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

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-1 alpha (SDF-1 alpha) 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-1 alpha, 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-1 alpha-cAMP pathway activation.