GLP-1 receptor agonists in diabetic kidney disease: from the patient-side to the bench-side

Abstract

Diabetic kidney disease (DKD), one of the most common and severe microvascular complications of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Since the development of renin-angiotensin system inhibition nearly three decades ago, no new therapeutic agents have received regulatory approval for treatment of DKD. Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of newer antihyperglycemic agents, have shown promise for prevention of DKD onset and progression. This perspective summarizes clinical and experimental observations to give insight into biological mechanisms beyond glycemic control, such as natriuresis and anti-inflammatory actions, for preservation of kidney function in patients with diabetes.

Keywords: albuminuria; anti-inflammatory therapy; diabetes; end-stage renal disease.

Fig. 1.

Values estimated by chronic kidney disease epidemiology collaboration equation by cystatin C or creatinine. A: data presented as estimated glomerular filtration rate (eGFR) values by geometric least squares mean from log-transformed analysis. B: data presented as actual untransformed change from baseline in eGFR values [least squares mean, 95% confidence interval (CI)]. C: actual untransformed data macroalbuminuria status at baseline, with values presented as LSM (95% CI). *Versus baseline. †Versus insulin glargine. [Modified from Tuttle et al. (36) with permission from Elsevier.]

Fig. 2.

Conceptual model of hypothesized mechanisms for activation of natriuretic and antioxidant mechanisms by glucagon-like peptide 1 (GLP-1) receptor agonists. GLP-1 receptor agonists inhibit Na⁺/H⁺ exchanger 3 (NHE3) via a protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) dependent pathway to induce natriuresis. Antioxidant effects of GLP-1 receptor agonists occur through activation of protein kinase A and inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.