Renal Effects of SGLT2 Inhibitors: An Update

Josselin Nespoux; Volker Vallon

Disclosures

Curr Opin Nephrol Hypertens. 2020;29(2):190-198. 

In This Article

SGLT2 Inhibition Improves Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus Patients With Preserved Kidney Function and Established Chronic Kidney Disease

SGLT2 inhibition improved renal and cardiovascular outcomes in T2DM patient with high cardiovascular risk.[7] The initial trials were conducted in patients with an overall relatively well preserved kidney function, although subanalyses indicated that the beneficial effects may extend to patients with CKD.[8] SGLT2 inhibitors block renal tubular glucose reabsorption and thus their glucose-lowering efficacy depends on the amount of filtered glucose, and thus glomerular filtration rate (GFR). Consequently, SGLT2 inhibitors have not been indicated in T2DM patients with more advanced CKD. Recently, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial assessed the effects of canagliflozin treatment vs. placebo on renal outcomes and secondary cardiovascular outcomes in T2DM patients with albuminuric CKD.[9] The 4401 patients enrolled had an eGFR of 30 to less than 90 ml/min/1.73 m2 and albuminuria (ratio albumin-to-creatinine >300 to 5000 mg/g) and were followed over a median period of 2.62 years. Patients were receiving renin--angiotensin system (RAS) blockers as standard treatment. Canagliflozin reduced the risk of the primary outcome composite of ESRD (dialysis, transplantation, or a sustained estimated GFR of <15 ml/min/1.73 m2) by 30%, reduced the risk of the renal-specific composite of ESRD, a doubling of the creatinine level or death from renal causes, by 34% and reduced the risk of ESRD by 32% vs. placebo. Canagliflozin also lowered the risk of cardiovascular death, myocardial infarction, stroke, and lowered the rate of hospitalization for heart failure.[9] These findings are consistent with a previous systematic review and meta-analysis of multiple randomized controlled trials that included patients with T2DM and CKD treated with an SGLT2 inhibitor.[10] Reduction in HbA1c was modest in T2DM patients with CKD compared with the reductions observed in the general T2DM population;[11] however, the beneficial effects of SGLT2 inhibitors on cardiovascular and renal outcomes was preserved without raising additional safety concerns.[10] Overall, these studies suggest that SGLT2 inhibition prevents cardiovascular and renal outcomes in T2DM patients with CKD through mechanisms that are at least in part independent of blood glucose reduction. On the basis of the findings of the CREDENCE trial, the US Food and Drugs Administration (FDA) approved canagliflozin (Invokana) to treat diabetic kidney disease (DKD) and reduce the risk of hospitalization for heart failure in patients with T2DM and DKD.[12] Mathematical modeling indicated that the natriuretic and diuretic effect of SGLT2 inhibition is preserved in CKD because of a high load of glucose on the single nephron level. This high glucose load was the consequence of higher levels of blood glucose and single nephron hyperfiltration in remaining nephrons, and induced paracellular sodium secretion in the proximal tubule thereby preserving a natriuretic, kaliuretic and diuretic effect despite reduced nephron number[13] (Figure 1).

Figure 1.

Proposed natriuretic effect of SGLT2 inhibition in diabetic chronic kidney disease. Depicted are effects of hyperglycemia or CKD (black arrows) and the effect of SGLT2 inhibition (grey arrows). CKD lowers nephron number and increases single nephron GFR in remaining nephrons. Together with hyperglycemia, this results in high single tubule glucose load. Mathematical modeling predicts that SGLT2 inhibition under these conditions increases the osmotic effect of luminal glucose to an extent that paracellular sodium secretion is induced in the proximal tubule, thereby preserving a robust natriuretic, diuretic and kaliuretic effect. This may contribute to the preserved blood pressure-lowering effect of SGLT2 in diabetic CKD. CKD, chronic kidney disease; GFR, glomerular filtration rate; MD, macula densa; SNGFR, single nephron glomerular filtration rate; UK, urinary excretion of potassium; UNa, urinary excretion of sodium; UV, urinary flow rate.

Recent meta-analyses also reported that SGLT2 inhibition is associated with a robust and consistent reduction in acute kidney injury (AKI).[14,15] In accordance, dapagliflozin treatment decreased urinary levels of markers of glomerular and tubular injury in T2DM patients,[16,17] an effect also shown in diabetic rats[18,19] (Figure 2). Luseogliflozin prevented renal capillary rarefaction and reduced hypoxia and fibrosis in a murine model of renal ischemia–reperfusion.[20] SGLT2 gene-knockout in mice, however, did not affect ischemia–reperfusion injury and subsequent GFR recovery in preliminary studies in the bilateral renal artery clamping model of ischemia–reperfusion injury.[21] In comparison, Nespoux et al.[22] showed that gene-knockout of SGLT1 did not affect the initial kidney injury but improved kidney recovery in this model. Renal SGLT1 expression appeared to recover before SGLT2 in this model, which may have enhanced the transport burden in the outer medulla during recovery from ischemia–reperfusion injury.

Figure 2.

Proposed kidney protective effects of SGLT2 inhibition. Depicted are effects of diabetes/hyperglycemia (black arrows) and the effect of SGLT2 inhibition (grey arrows). Included is the tubular hypothesis of SGLT2 inhibition-mediated renoprotection in diabetes, including decreased glomerular hyperfiltration via adenosine-dependent hemodynamic changes, which reduce the tubular transport burden and preserve GFR in the long-term. Depicted are also the various influences of SGLT2 inhibition on renal metabolism and mitochondrial and endothelial integrity; as well as the uricosuric effect of SGLT2 inhibition. AKI, acute kidney injury; CVOTs, cardiovascular outcome trials; GFR, glomerular filtration rate; JGA juxtaglomerular apparatus; MD, macula densa; SNGFR, single nephron glomerular filtration rate; T2DM, type 2 diabetes mellitus; URAT1, urate transporter 1.

Currently, the randomized placebo-controlled CKD outcome trials Dapa-CKD and Empa-Kidney (ClinicalTrials.gov Identifiers: NCT03036150 and NCT03594110, respectively) are conducted in patients with established kidney disease, with or without diabetes, and treatment with the SGLT2 inhibitor dapagliflozin or empagliflozin, respectively. These trials are expected to provide further insights into the beneficial effects of SGLT2 inhibitors in CKD populations beyond glycemic control.[23,24]

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