A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks

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 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 an 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 preceding the counterpoint narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider 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 provided below, Dr. Nauck provides a defense of incretin-based therapies and that benefits clearly outweigh any concern of risk.

Figure 1

ORs for the diagnosis of (A and C) or hospitalization for (B and D) acute pancreatitis in association with a medication of exenatide (GLP-1 receptor agonist, upper panels) or sitagliptin (DPP-4 inhibitor, lower panels). ORs and their 95% CIs and related P values were obtained directly or calculated (GraphPAD PRISM 5.02) from published analysis of claims databases. Data have been taken from the references quoted in the figure (–21, 24, 50). Recent exposures: medication prescribed for use between 2 years and 30 days before hospitalization; current exposures: medication prescribed for use <30 days before hospitalization.

Figure 2

Relative risk for major cardiovascular events reported as adverse events during phase 3 studies with the GLP-1 receptor agonists exenatide and liraglutide (upper panel) and with the DPP-4 inhibitors sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin (lower panel) compared with pooled comparators (placebo or active control medications). The relative risk is displayed together with the 95% CIs (bars). Data have been taken from the references quoted in the figure (–43).