Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease

Abstract

Purpose of Review This review offers a critical narrative evaluation of emerging evidence that sodium-glucose co-transporter-2 (SGLT2) inhibitors exert nephroprotective effects in people with type 2 diabetes. Recent Findings The SGLT2 inhibitor class of glucose-lowering agents has recently shown beneficial effects to reduce the onset and progression of renal complications in people with and without diabetes. Randomised clinical trials and ‘real world’ observational studies, mostly involving type 2 diabetes patients, have noted that use of an SGLT2 inhibitor can slow the decline in glomerular filtration rate (GFR), reduce the onset of microalbuminuria and slow or reverse the progression of proteinuria. Summary The nephroprotective effects of SGLT2 inhibitors are class effects observed with each of the approved agents in people with a normal or impaired GFR. These effects are also observed in non-diabetic, lean and normotensive individuals suggesting that the mechanisms extend beyond the glucose-lowering, weight-lowering and blood pressure-lowering effects that accompany their glucosuric action in diabetes patients. A key mechanism is tubuloglomerular feedback in which SGLT2 inhibitors cause more sodium to pass along the nephron: the sodium is sensed by macula cells which act via adenosine to constrict afferent glomerular arterioles, thereby protecting glomeruli by reducing intraglomerular pressure. Other effects of SGLT2 inhibitors improve tubular oxygenation and metabolism and reduce renal inflammation and fibrosis. SGLT2 inhibitors have not increased the risk of urinary tract infections or the risk of acute kidney injury. However, introduction of an SGLT2 inhibitor in patients with a very low GFR is not encouraged due to an initial dip in GFR, and it is prudent to discontinue therapy if there is an acute renal event, hypovolaemia or hypotension.

The Effect of SGLT2 Inhibition on Diabetic Kidney Disease in a Model of Diabetic Retinopathy

“…In addition, an important method SGLT2 inhibitors promote nephroprotection is by tubuloglomerular feedback, in which SGLT2 inhibitors cause more sodium to pass along the nephron. This influx of sodium is sensed by macula cells to constrict afferent glomerular arterioles, and this reduces blood flow, thereby protecting glomeruli by reducing intraglomerular pressure [11]. These mechanisms support the synergistic effect exerted by these medications and together could explain the benefits of SGLT2 inhibitors in DKD.…”

“…SGLT2 inhibitors are a novel class of antidiabetic medications currently approved (2013) by the Food and Drug Administration (FDA) for the treatment of diabetes [9]. SGLT2 is a high-capacity, low affinity glucose co-transporter, mainly found in the S1 and S2 segments of the renal convoluted proximal tubules, and is required for the reabsorption of majority of the glucose (~90-95%) filtered by the kidney [10,11]. In patients with diabetes mellitus, SGLT2 inhibitors increase glucosuria by blocking glucose reabsorption in the renal proximal tubule, and hence lower plasma glucose levels, independent of insulin stimulation [12].…”

Quality of care and prescription patterns among patients with diabetic kidney disease—a large-scale cohort study from Taiwanese clinics

“…Because of the cardio- and reno-protective effects, SGLT-2 inhibitors and GLP-1 RAs have been recommended to diabetes patients with ASCVD, heart failure or CKD ( American Diabetes Association Professional Practice et al, 2022 ). Several large-scale randomized controlled trials have proved SGLT-2 inhibitors improve renal composite outcomes, slow eGFR decline and decrease albuminuria ( Bailey, Day & Bellary, 2022 ). The reno-protective effect is now considered independent of glucose lowering effect.…”

A Systematic Review of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and Sympathetic Nervous System Inhibition: An Underrated Mechanism of Cardiorenal Protection

“…Our findings added to the previous evidence that SGLT2 inhibitors significantly halt the progression of renal disease and reduce its severity. Specifically, SGLT2 inhibitors significantly reduced the composite renal endpoints (progression to macro-albuminuria, serum creatinine doubling, the start of renal replacement therapy (RRT), or death resulting from the renal disease [ 13 , 14 , 5 ]. While SGLT2 inhibitors, through different mechanisms, lower blood glucose, body weight, improve hematocrit and blood pressure, as a result, predicting the net effect of SGLT2 inhibitors on CV outcomes was difficult.…”

“…This relationship explains that the CV effects of empagliflozin may not be dependent on its glucose-lowering effect [ 4 ]. Sodium-glucose cotransporter 2 inhibitor (SGLT2i) reduced a composite of deteriorating eGFR, end-stage renal disease (ESRD), or renal mortality by roughly 33%, according to different meta-analyses of the data from the above-mentioned cardiovascular outcome trials (CVOTs) and other trials as shown in Figure 1 [ 5 ].…”