Dipeptidyl peptidase 4 inhibitors as novel agents in improving survival in diabetic patients with colorectal cancer and lung cancer: A Surveillance Epidemiology and Endpoint Research Medicare study

Abstract

Background Dipeptidyl peptidase 4 (DPP4) is a cell surface protein that can act as a tumor suppressor or activator, depending upon the level of expression and interaction with the microenvironment and chemokines. DPP4 inhibitors are used to treat diabetes. Methods We conducted this Surveillance Epidemiology and Endpoint Research‐Medicare database study to evaluate the role of DPP4 inhibitors on the overall survival (OS) of diabetic patients diagnosed with colorectal (CRC) and lung cancers. Results Diabetic patients with CRC or lung cancer who were treated with DPP4 inhibitors exhibited a statistically significant survival advantage (hazard ratio [HR] of 0.89; CI: 0.82‐0.97, P = 0.007) that remained significant after controlling for all other confounders. When DPP4 inhibitors were used in combination of metformin which is known to suppress cancer, the survival advantage was even more pronounced (HR of 0.83; CI: 0.77‐0.90, P < 0.0001). Data were then analyzed separately for two cancer types. In the CRC‐only cohort, the use of DPP4 inhibitors alone had a positive trend but did not meet statistically significant threshold (HR of 0.87; CI: 0.75‐1.00, P = 0.055), while the combined use of DPP4 inhibitors and metformin was associated with statistically significant survival advantage (HR of 0.77; CI: 0.67‐0.89, P = 0.003). Similarly, for the lung cancer cohort, use of DPP4 alone was not found to be statistically significant (HR of 0.93; CI: 0.83‐1.03, P = 0.153), whereas lung cancer patients treated with the combination of DPP4 inhibitors and metformin showed statistically significant survival advantage (HR of 0.88; CI: 0.80‐0.97, P = 0.010). Conclusions DPP4 inhibition in CRC and lung cancer is associated with improved OS, which possibly may be due to the effect of DPP4 inhibition on immunoregulation of cancer.

Impact of DPP4 Inhibitors in Survival of Patients With Prostate, Pancreas, and Breast Cancer

“…The study showed significant advantage in progression-free survival and a positive trend in overall survival (OS); however, OS did not reach the level of statistical significance likely due to small sample size (12). To further clarify the role of DPP4i, we conducted a SEER (Surveillance Epidemiology and Endpoint Research)-Medicare analysis of colorectal cancer and lung cancer patients, which also showed a similar trend toward beneficial effects associated with CD26/DPP4 inhibition (13). Apart from colorectal and lung cancer, CD26/DPP4 protein is well-expressed in prostate cancer cells, while its expression in pancreatic or breast cancer cells is relatively lower (1,2,14).…”

A Novel Purification Procedure for Active Recombinant Human DPP4 and the Inability of DPP4 to Bind SARS-CoV-2

“…DPP4 preferentially cleaves after proline or alanine in the penultimate position from the N-terminus of polypeptides. DPP4 cleavage of the incretin peptides, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), have led to the development of DPP4 selective inhibitors as a successful type 2 diabetes mellitus (T2DM) therapy [4,[13][14][15][16]. The outer surface of the propeller domain of DPP4 contains binding sites for other proteins, most notably the non-catalytic binding with human adenosine deaminase (ADA) [6,8,17,18].…”

The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease

“…Interestingly, DPP-4 can act either as a tumor activator or suppressor depending on paracrine signals, the microenvironment, and molecular interactions [42,43]. The pharmacological inhibition of DPP-4 in lung cancer patients showed improved overall survival, which was attributed to the effect of DPP-4 inhibition on tumor immunoregulation [44,45]. Information on the role of DPP-4/CD26 in tumor biology can be inferred from either transgenic animals that lack DPP-4 or its pharmacological inhibition.…”