Exploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials

Abstract

Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a relatively new class of non-insulin glucose-lowering agents, belonging to the incretin family, which are able to improve glycemic control with a favorable safety profile, since they are associated with a low risk of hypoglycemia, no weight gain, and good tolerability in patients with chronic renal failure. Some experimental and clinical studies suggest that these drugs may exert significant pleiotropic effects, in particular on chronic kidney disease (CKD) progression, but data from clinical trials are still controversial. In an effort to clarify the effects of DPP-4 inhibitors (DPP-4is) on diabetes-related renal damage, we performed a narrative review of available clinical trials and other experimental studies focusing on renal effects of DPP-4is. Currently, there is no conclusive evidence proving the usefulness of this drug class for improving diabetes-related renal damage. However, our literature review suggests that DPP-4is are safe and well tolerated in type 2 diabetes mellitus (T2DM) patients with CKD. More importantly, results from the reviewed studies indicate that DPP-4 inhibitor therapy may improve two major risk factors for diabetic nephropathy, such as hyperglycemia and albuminuria, resulting in potential renal benefits beyond glycemic control. Despite several limitations, the conclusions of our review corroborate previous evidence on the potential renal benefits of DPP-4is, highlighting the urgent need of future trials adequately powered and designed on hard renal outcomes to ascertain (or contradict) the therapeutic benefit of DPP-4is in T2DM and CKD patients.

Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes

“…Several recent reviews have explored the effects of DPP-4is on surrogate renal outcomes [70][71][72]. Renal protection has been demonstrated in various animal models implicating different underlying mechanisms independent of glucose control, including: upregulation of GLP-1 and GLP-1 receptors; inhibition of renal DPP-4 activity; attenuation of inflammasome activation, reduction of oxidative stress; mitochondrial dysfunction and apoptosis; suppression of connective-tissue growth factor; limitation of TGFb-related fibrosis and nuclear factor (NF)-kB p65-mediated macrophage infiltration; reduction of renal tubulointerstitial fibronectin; upregulation of stromal cell-derived factor-1; suppression of advanced glycation end-products; regulation of proliferation of preglomerular vascular smooth muscle and mesangial cells; and attenuation of rises in blood pressure [70][71][72][73]. However, despite such promising results in animal models, data on surrogate biological markers of renal function (UACR, eGFR) and clinical renal outcomes (progression to ESRD) are still relatively scanty in patients with T2DM, and mostly demonstrate the safety rather than true efficacy of DPP-4is regarding renal protection [70].…”

“…Overall, the renal-protective potential of DPP-4is remains largely unproven in humans and merits further investigation [70,72]. Several reasons may explain why DPP-4is failed to positively impact renal outcomes in RCTs.…”

Identification of subgroups of patients with type 2 diabetes with differences in renal function preservation, comparing patients receiving sodium‐glucose co‐transporter‐2 inhibitors with those receiving dipeptidyl peptidase‐4 inhibitors, using a supervised machine‐learning algorithm (PROFILE study): A retrospective analysis of a Japanese commercial medical database

“…Although prior studies have indirectly compared the effects of SGLT2 inhibitors and DPP‐4 inhibitors on glycaemic control, body weight and cardiovascular events, none, to our knowledge, has compared their effects on renal function. Furthermore, the effects of DPP‐4 inhibitors on renal function in clinical practice are not well established . The present study, therefore, offered us an opportunity to explore the effects of SGLT2 inhibitors and DPP‐4 inhibitors on renal function in patients with type 2 diabetes.…”

“…Furthermore, the effects of DPP-4 inhibitors on renal function in clinical practice are not well established. 26,27 The present study, therefore, offered us an opportunity to explore the effects of SGLT2 inhibitors and DPP-4 inhibitors on renal function in patients with type 2 diabetes.…”

The privileged position of glp-1 in diabetic nephropathy

“…These changes result in a clinical presentation that is characterized by proteinuria, hypertension, and progressive reductions in kidney function. [20][21][22][23][24][25][26] Incretins (GLP-1) and glucose dependent insulinotropic peptide (GIP) are small peptides produced by cells of the small intestine as a response to the ingestion of various nutrients. They participate in the regulation of carbohydrate homeostasis through the increase in the production of insulin in a glucose dependent manner, and suppression of the production of glucagon by pancreatic alpha cells.…”