Renal Benefits of SGLT 2 Inhibitors and GLP-1 Receptor Agonists: Evidence Supporting a Paradigm Shift in the Medical Management of Type 2 Diabetes

Abstract

Diabetic nephropathy (DN) is one of the most perilous side effects of diabetes mellitus type 1 and type 2 (T1DM and T2DM).). It is known that sodium/glucose cotransporter 2 inhibitors (SGLT 2i) and glucagone like peptide-1 receptor agonists (GLP-1 RAs) have renoprotective effects, but the molecular mechanisms are still unknown. In clinical trials GLP-1 analogs exerted important impact on renal composite outcomes, primarily on macroalbuminuria, possibly through suppression of inflammation-related pathways, however enhancement of natriuresis and diuresis is also one of possible mechanisms of nephroprotection. Dapagliflozin, canagliflozin, and empagliflozin are SGLT2i drugs, useful in reducing hyperglycemia and in their potential renoprotective mechanisms, which include blood pressure control, body weight loss, intraglomerular pressure reduction, and a decrease in urinary proximal tubular injury biomarkers. In this review we have discussed the potential synergistic and/or additive effects of GLP 1 RA and SGLT2 inhibitors on the primary onset and progression of kidney disease, and the potential implications on current guidelines of diabetes type 2 management.

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

“…GLP-1 receptor agonists (GLP-1 RA) are used in the metabolic control of obesity and T2DM patients because they enhance glucose-dependent insulin synthesis and secretion, proliferation of β-cells, inhibition of β-cells apoptosis, delay of gastric emptying and regulation of appetite by satiety-effects with body weight reduction [323][324][325]. GLP-1 RA reduces albuminuria and histological renal damage [326], and downregulates genes related to inflammation (NF-κB, TNF-α, MCP-1) [327], oxidative stress (Nox4 and subunits gp91phox, p22phox, p47phox) [328], de novo lipogenesis/lipotoxicity (SREBP-1; ABCA1) [329] and fibrosis (α-SMA, fibronectin, collagen I) [330].…”

Kidney Inflammation, Injury and Regeneration

“…In addition, the potential of cell-based therapy approaches that use mesenchymal stromal/stem cells (MSCs) or their derivates is summarized [23][24][25]. This edition is complemented by a series of reviews that deal with the current data situation on other very specific topics like diabetes and diabetic nephropathy [26][27][28], as well as new therapeutic targets [29].In this Special Issue, twelve original research articles are presented that dealt with different questions and the research models used within. The findings of Mocker and co-workers demonstrate that renal chemerin expression, a chemoattractant adipokine, is associated with processes of inflammation and fibrosis during renal damage [2].…”

“…In addition, the potential of cell-based therapy approaches that use mesenchymal stromal/stem cells (MSCs) or their derivates is summarized [23][24][25]. This edition is complemented by a series of reviews that deal with the current data situation on other very specific topics like diabetes and diabetic nephropathy [26][27][28], as well as new therapeutic targets [29].…”

No Cytotoxic and Inflammatory Effects of Empagliflozin and Dapagliflozin on Primary Renal Proximal Tubular Epithelial Cells under Diabetic Conditions In Vitro

“…In addition, a series of in vitro cytotoxicological investigations were conducted to evaluate a mode of action for gliflozin-associated effects. In addition to the in vitro studies, the effects of gliflozins on the kidney were also assessed in several in vivo studies and in clinical trials (currently reviewed by Ninčević and co-workers [34]), which should not be discussed here. Cytotoxicity and inflammation mediated by high glucose is directly responsible for pathological changes in diabetic nephropathy [35].…”