Renal and Cardiac Effects of DPP-4 Inhibitors – from Preclinical Development to Clinical Research

Abstract

Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta-analyses of combined Phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal Phase III, placebo-controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials – beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure.

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

“…8 Recently, investigations of DPPIV have focused on identifying new physiologically relevant substrates, such as RANTES, neuropeptide Y, and substance P. 9,10 High-mobility group box-1 (HMGB-1) protein is a cytokine identified in 2012 as a substrate of DPPIV that mediates responses to infection, injury, and inflammation. 11,12 A 2012 paper proposed HMGB-1 as a causative factor in renal damage.…”

The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial

“…These results demonstrated, for the first time, that switching to a small dose of sitagliptin based on the renal function has been demonstrated to be effective and safe when administered to the T2DM patients with moderate to severe renal dysfunction. The renal excretion rates as unchanged sitagliptin, alogliptin, vildagliptin, and linagliptin were reported to be 80, 60-71, 21, and < 6%, respectively, showing a higher excretion rate of sitagliptin in the urine compared to any other DPP-4 inhibitors [20]. The concentration of sitagliptin at a decreased dose depending on the degree of renal dysfunction in the tubular lumen was unknown.…”

Efficacy of Saxagliptin versus Mitiglinid in patients with type 2 diabetes and end-stage renal disease

“…Several reports suggest that DPP-4 inhibitors have antiinflammatory effects and can improve bone marrow function [45,46]. The possibility of scission protection by DPP-4 with antiinflammatory agents such as BNP/ANP (brain natriuretic peptide/atrial natriuretic peptide) or NPY (neuropeptide), which are substrates of DPP-4, is suggested, and an intracorporeal inflammation condition is therefore thought to be ameliorated by DPP-4 inhibitor [47][48][49][50]. This may explain the improved iron bioavailability.…”