a limited series of samples from diabetic individuals who did or did not receive incretin therapy and a cohort not known to have diabetes (7). Seven of the diabetic samples were from patients who received sitagliptin and one who received exenatide, all for unknown periods of time beyond 1 year. Pancreata were procured from brain-dead organ donors by the Network for Pancreatic …

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  1. Diabetes vol. 62 no. 7 2178-2180
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