Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D

Abstract

The management of type 2 diabetes (T2D) involves decreasing plasma glucose levels and reducing cardiovascular and microvascular complications. Diabetic kidney disease (DKD), defined as presence of albuminuria, impaired glomerular filtration, or both, is an insidious microvascular complication of diabetes that generates a substantial personal and clinical burden. The progressive reduction in renal function and increased albuminuria results in an increase of cardiovascular events. Thus, patients with DKD require exhaustive control of the associated cardiovascular risk factors. People with diabetes and renal impairment have fewer options of antidiabetic drugs because of contraindications, adverse effects, or altered pharmacokinetics. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) reduce blood glucose concentrations by blocking the uptake of sodium and glucose in the proximal tubule and promoting glycosuria, and these agents now have an important role in the management of T2D. The results of several cardiovascular outcomes trials suggested that SGLT2i are associated with improvements in renal endpoints in addition to their reduction in cardiovascular events and mortality, which represents a major advance in the care of this population. The dedicated kidney outcomes trials have confirmed the renoprotective action of SGLT2i across different glomerular filtration and albuminuria values, even in patients with non-diabetic chronic kidney disease. Notably, this improvement in kidney function may indirectly benefit cardiac function through multifaceted interorgan cross talk, which can break the cardiorenal vicious circle linked to T2D. In this article, we briefly review the different mechanisms of action that may explain the renal beneficial effects of SGLT2i and disclose the results of the key renal outcome trials and the subsequent update of related clinical guidelines.

Keywords: Albuminuria; Cardiorenal continuum; Chronic kidney disease; Diabetic kidney disease; SGLT2i; Type 2 diabetes.

Fig. 1

Pharmacological recommendations to reduce kidney and cardiovascular risks in patients with CKD and T2D. ACEi angiotensin-converting enzyme inhibitor, ADA American Diabetes Association, ARB angiotensin receptor blocker, CV cardiovascular, EASD European Association for the Study of Diabetes, eGFR estimated glomerular filtration rate, ESC European Society of Cardiology, GLP-1 RA glucagon-like peptide 1 receptors agonist, KDIGO Kidney Disease: Improving Global Outcomes, UACR urine albumin-to-creatinine ratio

Fig. 2

Across the cardiorenal continuum and its SGLT2 inhibitors clinical trials Adapted from Fontes-Carvalho et al. [56]