Therapeutic Targeting of SGLT2: A New Era in the Treatment of Diabetes and Diabetic Kidney Disease

Abstract

As the prevalence of diabetic kidney disease (DKD) continues to rise, so does the need for a novel therapeutic modality that can control and slow its progression to end-stage renal disease. The advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors has provided a major advancement for the treatment of DKD. However, there still remains insufficient understanding of the mechanism of action and effectiveness of this drug, and as a result, its use has been very limited. Burgeoning evidence suggests that the SGLT2 inhibitors possess renal protective activities that are able to lower glycemic levels, improve blood pressure/hemodynamics, cause bodyweight loss, mitigate oxidative stress, exert anti-inflammatory and anti-fibrotic effects, reduce urinary albumin excretion, lower uric acid levels, diminish the activity of intrarenal renin-angiotensin-aldosterone system, and reduce natriuretic peptide levels. SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m2, associated with a constellation of signs of metabolic reprogramming, including enhanced ketogenesis, which may be responsible for the correction of metabolic reprogramming that underlies DKD. This article aims to provide a comprehensive overview and better understanding of the SGLT2 inhibitor and its benefits as it pertains to renal pathophysiology. It summarizes our recent understanding on the mechanisms of action of SGLT2 inhibitors, discusses the effects of SGLT2 inhibitors on diabetes and DKD, and presents future research directions and therapeutic potential.

Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment

“…Other potential advantages from SGLT2 inhibitors may be reduction of anti-inflammatory, anti-oxidant, and anti-fibrotic markers [ 94 ]. In addition, studies with Ipragliflozin, Dapagliflozin, and Empagliflozin found decreased levels for oxidative stress and macrophages markers (MCP-1, NF-kB, 8-OhdG, L-fatty acid, interleukin-6, monocyte-attractive-protein-1) [ 95 , 96 , 97 ]. Regarding adverse effects, the most commonly observed were genital infections, urinary tract infections, bone fractures, or diabetic ketoacidosis [ 89 , 98 ].…”

Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials

“…The SGLT2i are a new category of anti-diabetic drugs, approved by the Food and Drug Administration (FDA), used to treat patients with type 2 diabetes ( 27 ). SGLT2i family includes dapagliflozin, empagliflozin, luseogliflozin, ipragliflozin, phlorizin, and canagliflozin ( 28 ).…”

The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy

“…Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the most recent and promising development in the treatment of diabetes and have recently been approved for use in diabetic nephropathy for people with T2DM. The inhibitors block glucose reabsorption in the proximal tubule, increasing glucose excretion in the urine, allowing blood glucose to be controlled without the risk of hypoglycaemia ( Shaffner et al, 2021 ), reducing glomerular hyperfiltration through sodium mediated activation of tubuloglomerular feedback ( Davidson, 2019 ). Dapagliflozin, an SGLT2 inhibitor, has been shown to reduce renal injury even in the absence of diabetes, through inhibition of the NLRP3 inflammasome, protecting against kidney fibrosis ( Ke et al, 2022 ).…”