Nephroprotection by SGLT2 Inhibition: Back to the Future?

Nicola, Luca De; Gabbai, Francis B.; Garofalo, Carlo; Conte, Giuseppe; Minutolo, Roberto

doi:10.3390/jcm9072243

Cited by 27 publications

(28 citation statements)

References 65 publications

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“…In CKD patients, a fall of GFR is observed in the first weeks of protein restriction; afterwards, however, kidney function stabilizes and the disease tends to progress slower than in patients on an unrestricted diet. This observation, derived from the classic MDRD trial, is consistent with an initial reduction of hyperfiltration followed by a slower CKD progression and is comparable to the "check-mark" sign ( √ ) described in the course of treatment with SGLT2i, as mentioned above (23). The quality of dietary proteins modulates glomerular hemodynamics and the perm-selectivity of the glomerular basement membrane.…”

Section: Effects Of Dietary Manipulation On Renal Hemodynamics and Kisupporting

confidence: 83%

Nephroprotection by SGLT2i in CKD Patients: May It Be Modulated by Low-Protein Plant-Based Diets?

et al. 2020

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Sodium-glucose-transporter 2 inhibitors (SGLT2i) are a new class of anti-diabetic drugs that in large trials such as CREDENCE have shown also a reduction of glomerular hyperfiltration and albuminuria in type 2 diabetic patients. Hence, the interest toward SGLT2i is focused toward this potential nephroprotective effect, in order to reduce the progression to overt nephropathy, and it seems to be confirmed in the most recent DAPA-CKD trial. This is the reason why the indication for SGLT2i treatment has been extended to chronic kidney disease (CKD) patients with eGFR up to 30 ml/min, namely with CKD stage 1–3. In patients with CKD stage 3 to 5, the most recent KDIGO guidelines recommend low-protein diet and plant-based regimens to delay end-stage kidney disease (ESKD) and improve quality of life. Similarly to SGLT2i, low-protein diets exert renal-protective effects by reducing single nephron hyperfiltration and urinary protein excretion. Beyond the glomerular hemodynamic effects, both protein restriction and SGLT2i are able to restore autophagy and, through these mechanisms, they may exert protective effects on diabetic kidney disease. In this perspective, it is likely that diet may modulate the effect of SGLT2i in CKD patients. Unfortunately, no data are available on the outcomes of the association of SGLT2i and low-protein and/or vegan diets. It is therefore reasonable to investigate whether CKD patients receiving SGLT2i may have further advantages in terms of nephroprotection from the implementation of a low-protein and/or plant-based diet or whether this association does not result in an additive effect, especially in vascular nephropathies.

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Section: Effects Of Dietary Manipulation On Renal Hemodynamics and Kisupporting

confidence: 83%

Nephroprotection by SGLT2i in CKD Patients: May It Be Modulated by Low-Protein Plant-Based Diets?

et al. 2020

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“…This initial eGFR dip is not only manifest after SGLT2is initiation but also as a hemodynamic response to low salt diet, RAAS inhibition, and antihypertensive treatments. Nevertheless, according to the first analysis the relationship between the eGFR dip and the following normalization of eGFR slope seems to be stronger for SGLT2is than for the other pharmacological and non-pharmacological treatments (80). Future studies should provide more insights into this topic given that diabetic kidney disease patients are likely to be at lower risk of hard renal endpoints mainly after a positive response in terms of albuminuria and eGFR during the 1st weeks of treatment, as shown in previous positive and even negative randomized trials from the past decades (129).…”

Section: Future Perspectives: the Use Of Sglt2is In The Personalized Medicine Eramentioning

confidence: 93%

“…The novel drug family of SGLT2is has rapidly captured the attention of clinicians given their efficacy in slowing CKD progression and in reducing CV risk in patients with CKD and diabetes. This notwithstanding, since their introduction in clinical practice several studies raised concerns regarding their safety, particularly with regards to the risk of AKI (79,80). The mechanisms underlying the onset of AKI during treatment with SGLT2is are represented by their actions on glomerular hemodynamics, the effect of volume depletion and the hypoxic effect (73).…”

Section: Sglt2 Inhibitors and Acute Kidney Injurymentioning

confidence: 99%

“…Moreover, it has been shown that the biphasic trajectory is shared by almost all SGLT2is and it has been reported for both higher and lower basal eGFR levels (85,86). Due to these pieces of evidence, De Nicola et al hypothesized this initial dip of eGFR to be a "check-mark sign" of SGLT2is activity (80). Data surrounding the true incidence of AKI after SGLT2is are controversial.…”

Section: Sglt2 Inhibitors and Acute Kidney Injurymentioning

confidence: 99%

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Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge

et al. 2021

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Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.

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“… 8 , 9 , 10 However, in several randomized trials, SGLT2i use was associated with an initial estimated glomerular filtration rate (eGFR) decline, eGFR dip, within a few weeks and up to 6 months following initiation of therapy. 11 The eGFR dip is generally followed by recovery and stabilization during the subsequent months; in the long‐term, SGLT2i use was associated with relative eGFR preservation compared with placebo. 11 …”

mentioning

confidence: 99%

Clinical Implications of Estimated Glomerular Filtration Rate Dip Following Sodium‐Glucose Cotransporter‐2 Inhibitor Initiation on Cardiovascular and Kidney Outcomes

Bowe

Gibson

McGill

et al. 2021

JAHA

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Background The frequency of the initial short‐term decline in estimated glomerular filtration rate (eGFR), eGFR dip, following initiation of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) and its clinical implications in real‐world practice are not clear. Methods and Results We built a cohort of 36 638 new users of SGLT2i and 209 025 new users of other antihyperglycemics. Inverse probability weighting was used to estimate the excess rate of eGFR dip, risk of the composite cardiovascular outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or all‐cause mortality, and risk of the composite kidney outcome of eGFR decline >50%, end‐stage kidney disease, or all‐cause mortality. In the first 6 months of therapy, compared with other antihyperglycemics, excess rates of eGFR dip >10% and eGFR dip >30% were 9.86 (95% CI: 8.83–11.00) and 1.15 (0.70–1.62) per 100 SGLT2i users, respectively. In mediation analyses that accounted for eGFR dipping, SGLT2i use was associated with reduced risk of cardiovascular and kidney outcomes (hazard ratio, 0.92 [0.84–0.99] and 0.78 [0.71–0.87], respectively); the magnitude of the association reduced by eGFR dipping was small for both outcomes. SGLT2i was associated with reduced risk of both outcomes in those with higher than average probability of eGFR dip >10% or 30%. Compared with discontinuation, continued use of SGLT2i at 6 months was associated with reduced risk of cardiovascular and kidney outcomes in those with no eGFR dip or eGFR dip ≤10%, in those with eGFR dip >10%, and in those with eGFR dip >30%. Conclusions The salutary association of SGLT2i with cardiovascular and kidney outcomes was maintained regardless of eGFR dipping; concerns about eGFR dipping should not preclude use, and occurrence of eGFR dip after SGLT2i initiation may not warrant discontinuation.

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Nephroprotection by SGLT2 Inhibition: Back to the Future?

Cited by 27 publications

References 65 publications

Nephroprotection by SGLT2i in CKD Patients: May It Be Modulated by Low-Protein Plant-Based Diets?

Nephroprotection by SGLT2i in CKD Patients: May It Be Modulated by Low-Protein Plant-Based Diets?

Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge

Clinical Implications of Estimated Glomerular Filtration Rate Dip Following Sodium‐Glucose Cotransporter‐2 Inhibitor Initiation on Cardiovascular and Kidney Outcomes

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