The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

Abstract

We performed a review of the literature to determine whether the dipeptidyl peptidase-4 inhibitors (DPP4-I) may have the capability to directly and positively influence diabetic microvascular complications. The literature was scanned to identify experimental and clinical evidence that DPP4-I can ameliorate diabetic microangiopathy. We retrieved articles published between 1 January 1980 and 1 March 2014 in English-language peer-reviewed journals using the following terms: (“diabetes” OR “diabetic”) AND (“retinopathy” OR “retinal” OR “nephropathy” OR “renal” OR “albuminuria” OR “microalbuminuria” OR “neuropathy” OR “ulcer” OR “wound” OR “bone marrow”); (“dipeptidyl peptidase-4” OR “dipeptidyl peptidase-IV” OR “DPP-4” OR “DPP-IV”); and (“inhibition” OR “inhibitor”). Experimentally, DPP4-I appears to improve inflammation, endothelial function, blood pressure, lipid metabolism, and bone marrow function. Several experimental studies report direct potential beneficial effects of DPP4-I on all microvascular diabetes-related complications. These drugs have the ability to act either directly or indirectly via improved glucose control, GLP-1 bioavailability, and modifying nonincretin substrates. Although preliminary clinical data support that DPP4-I therapy can protect from microangiopathy, insufficient evidence is available to conclude that this class of drugs directly prevents or decreases microangiopathy in humans independently from improved glucose control. Experimental findings and preliminary clinical data suggest that DPP4-I, in addition to improving metabolic control, have the potential to interfere with the onset and progression of diabetic microangiopathy. Further evidence is needed to confirm these effects in patients with diabetes.

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

“…In support of this speculation, several papers have reported the glucose-independent renoprotective effects of DPP-4 inhibition in animal models of diabetic nephropathy. 15,16,18,27 In the present study, we could not clarify the underlying mechanism for the suppression of AGE-RAGE axis in DPP-4-deficient STZ rats. However, it is unlikely that DPP-4 deficiency decreased renal AGEs levels by improving glycemic or lipid parameters because there was no significant difference of these parameters between DPP-4-deficient STZ rats and wild-type STZ rats.…”

“…[15][16][17] Indeed, linagliptin, an inhibitor of DPP-4, ameliorated kidney fibrosis in type 1 diabetic mice by blocking the endothelial-tomesenchymal transition. 16 Linagliptin administered in addition to stable renin-angiotensin-aldosterone system inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction.…”

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].…”

Factors Associated with Microalbuminuria Remission in Patients with Type 2 Diabetes: Importance of Early Intervention for Microalbuminuric Patients (TSUGARU STUDY)

“…The results suggest that the strict control of the UAE levels is very important. Recently, it was reported that Dpp-4 inhibitors and sodium glucose cotransporter (SGLT)-2 inhibitors decreases albuminuria in patients with DN (17,18). Consequently, the early intervention, example, the use of RAS inhibitors, Dpp-4 inhibitors and/or SGLT-2 inhibitors might be effective for promoting microalbuminuria remission.…”