SGLT2 Inhibition in the Diabetic Kidney—From Mechanisms to Clinical Outcome

Abstract

Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously. Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs approximately 90% of filtered glucose. In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter type 2 contributes to the maintenance of hyperglycemia. Inhibiting these transporters has been shown to effectively improve glycemic control through inducing glycosuria and is generally well tolerated, although patients experience more genital infections. In addition, sodium-glucose cotransporter type 2 inhibitors favorably affect body weight, BP, serum uric acid, and glomerular hyperfiltration. Interestingly, in the recently reported first cardiovascular safety trial with a sodium-glucose cotransporter type 2 inhibitor, empagliflozin improved both renal and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. Because the benefits were seen rapidly after initiation of therapy and other glucose-lowering agents, with the exception of liraglutide and semaglutide, have not been able to improve cardiovascular outcome, these observations are most likely explained by effects beyond glucose lowering. In this mini review, we present the drug class of sodium-glucose cotransporter type 2 inhibitors, elaborate on currently available renal and cardiovascular outcome data, and discuss how the effects of these agents on renal physiology may explain the data.

The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

“…Our analysis also showed that the magnitude of UACR reduction was similar in patients treated with and without RASi at baseline. This is in contrast to previous literature in which it has been proposed that SGLT-2 inhibition with concomitant RASi may synergistically boost the alternative RAS axis, leading to upregulation of angiotensin (1)(2)(3)(4)(5)(6)(7). 37 In our analysis, we did not find modulation by RASi or any indication of a possible synergistic effect, thus the effect of RASi is probably smaller.…”

“…Sodium-glucose co-transporter-2 (SGLT-2) inhibitors, such as dapagliflozin, lower blood glucose levels by blocking glucose reuptake in the proximal tubule, resulting in urinary glucose excretion. 1 Beyond their glucose-lowering effect, evidence from recent cardiovascular (CV) outcomes trials (CVOTs) [2][3][4] indicates that whereas the effects of SGLT-2 inhibitors on major adverse CV events might be limited to patients with established CV disease, the beneficial effects on heart failure and renal function might be applicable to a broad population of patients with type 2 diabetes (T2D). [5][6][7] In particular, in these trials, SGLT-2 inhibitors delayed the progression of nephropathy.…”

Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus

“…Selective SGLT2 inhibitors have been developed to reduce glucose reabsorption in renal proximal tubules improving glycemic control in patients with T2DM [23]. As this has the effect of redistributing the glucose out of the PTC and into the lumen/urine, we undertook this study to determine the effect of this redistribution on intrarenal RAS activation, blood pressure, and kidney injury.…”

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

“…Specifically, it was associated with a statistically significant lower incidence rate of macroalbuminuria (38%), doubling of serum creatinine and eGFR# 45 ml/min per 1.73 m 2 (44%), and initiation of dialysis (55%). In addition, as we mentioned above, the sodium glucose transport type 2 inhibitor also can ameliorate the autophagy process that is down regulated in the proximal tubular cells due to hyperglycemia [57][58][59][60][61].…”