Context-dependent effects of dipeptidyl peptidase 4 inhibitors

The antidiabetic mechanism of dipeptidyl peptidase 4 (DPP4) inhibitors is attributed to attenuation of incretin metabolism. Because DPP4 has at least 45 substrates, context-dependent off-target effects of DPP4 inhibitors are likely. Here, we consider the clinical ramifications of the context-dependent effects of DPP4 inhibitors.

Although incretins protect organs from diabetic injury, nonincretin DPP4 substrates also accumulate when DPP4 is inhibited. Neuropeptide Y(1-36), peptide YY(1-36), and CXCL12α(1-68) are DPP4 substrates, and emerging results suggest that these peptides promote heart and kidney damage or increase blood pressure. Because levels of, and cellular responses to, these peptides vary depending on context, likely the harmful effects of DPP4 inhibitors are context-dependent. This conclusion is supported by the contrasting results of preclinical studies, some showing cardiorenal protection and others demonstrating harmful effects on the heart and kidneys. Likewise, some preclinical studies report antihypertensive and others prohypertensive effects of DPP4 inhibitors. Several randomized clinical trials, observational studies, and meta-analyses describe detrimental effects of DPP4 inhibitors on outcomes, although others do not (context-dependence).

The beneficial effects of DPP4 inhibitors might be optimized by careful patient selection or by coadministration of Y1 or CXCR4 receptor antagonists to eliminate the off-target effects of DPP4 inhibition.