DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria <i>via</i> up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy

Abstract

DipeptiDyl peptiDase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which enhances circulating levels of a gut incretin hormone, glucagon-like peptide-1 (GLP-1), by inhibiting the degradation of GLP-1 [1]. GLP-1 stimulates insulin secretion from pancreatic β-cells in a blood glucose-dependent manner and suppresses glucagon release from pancreatic abstract. Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.

Amelioration of Early Markers of Diabetic Nephropathy by Linagliptin in Fructose-Streptozotocin-Induced Type 2 Diabetic Rats

“…To the authors' knowledge, this is the first study that evaluates the effect of a DPP-4 inhibitor on renal vanin-1 in experimental DN. The antioxidant properties attributed to DPP-4 inhibitors were depicted in experimental diabetic models [36,52] and T2D patients [53].…”

Influence of Dipeptidyl Peptidase-IV Inhibitor Sitagliptin on Extracellular Signal-Regulated Kinases 1/2 Signaling in Rats with Diabetic Nephropathy

“…As the first approved DPP-IV inhibitor to reach the market, sitagliptin can reduce the inactivation of GLP-1 and increase active GLP-1 levels in vivo by selectively inhibiting DPP-IV to effectively control BG [35]. Fujita et al [36] recently found that DPP-IV inhibitors can activate cAMP/PKA signaling channels in patients with early type-2 DN, reducing oxidative stress, inhibiting apoptosis, improving proteinuria, and protecting the kidney by upregulating GLP-1. …”

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

“…In addition, type 2 diabetic patients, treated with saxagliptin and followed for a median of 2.1 years, were significantly more likely than patients treated with placebo, to have a lower UACR (Scirica et al 2013). Moreover, Fujita and coworkers (Fujita et al 2014b) performed a cross-over study to investigate the effects of sitagliptin and alogliptin in twelve patients, with diabetic nephropathy, taking ARBs. The treatment regimen consists of three periods; sitagliptin for 4 weeks, alogliptin for 4 weeks and again sitagliptin for 4 weeks.…”