GLP-1 Receptor Agonists and Kidney Protection

Abstract

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is determined by specific pathological structural and functional alterations of the kidneys in patients with diabetes, and its clinical manifestations are albuminuria and decline of glomerular filtration rate (GFR). Apart from renin–angiotensin–aldosterone system (RAAS) inhibitors, no other drugs are currently available as therapy for diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. Clinical benefits of GLP-1R agonists were acknowledged due to data from large randomized phase III clinical trials conducted to assess their cardiovascular(CV) safety. These drugs improved renal biomarkers in placebo-controlled clinical studies, with effects supposed to be independent of the actions on glycemic control. In this review, we will focus on the actions of GLP-1R agonists on glucose metabolism and kidney physiology, and evaluate direct and indirect mechanisms through which these drugs may confer renal protection.

GLP-1 Receptor Agonists and Diabetic Kidney Disease: A Call of Attention to Nephrologists

“…GLP-1R activation leads to stimulation of cyclic adenosine monophosphate-protein kinase A pathways, producing antioxidative effects; it, therefore, seems likely that GLP-1 protects the kidney from oxidative injury [40]. In the diabetic nephropathy rat model, GLP-1RA also downregulated expression of several inflammatory biomarkers in rats, such as tubulointerstitial tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1(MCP-1), collagen I, alpha-smooth muscle actin (α-SMA) and fibronectin, all reported to play a role in diabetic nephropathy, as well as ameliorating kidney tubules and tubulointerstitial lesions [70].…”

Renal Outcomes in Type 2 Diabetes: A Review of Cardiovascular and Renal Outcome Trials

“…This is likely The number of participants in each trial is denoted by n eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, HR hazard ratio, ACR albumin-to-creatinine ratio a Results presented as the number of participants with an event per 1000 patient years mediated directly via inhibition of the sodium-hydrogen exchanger 3 (NHE3) in the proximal tubular cells, which augments tubuloglomerular feedback by increasing the sodium load at the macula densa. Furthermore, GLP-1 analogues have been observed to reduce plasma renin and angiotensin levels, further promoting natriuresis and reducing albuminuria [40]. The net impact of these effects is stimulation of afferent arteriolar vasodilatation and inhibition of efferent arteriolar vasoconstriction, resulting in a neutral impact on GFR in general [41].…”

“…The net impact of these effects is stimulation of afferent arteriolar vasodilatation and inhibition of efferent arteriolar vasoconstriction, resulting in a neutral impact on GFR in general [41]. The mechanism by which these drugs reduce albuminuria remains unclear, though several possible mechanisms have been suggested, including the natriuretic effect of GLP-1 analogues, reductions in inflammation and oxidative stress, and reductions in body weight, blood pressure and hyperglycaemia [40,42,43].…”

Kidney health for everyone everywhere— from prevention to detection and equitable access to care

“…18 Another emerging antidiabetic agent in delaying kidney injury is the glucagon-like peptide-1 receptor agonist. 19 A glycated haemoglobin level of <7% should be the goal. Whereas acute kidney injury (AKI) may or may not cause de novo CKD, AKI events that are superimposed on pre-existing CKD may accelerate disease progression.…”