SGLT2 inhibitors: Beyond glycemic control

Abstract

Multiple randomized controlled trials have extensively examined the therapeutic effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors, ushering in a transformative approach to treating individuals with type 2 diabetes mellitus (DM). Notably, emerging reports have drawn attention to the potential positive impacts of SGLT2 inhibitors in nondiabetic patients. In an effort to delve into this phenomenon, a comprehensive systematic literature review spanning PubMed (NLM), Medline (Ovid), and Cochrane Library, covering publications from 2000 to 2024 was undertaken. This systematic review encompassed twenty-six randomized control trials (RCTs) involving 35,317 participants. The findings unveiled a multifaceted role for SGLT2 inhibitors, showcasing their ability to enhance metabolic control and yield cardioprotective effects through a reduction in cardiovascular death (CVD) and hospitalization related to heart failure (HF). Additionally, a renalprotective effect was observed, evidenced by a slowdown in chronic kidney disease (CKD) progression and a decrease in albuminuria. Importantly, these benefits were coupled with an acceptable safety profile. The literature also points to various biological plausibility and underlying mechanistic pathways, offering insights into the association between SGLT2 inhibitors and these positive outcomes in nondiabetic individuals. Current research trends indicate a continual exploration of additional role for SGLT2 inhibitors in. Nevertheless, further research is imperative to fully elucidate the mechanisms and long-term outcomes associated with the nondiabetic use of SGLT2 inhibitors.

Keywords: Cardiovascular disease; Chronic kidney disease; IgA nephropathy; Metabolism; SGLT2; Systematic review.

Fig. 1

PRISMA Flow Diagram.

Fig. 2

The Cochrane Risk of Bias assessment tool.

Fig. 3

Postulated mechanisms for the nondiabetic action of SGLT2 inhibitors. SGLT2 inhibitors have both cardioprotective and renoprotective effect in addition to metabolic effect. The cardioprotective effect includes direct cardiovascular effect as well as indirectly through action on renal system and is manifested through improvement of cardiac parameters, decrease in heart failure as well as promotion of cardiac remodeling. Renal effect is through both direct and indirect pathways resulting in glycosuria, nitrituria, decrease in proteinuria, inflammation, vasodilation, decrease preload, hormonal effect as well as increased hematocrit and erythropoietin. Some of the metabolic effects included decreased BMI, decreased adiposity, change in appetite and weight among others. (Abbreviations: NF-κB – Nuclear factor kappa B; MCP-1 – Monocyte chemoattractant protein-1; TGF-β – Transforming growth factor β; NEFA – Non-esterified fatty acids; NO – Nitric oxide; Na – Sodium; O₂ – Oxygen; N₂ – Nitrogen; LDL – Low density lipoprotein; HDL – High density Lipoprotein;↑– increase in; ↓ – decrease in).