PRESENTED BY
KATHERINE TUTTLE AND HIDDO LAMBERS HEERSPINK

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Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Change IME

Chronic kidney disease (CKD) is highly prevalent worldwide, with up to 14% of people affected in some regions, and the number of potential or productive life years lost due to premature death or disability is rising, regardless of the underlying cause of renal damage (1, 2). It is estimated that more than 5 million individuals will require renal replacement therapy by 2030, presenting a substantial burden on health services worldwide (3, 4). Despite the efforts to alleviate the burden of CKD, most therapeutics investigated have failed to achieve significant beneficial effects on disease progression in either diabetic kidney disease (DKD) or non-diabetic kidney disease (NDKD), (5-17). There is, therefore, a pressing need for novel renoprotective therapies that would stabilise kidney function and delay the need for renal replacement therapy.

The 2020 ERA-EDTA first fully virtual conference presented an occasion to discuss the latest treatment strategies for DKD, and their possible benefits on CKD progression in both DKD and NDKD patients. At a virtual panel meeting, moderated by Professor Adeera Levin, Professors Katherine Tuttle and Hiddo Lambers Heerspink shared their views on the possible role of sodium–glucose co-transporter 2 (SGLT2) inhibitors in preserving kidney function.
Insights from SGLT2 inhibitor trials – could the answer be in front of us?
Diabetes is the leading cause of CKD worldwide and was responsible for 42% of CKD cases in 2016 (18).
An estimated 40% of the 476 million adults with diabetes will develop CKD globally (18, 19). The risk of CKD development and progression to end-stage renal disease (ESRD) increases with the duration of diabetes, particularly in patients with an insulin-resistant form of the disease (20). Moreover, the number of deaths due to Type 2 diabetes (T2D) and CKD increased by 94% almost doubled between 1990–2012 (21). All this data accentuates the need for more effective therapies to improve the prognosis for DKD patients.
Several recent randomised controlled clinical trials: EMPA-REG OUTCOME, CANVAS Program, CREDENCE, DELIGHT and DECLARE-TIMI 58, as well as a real-world observational cohort study, CVD-REAL 3, have investigated the effect of SGLT2 inhibitors on the risk of kidney disease endpoints in T2D patients, and demonstrated very promising results (7, 22-29). In EMPA-REG OUTCOME, CANVAS Program, CREDENCE and DECLARE-TIMI 58, SGLT2 inhibitors reduced the risk of progressing to renal composite endpoints, inclusive of: doubling of serum creatinine, a ≥40% fall in estimated glomerular filtration rate (eGFR), progression to ESRD, renal replacement therapy, or kidney death (7, 23, 28, 30-36) . These effects were consistent across a range of baseline urine albumin:creatinine ratio (UACR) and eGFR (37). Furthermore, in these trials and in a real-world population, SGLT2 inhibitors provided long-term stabilisation of eGFR, following an initial reversible decline in kidney function (7, 23, 25, 28, 29, 38, 39). These results were also consistent regardless of cardiovascular status or background therapies, as well as across a range of baseline UACR and eGFR (25, 38). Finally, SGLT2 inhibitors also reduced UACR, prevented progression and increased regression of albuminuria (40). Based on this evidence, the EURECA-m and the DIABESITY working groups of the ERA-EDTA have recently published a consensus statement on the use of SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for nephroprotection and cardioprotection in patients with diabetes and CKD (Figure 1).

Figure 1. The latest ERA-EDTA recommendations on the use of SGLT2 inhibitor and GLP-1 receptor agonist for patients with T2D and CKD (41, 42)

Extending the use of SGLT2 inhibitors from diabetic to non-diabetic CKD
The superiority of SGLT2 inhibitor canagliflozin compared with placebo in reducing the risk of ESRD in T2D patients with CKD in the CREDENCE trial gave rise to the question as to whether these results were glycaemia dependent, or whether these agents could potentially be renoprotective even in non-diabetic individuals (7). The CREDENCE trial demonstrated stabilisation of eGFR with canagliflozin, even in a population with near-optimal glycaemic control (glycated haemoglobin [HbA1c] <7%), while the CANTATU trial found that compared with glimepiride, canagliflozin stabilised eGFR and reduced UACR in T2D patients with similar level of glycaemic control (7, 43, 44). These results suggest that the renoprotective effects of canagliflozin are not dependent on the effects on HbA1c. Multiple mechanisms have been proposed to explain the renoprotective effects of SGLT2 inhibitors: improvement in tubular oxygenation, suppression of both sympathetic nervous system and intrarenal renin–angiotensin system activity, as well as reduction in intraglomerular pressure, inflammation and fibrosis (45, 46). Of these, possibly the most important renoprotective mechanism associated with SGLT2 inhibition is prevention of hyperfiltration and associated elevated intraglomerular pressure via restoration of tubuloglomerular feedback (47). By blocking glucose-linked sodium reabsorption in the proximal tubules, SGLT2 inhibitors increase sodium delivery to the macula densa, thus triggering afferent arteriole constriction and reducing intraglomerular hyperfiltration (Figure 2).

Figure 2. The renoprotective effect of SGLT2 inhibitors via restoration of tubuloglomerular feedback (47, 48)

This renal haemodynamic effect is supported by an open-label study in patients with Type 1 diabetes, which found that empagliflozin reduced renal blood flow and glomerular filtration rate (GFR), but increased renal vascular resistance (RVR), (47). Similarly, a study comparing the effect of dapagliflozin with gliclazide in T2D, revealed that dapagliflozin reduced GFR and renal plasma flow, and increased filtration fraction; however, RVR had decreased (49). This decrease in RVR coupled with reduced post-glomerular arteriolar resistance suggests SGLT2 inhibition alters renal haemodynamics via post-glomerular vasodilatation, rather than pre-glomerular vasoconstriction (49).

It has recently been hypothesised that the reduction in intraglomerular hyperfiltration with SGLT2 inhibitors could translate into renoprotective effects in other non-diabetes renal diseases that share this common pathophysiological feature.

DAPA-HF was the first SGLT2 inhibitor outcomes trial in patients with and without diabetes. Dapagliflozin demonstrated a consistent reduction in the risk of worsening heart failure or CV death in HF patients with reduced ejection fraction irrespective of baseline diabetes status (50, 51). Moreover, compared with placebo, dapagliflozin numerically reduced the risk of progressing to the renal composite endpoint and significantly reduced the slope of eGFR decline, both in patients with and without diabetes (52, 53). The recently completed DIAMOND trial concluded that 6-week treatment with dapagliflozin did not affect proteinuria, but did induce a reversible decline in the measured GFR, and a reduction in body weight and blood pressure in patients with NDKD (55, 56). The DAPA-CKD trial represents the first SGLT2 inhibitor renal outcomes trial in CKD in patients with and without diabetes, and has been stopped prematurely due to the ‘overwhelming efficacy’ of dapagliflozin (57, 58). The detailed results from this trial are yet to be published and will, hopefully, shed more light on the potential benefits of SGLT2 inhibitors in CKD patients without diabetes.

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