What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors?

Abstract

Over the past 5 years, sodium-glucose cotransport 2 (SGLT2) inhibitors have been increasingly regarded as glycaemic agents with cardiovascular (CV) and renal protective effects. The CV benefits of SGLT2 inhibitors have been well established in patients with type 2 diabetes (T2D) and a range of CV comorbidities at baseline. Subsequently, the renal benefits of SGLT2 inhibitors were established in the CREDENCE trial, a dedicated renal outcome trial where canagliflozin reduced the primary composite renal outcome by 30%. In light of these trials, clinical practice guidelines have rapidly evolved, recommending the use of SGLT2 inhibitors as renal and cardioprotective agents in appropriate patient populations. Accordingly, it is important to have an in-depth understanding of the evidence underlying the use of SGLT2 inhibitors in patients with T2D based on published clinical trials and real-world evidence (RWE) studies, as well as information related to potential safety concerns. To accomplish this, we reviewed the evidence for renal protection and safety with SGLT2 inhibitors in the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 CV safety trials, and in the growing body of evidence emerging from real-world studies. This body of work has shown that SGLT2 inhibitors reduce the risk of surrogate renal endpoints such as albuminuria and mitigate the risk of hard renal endpoints including doubling of serum creatinine and end-stage kidney disease in patients with T2D. K E Y W O R D S diabetic nephropathy, SGLT2 inhibitor 1 | INTRODUCTION Sodium-glucose cotransport-2 (SGLT2) inhibitors have been in clinical use for >5 years and were originally developed and prescribed to achieve additional glucose lowering by inducing glycosuria. As part of Food and Drug Administration (FDA) mandated requirements put in place in 2008, as a novel glucose lowering therapy, SGLT2 inhibitors underwent extensive safety evaluation in cardiovascular outcome trials (CVOTs). Accordingly, over the past 5 years, a large body of evidence has emerged from these CVOTs, and from observational realworld evidence (RWE) studies, as discussed and reviewed elsewhere. 1In stark contrast with other anti-hyperglycaemic agents assessed in CVOTs up to that time, SGLT2 inhibitors were shown to have substantial cardiovascular (CV) and renal protective effects across each medication in the class, and across all subgroups analysed to date.These CVOT results have transformed the way that SGLT2 inhibitors are thought about as therapies for patients with type 2 diabetes (T2D). In perhaps, the same way that ACE inhibitors and ARBs were Vikas S. Sridhar and Habib U. Rahman are the co-first authors.

A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy

“…Subsequently, in large cardiovascular outcome trials involving participants with type 2 diabetes, empagliflozin, canagliflozin and dapagliflozin slowed the rate of decline of eGFR and reduced albuminuria with a similar eGFR trend observed for ertugliflozin. [9][10][11][12] In type 1 and type 2 diabetes, clinical studies have shown that early and reversible reductions in eGFR occurred on initiation of SGLT2 inhibitor therapy, including in those participants with good glycaemic control, [13][14][15] suggesting that SGLT2 inhibitors reduce intraglomerular pressure, which may preserve long-term kidney function. This same effect was also observed in patients with proteinuric chronic kidney disease (CKD) without diabetes, 16 providing a rationale for the use of these agents as renoprotective therapies in patients with CKD due to causes other than diabetes.…”

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

“…Subsequently, it was shown that a major effect of empagliflozin consisted in an acute reduction of eGFR and albuminuria, followed by long-term stability and preservation of eGFR, compared with the doubling of eGFR deterioration in the placebo group over the same period of time (3.1 years of median follow-up) [56]. Renal benefits provided by empagliflozin was observed even in patients with compromised renal function, independently from baseline HbA1c and achieved regardless of concomitant medications interacting with renal function [57,58].…”

“…The secondary endpoint of a sustained 40% reduction in eGFR, death from renal cause, or the need for renal replacement therapy (RRT) was significantly reduced by canagliflozin (HR 0.60; 95% CI 0.47-0.77) [59]. Interestingly, the effect on CV and renal outcomes did not differ according to the presence of baseline CKD (defined as eGFR < 60 ml/min/1.73 m 2 ), albuminuria, eGFR, or BMI [58].…”

Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant Antirhea borbonica, Reduces Renal Tubulointerstitial Fibrosis

“…Diabetic kidney disease remains the main cause of CKD, leading to end-stage kidney disease in both type 1 and type 2 diabetes [10]. Recently, sodium-glucose linked transporter-2 (SGLT2) inhibitors appeared to be the most promising nephroprotective drugs in diabetic kidney disease [11,12]; however, an antifibrotic effect has only been evidenced in animal studies [13]. There is thus a need and ample space to develop new therapeutic approaches targeting tubulointerstitial fibrosis in the kidney for combatting these pathological processes [14].…”