SGLT2 inhibitors: β blockers for the kidney?

In their research digest, Sattar and Preiss1Sattar N Preiss D Research digest.Lancet Diabetes Endocrinol. 2016; 4: 651Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar describe current thinking that attributes the beneficial effects on kidney disease progression in the EMPA-REG OUTCOME trial2Wanner C Inzucchi SE Lachin JM et al.for the EMPA-REG OUTCOME InvestigatorsEmpagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2069) Google Scholar to haemodynamic changes. Such changes, whereby increased sodium delivery to the macula densa in the setting of sodium-glucose cotransporter 2 (SGLT2) inhibition augments glomerular afferent arteriolar tone, nicely explain the initial decrease in estimated glomerular filtration rate, which is reversed by withdrawal of the study drug. How such a reduction in single-nephron hyperfiltration might lead to kidney protection is a far more vexing issue than these aforementioned changes, particularly considering that tubulointerstitial pathology is often the major feature of kidney disease in type 2 diabetes and that SGLT2 inhibition does not ameliorate the glomerular filtration rate decline in the remnant kidney model, where disease progression is driven by increased single-nephron glomerular filtration rate.3Zhang Y Thai K Kepecs DM Gilbert RE Sodium-glucose linked cotransporter-2 inhibition does not attenuate disease progression in the rat remnant kidney model of chronic kidney disease.PLoS One. 2016; 11: e0144640Google Scholar But perhaps most telling of all are the effects of empagliflozin on acute kidney injury and acute renal failure in EMPA-REG OUTCOME,2Wanner C Inzucchi SE Lachin JM et al.for the EMPA-REG OUTCOME InvestigatorsEmpagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2069) Google Scholar the caveats of this post-hoc analysis of adverse events notwithstanding. By reducing postglomerular perfusion, the haemodynamic theory would posit an increase in both acute kidney injury and acute renal failure with empagliflozin, but the reverse occurred. Such findings suggest that non-haemodynamic, non-glomerular mechanisms might contribute to the salutary renal effects of SGLT2 inhibition. Charged with an enormous role in electrolyte, organic solute, and water reabsorption, the high energy requirements of the proximal tubule render it particularly susceptible to hypoxia and oxidative stress. As a result of increased luminal glucose concentration, sodium-glucose cotransporter (SGLT) activity increases in diabetes, mandating a commensurate increase in proximal tubular sodium ion reabsorption. Although SGLT-mediated transport is frequently viewed as not requiring energy, translocation of glucose and sodium ions across the apical membrane is a result of the electrochemical gradient generated by basolateral extrusion of sodium ions. This extrusion is, notably, energy dependent, mediated by sodium-potassium ATPase. Indeed, reclamation of filtered sodium ions by the proximal tubule accounts for most of the kidney's oxygen consumption.4Hansell P Welch WJ Blantz RC Palm F Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension.Clin Exp Pharmacol Physiol. 2013; 40: 123-137Crossref PubMed Scopus (168) Google Scholar As might therefore be expected, the enhanced proximal tubule glucose and sodium ion reabsorption of diabetes brings with it an increase in oxygen demand, which can be abolished by administration of the sodium-glucose cotransporter 1 and 2 inhibitor phlorizin.5Korner A Eklof AC Celsi G Aperia A Increased renal metabolism in diabetes: mechanism and functional implications.Diabetes. 1994; 43: 629-633Crossref PubMed Scopus (146) Google Scholar Such effects, analogous to those of a β blocker in reducing the excessive energy demands of the failing heart, would seemingly provide a cogent basis for the renoprotective effect of SGLT2 inhibition. To understand how proximal tubular hypoxia might lead to the structural and functional manifestations of diabetic kidney disease, the work of Fine and Norman,6Fine LG Norman JT Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics.Kidney Int. 2008; 74: 867-872Summary Full Text Full Text PDF PubMed Scopus (345) Google Scholar which establishes hypoxia as a major driver of kidney disease progression, seems particularly relevant. The elegant studies of Bonventre,7Bonventre JV Can we target tubular damage to prevent renal function decline in diabetes?.Semin Nephrol. 2012; 32: 452-462Summary Full Text Full Text PDF PubMed Scopus (143) Google Scholar the findings from which show how selective proximal tubular injury leads to interstitial fibrosis, microvascular loss, and glomerulosclerosis, are also worth reflecting on. By reducing the excessive energy demands of the proximal tubule in diabetes, SGLT inhibition might ameliorate the functional and structural manifestations of diabetic kidney disease, in addition to or independently of any haemodynamic effects. This non-haemodynamic paradigm has implications for the role of SGLT inhibition, not only in the setting of diabetic kidney disease, but also in other forms of kidney injury that are similarly characterised by proximal tubular injury, including those that result from drug toxicity. I have received grants, personal fees, and continuing medical education honoraria from AstraZeneca and Boehringer-Ingelheim, personal fees and continuing medical education honoraria from Merck and Jannsen, and personal fees from Servier. Research digestWith buses, we often wait for one for a long time, only for two to arrive together; so is the case, it seems, for trials. Following quickly on from the cardiovascular results of the EMPA-REG OUTCOME trial, the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial investigators have now reported a 13% lower risk of cardiovascular events in 9340 patients with diabetes and high cardiovascular risk on once daily liraglutide injections compared with placebo over an average follow-up of 3·8 years. Full-Text PDF