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.

Keywords: GLP-1 receptor agonists; SGLT2 inhibitors; diabetes mellitus; diabetic nephropathy; molecular mechanisms.

Figure 1

Mechanism of action of SGLT2i and GLP 1RA on kidney. SGLT2i inhibit glucose and sodium transport via SGLT2 and GLUT 2 transporters which are responsible for 90% of glucose reabsorption thus inducing glucosuria, diuresis, natriuresis, and uric acid excretion. At the same time GLP 1RA via NHE3 are also promoting diuresis and natriuresis. Influx of sodium to macula densa is increased thus affecting afferent vasoconstriction causing reduction in intraglomerular pressure and proteinuria through tubuloglomerular feedback. Both, GLP 1RA and SGLT2i induce suppression of inflammatory markers such as TGFβ, IL6, TNFα, decreasing glomerusclerosis and tubulointerstitial lesions and causing afferent vasoconstriction (induction of NO is also involved). GLP 1RA therapy leads to a decrease in RAAS activity causing efferent vasodilatation, while the effect of SGLT2i is quite the opposite, it increases RAAS activity due to natriuresis and volume depletion implying that positive effect on intraglomerular pressure is mediated completely through tubuloglomerular feedback; ↑ increase; ↓ decrease.