A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe?

Abstract

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk.

Figure 1

GLP-1 actions on exocrine pancreas in animal studies depend on compartment studied and pancreas health. The histological characteristics of the transition from normal pancreas to premalignant changes (PanINs) typically present in the progression from asymptomatic chronic pancreatitis to cancer and, as established by human pathological and mouse genetic studies (top panel, modified from Maitra and Hruban [31]). In nondiabetic animal studies, exposure of pancreas to GLP-1 therapies has minimal discernible impact except in the pancreatic duct gland compartment where marked proliferation generates intraductal papillary projections (A: Pancreatic duct glands are markedly expanded in nondiabetic rats treated with exenatide 10 μg/kg daily for 12 weeks). However the pancreatic ducts show no obvious abnormalities in the same animals. B: In contrast, GLP-1 therapy accelerates pancreatitis and neoplasia in mice prone to chronic pancreatitis. C: Formation of PanINs and pancreatitis are markedly accelerated in the Pdx1-Cre; LSL-Kras^G12D mouse model treated with exenatide 5 nmol/kg for 12 weeks. A, B, and C used with permission from Gier et al. (8).

Figure 2

GLP-1 receptors (GLP-1R) are expressed in premalignant lesions in human thyroid. A: Human thyroid immunostained by immunofluorescence for calcitonin (green), GLP-1 receptor (red), and nuclei (blue) in a normal thyroid (left) and in C-cell hyperplasia (right). Yellow color indicates GLP-1 receptor expression in C cells, which is present occasionally in normal thyroid and frequently in C-cell hyperplasia. B: Human thyroid from papillary thyroid cancer (left and right panels) stained by immunohistochemistry for GLP-1 receptor (GLP-1R) (brown). GLP-1 receptor expression is present in ~20% of papillary thyroid cancers and most medullary thyroid cancers. Used with permission from Gier et al. (28).