Incretin Therapy and Pancreatic Pathologies: Background Pathology Versus Drug-Induced Pathology in Rats

  1. Chee W. Chia
  1. National Institute on Aging, National Institutes of Health, Baltimore, MD
  1. Corresponding author: Josephine M. Egan, eganj{at}mail.nih.gov.

It is essential that postmarketing surveillance be conducted for any new drug, especially if the drug is a trailblazer for a new class of compounds, so that possible safety concerns not detected during clinical trials can be brought to light. It is also usual for a new drug class to be first marketed as a “game changer,” followed by its vilification for potential safety issues (usually accompanied by lawsuits). Over time, its true benefits and safety profile are refined, confirmed, or denied after it has been used in the general population by large numbers of patients with a wide variety of medical conditions. The whole process can take years and sometimes involves a seesaw of both easing and adding restrictions to its clinical use as witnessed in the recent easing by the U.S. Food and Drug Administration (FDA) of the restrictions on rosiglitazone (1). Even when a drug has been in use for a long time, its complete mechanisms of action may remain enigmatic; e.g., the basic mechanisms of action for biguanides are still being determined even though their glucose-lowering properties have been known for 85 years.

Two novel classes of compounds for lowering blood glucose in type 2 diabetes came on the U.S. market recently—glucagon-like peptide 1 (GLP-1) receptor agonists (exenatide in 2005) and dipeptidyl peptidase-4 (DPP4) inhibitors (sitagliptin in 2006). Since then, the FDA has approved other agents in these two drug classes: liraglutide, a GLP-1 receptor agonist, and vildagliptin, saxagliptin, linagliptin, and alogliptin, all DPP4 inhibitors. Though both drug classes are commonly referred to as GLP-1–based or incretin-based therapies and epidemiological studies often lump the two classes of drugs together in analyses, it needs pointing out that “incretin therapy” is not precise terminology. While exenatide and liraglutide are ligands exclusively of the GLP-1 receptor, the effects of …

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