Renal protection: a leading mechanism for cardiovascular benefit in patients treated with SGLT2 inhibitors

Abstract

Initially developed as glucose-lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have demonstrated to be effective agents for the risk reduction of cardiovascular (CV) events in patients with type 2 diabetes mellitus (T2DM). Subsequently, data has emerged showing a significant CV benefit in patients treated with SGLT2i regardless of diabetes status. Renal protection has been initially evaluated in CV randomized trials only as secondary endpoints; nonetheless, the positive results gained have rapidly led to the evaluation of nephroprotection as primary outcome in the CREDENCE trial. Different renal and vascular mechanisms can account for the CV and renal benefits enlightened in recent literature. As clinical guidelines rapidly evolve and the role of SGLT2i appears to become pivotal for CV, T2DM, and kidney disease management, in this review, we analyze the renal effects of SGLT2, the benefits derived from its inhibition, and how this may result in the multiple CV and renal benefits evidenced in recent clinical trials.

Tackling type 2 diabetes-associated cardiovascular and renal comorbidities: a key challenge for drug development

“…SGLT2i is able to slow the progression of CKD by reducing barotrauma and proteinuria, glomerular hyperfiltration, and intraglomerular pressure. Other studies have also shown that SGLT2i can prevent oxidative stress, hypoxia, and fibrosis of renal tubules [73]. Moreover, SGLT2i reduces the activity of the sympathetic nervous system, thereby protecting the vascular system.…”

“…Moreover, SGLT2i reduces the activity of the sympathetic nervous system, thereby protecting the vascular system. The euglycemia, optimal blood pressure and lipid profile, and lower body weight induced by SGLT2i have been shown to protect small as well as large blood vessels [73]. Direct cardiac effects of SGLT2i have also been reported.…”

<p>Renal Outcomes Associated with the Use of Non-Insulin Antidiabetic Pharmacotherapy: A Review of Current Evidence and Recommendations</p>

“…58 The SGLT2iassociated renoprotective effects have been highlighted as a key mechanism for the reported cardiovascular benefits. 43 Meanwhile, the potential renoprotective effects of GLP-1A were attributed mainly to its impact on mitigating the progression of atherosclerosis-related vascular disease. 52 Consistently with our review findings, there are recent recommendations to consider either SGLT2i or GLP-1A as add on to metformin in patients who had mainly underlying atherosclerotic cardiovascular disease, and to consider SGLT2i first, in patients who had underlying chronic kidney disease and reduced heart failure, to be followed by GLP-1A if needed.…”

“…The direct mechanisms involve osmotic diuresis in overloaded cases in synergy with the given diuretic therapy and the suppression of oxidative stress and inflammation pathways. 43 Meanwhile, the indirect mechanisms include the ability to reduce blood pressure, body fat, body weight in addition to the uricosuric effect. 43 In a clinical trial, dapagliflozin was found to reduce blood pressure and body weight near the values reported for hydrochlorothiazide, although different underlying mechanisms exert diuretic effects.…”

“…43 Meanwhile, the indirect mechanisms include the ability to reduce blood pressure, body fat, body weight in addition to the uricosuric effect. 43 In a clinical trial, dapagliflozin was found to reduce blood pressure and body weight near the values reported for hydrochlorothiazide, although different underlying mechanisms exert diuretic effects. 20 As a consequence of reduced-sodium and glucose reabsorption in the tubules, SGLT2i enhances sodium and chloride delivery to the macula densa, resulting in the increased local secretion of vasoconstrictors that decrease the intraglomerular pressure and decrease the risk of hyperfiltration.…”