Cancer Adverse Events Associated with Dipeptidyl Peptidase 4 Inhibitors: Data Mining of Public FDA Adverse Event Reporting System

Purpose: Dipeptidyl peptidase 4 (DPP 4) is an important enzyme cleaving a variety of physiologically and pathophysiologically important peptides in the circulation, such as certain chemokines, mitogenic growth factors and incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This study evaluated the risk of cancer adverse events associated with anti-diabetic drugs targeting at DPP 4.

Methods: Using the FDA Adverse Event Reporting System (AERS) public database, the adverse events reports (AERs) associated with DPP IV inhibitors, such as sitagliptin, saxagliptin and linagliptin, were generated and evaluated. The AERs involving combination drugs were eliminated. Standardized pharmacovigilance tools were applied to detect the signal of cancer risk. Based on the AERs from 2007 to 2011, the reported cancer adverse events associated with DPP 4 inhibitors were analyzed. The most prevalent cancer signals were also identified.

Results: Among 12618 AERs associated with sitagliptin from 2007 to 2011, there were 223 cases of cancer adverse events. There is a significant correlation between the cancer proportional reporting ratio and the time course (R-sq=63.4%, P<0.001). Pancreatic cancer, leukemia, lung cancer, breast cancer and bladder cancer were the top five most prevalent cancers reported. Pancreatic cancers accounted for 22% of all combined cancer adverse events. The trend of cancer adverse events associated with saxagliptin from 2009 to 2011 was similar to that of sitagliptin. Currently there are not enough AERs on linagliptin approved by the FDA in 2011.

Conclusion: This study signals an increasing trend of cancer risk associated with DPP 4 inhibitors, such as sitagliptina and saxagliptin. Pancreatic cancer is the most prevalent cancer associated with DPP 4 inhibitors. Considering the limitation of AERS, such as under reporting, reporting bias and Webb-effect, this study signals the potential cancer risk associated with popular anti-diabetic drugs and provides goal for future randomized control studies.