Cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes (T2D) are prevalent and interconnected chronic diseases. A significant portion of the US adult population suffers from at least one of these conditions, and their co-occurrence significantly worsens patient outcomes. The cardiorenal continuum highlights the intertwined nature of these pathologies, with disorders in one system often affecting the other. T2D, in particular, elevates the risk of both macrovascular and microvascular complications, leading to substantial morbidity and mortality. Heart failure (HF) incidence is significantly higher in T2D patients, and CKD is a common consequence of T2D, further increasing the risk of cardiovascular events. The last decade has witnessed the emergence of sodium-glucose cotransporter-2 inhibitors (SGLT2is) as clinically beneficial agents across this cardiorenal spectrum. Initially developed for glucose lowering in T2D, subsequent trials revealed their significant impact on cardiovascular and renal outcomes, leading to expanded indications in CVD, CKD, and HF management, even in patients without T2D. Current guidelines recommend SGLT2is to mitigate the risk of HF, major adverse cardiovascular events (MACEs), and kidney disease progression. This review focuses on the glucose-independent mechanisms contributing to the cardiorenal protective effects of SGLT2is.

The review involved a targeted literature search of PubMed using keywords related to SGLT2 inhibitors, cardiovascular and renal outcomes, and mechanisms of action. English-language publications from July 2015 to December 2022 reporting clinical studies and meta-analyses were included, with additional studies identified from reference lists. The focus is on mechanisms supported by clinical data, differentiating well-understood mechanisms from those that are still under investigation.

The authors conducted a targeted literature search on PubMed using keywords related to SGLT2 inhibitors, cardiovascular and renal outcomes, and specific mechanisms of action. The search encompassed English-language articles published between July 2015 and December 2022, focusing on clinical studies and meta-analyses of SGLT2is. Further relevant studies were identified through reviewing the bibliographies of the initially retrieved publications. The review focuses on the glucose-independent mechanisms of action and their supporting clinical evidence.

SGLT2i's cardiorenal benefits are not solely attributable to glucose lowering. Inhibition of SGLT2 leads to increased renal glucose excretion, reducing plasma glucose levels and inducing a mild diuresis and natriuresis. Importantly, SGLT2i therapy restores tubuloglomerular feedback, leading to reduced intraglomerular pressure and preservation of renal function. While an initial decrease in estimated glomerular filtration rate (eGFR) is observed (around 5 mL/min/1.73 m²), this is transient and followed by recovery to baseline, suggesting hemodynamic changes rather than glomerular damage. Long-term use of SGLT2is demonstrates renal protection, reducing the progression of kidney disease irrespective of baseline eGFR and CKD stage. Albumin excretion is significantly reduced, and this effect reverses upon discontinuation, indicating a dependence on altered renal hemodynamics. SGLT2is demonstrate diuretic and natriuretic effects, decreasing preload and left ventricular filling pressure, and contributing to sustained reductions in blood pressure. The reduction in plasma volume doesn't lead to orthostatic hypotension, unlike with loop diuretics, and the natriuretic effect doesn't activate the renin-angiotensin-aldosterone system (RAAS). SGLT2is decrease sympathetic nervous system (SNS) activity, leading to reductions in blood pressure surrogates such as pulse pressure and aortic pulse wave velocity. Importantly, SGLT2is reduce the risk of hyperkalemia, a common complication in HF patients, even in those receiving RAAS inhibitors. SGLT2is favorably impact left ventricular size and function, reducing mass index and improving diastolic function. A reduction in ventricular arrhythmias is also observed, possibly due to decreased cardiac chamber size and reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels. The improvement in hemoglobin, hematocrit, and erythropoietin levels could be linked to modulation of iron regulatory proteins (hepcidin and erythroferrone). Reductions in serum uric acid levels are observed, although the exact mechanism is not directly through SGLT2 but possibly secondary to glucosuria. Modulation of intracellular sodium via sodium-hydrogen exchanger (NHE) inhibition might contribute to cardiorenal benefits, although this mechanism requires further investigation. The potential anti-inflammatory and antioxidant effects of SGLT2is are suggested by reductions in serum inflammatory markers and improvements in oxidative stress parameters. Alterations in lipolysis, ketone metabolism, and renal handling of ketone bodies are proposed as possible contributors, leading to a fasting-like metabolic environment.

The findings strongly support the pleiotropic effects of SGLT2is beyond glucose lowering in managing CVD, CKD, and HF. The restoration of tubuloglomerular feedback and subsequent hemodynamic changes are crucial for renal protection. The multifaceted actions on blood pressure, sympathetic tone, left ventricular function, and electrolyte balance contribute to improved cardiovascular outcomes. The transient eGFR dip early in treatment should not lead to discontinuation, as long-term renoprotection is evident. The data highlight the importance of considering SGLT2i therapy for patients across the cardiorenal spectrum, including those with and without T2D. Further research is necessary to completely elucidate the mechanisms related to intracellular sodium modulation, anti-inflammatory effects, and metabolic reprogramming, though existing evidence significantly advances our understanding of SGLT2is' broad therapeutic value.

SGLT2 inhibitors provide significant cardiovascular and renal benefits, driven by complex mechanisms independent of glucose-lowering effects. Improved tubuloglomerular feedback, altered hemodynamics, and reductions in sympathetic activation are key factors. These agents hold increasing importance in HF and CKD management, extending beyond T2D treatment. Future studies should further investigate proposed mechanisms to fully understand their diverse effects.

This is a narrative review, so it is subject to the biases inherent in selecting studies and interpreting their results. The evidence base for some proposed mechanisms, such as NHE inhibition and anti-inflammatory actions, remains limited and requires further investigation through large-scale, well-designed clinical trials.