Clinical Kidney Journal, 2019, vol. 12, no. 3, 322–325 doi: 10.1093/ckj/sfz019 Advance Access Publication Date: 6 March 2019 Editorial Comment EDITORIAL COMMENT Sodium-glucose cotransporter inhibitors: beyond glycaemic control Downloaded from https://academic.oup.com/ckj/article/12/3/322/5370330 by guest on 11 February 2022 Ander Vergara1,2, Conxita Jacobs-Cachá1,2,* and Marı́a José Soler1,2,* 1 Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain and 2Nephrology Research Group, Vall d’Hebron Research Institute (VHIR), Nephrology Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain Correspondence and offprint requests to: Marı́a José Soler; E-mail: mjsoler01@gmail.com. Conxita Jacobs-Cachá; E-mail: conxita.jacobs@vhir.org *These authors contributed equally to this work as senior authors. ABSTRACT Diabetes increases the risk of adverse cardiovascular and renal events. Recently, sodium–glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to reduce cardiovascular complications and slow diabetic kidney disease progression in patients with type 2 diabetes. The glycaemic control exerted by these drugs is not greater than the one achieved with other classical glucose-lowering medications such as sulphonylureas. For that reason, plausible renoprotective mechanisms independent from glycaemic control have been proposed such as blood pressure control, body weight loss, intraglomerular pressure reduction and a decrease in urinary proximal tubular injury biomarkers. Interestingly, the hypothesis that SGLT2 inhibitors have a direct renoprotective effect has been addressed in diabetic and non-diabetic models. In this editorial, we update the different postulated mechanisms involved in the cardiorenal protection afforded by SGLT2 inhibition in chronic kidney disease. Keywords: chronic kidney disease, diabetic nephropathy, SGLT2, type 2 diabetes Patients with type 2 diabetes mellitus (T2D) have a well-known angiotensin II receptor blockers (ARBs) administration [6, 7]. Of increased risk for premature death and cardiorenal complica- note, the combination of ACEi and ARBs has not demonstrated tions. Approximately 35% of patients with T2D will develop beneficial effects on cardiorenal protection in T2D over each diabetic kidney disease. Furthermore, recently published epide- agent alone [8]. Recently, a new class of anti-diabetic drugs—the miologic studies demonstrate that diabetic nephropathy contrib- sodium–glucose co-transporter 2 (SGLT2) inhibitors—has been uted 51% of the increased burden of chronic kidney disease (CKD) demonstrated to slow the progression of diabetic kidney disease since 1990 [1]. Before 2015, glucose-lowering medications were and to improve cardiovascular outcomes [9–11]. shown to only slightly reduce diabetic nephropathy progression SGLT2 and, to a lesser extent, SGLT1 are responsible for tu- during intensive therapy, and were associated with increased ad- bular glucose reabsorption in proximal tubules and, thus, they verse effects, mainly in frail patients. Interestingly, no benefit contribute importantly to glucose homoeostasis. The use of was found in macrovascular complications and death from car- SGLT2 inhibitors has proven to be effective in glycaemia control diovascular causes [2–5]. Until 2016, cardiorenal treatment in T2D in diabetic patients. SGLT2 inhibition increases urinary glucose has been limited to renin–angiotensin system blockade, either by excretion, decreasing blood glucose levels [12]. Canagliflozin, angiotensin-converting enzyme inhibitors (ACEi) or by dapagliflozin and empagliflozin are the approved SGLT2 Received: 30.1.2019; Editorial decision: 30.1.2019 C The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 322 Sodium-glucose cotransporter inhibitors | 323 Downloaded from https://academic.oup.com/ckj/article/12/3/322/5370330 by guest on 11 February 2022 FIGURE 1: Suggested mechanisms for cardiorenal protection with SGLT2 inhibition. inhibitors in the USA and Europe for treatment of T2D. These as restoring tubuloglomerular feedback, thus decreasing hyper- drugs were introduced into clinical practice between 2013 and filtration and albuminuria, and directly decreasing tubular in- 2015, after several clinical trials that demonstrated their efficacy jury, among others in T2D patients [9–11, 16, 18, 19] (Figure 1). in glucose lowering, and also in weight loss and reduction of For these reason, currently some clinical trials are ongoing to blood pressure [13]. Recent studies demonstrated that SGLT2 assess the effect of SGLT2 inhibition on non-diabetic CKD inhibitors in combination with renin-angiotensin system (RAS) patients [20]. blockade may decrease major cardiovascular events, usually The renoprotective effects of SGLT2 have also been measured as a composite outcome of death from cardiovascular explained by natriuresis resulting from inhibition of sodium causes, non-fatal myocardial infarction or non-fatal stroke [14, and glucose reabsorption. An increased sodium delivery to the 15]. The first trial focusing on the evaluation of renal outcomes macula densa activates the tubuloglomerular feedback that in diabetic kidney disease was published in 2016. Wanner et al. leads to afferent arteriole vasoconstriction and a reduction in [9] demonstrated that the administration of empagliflozin in intraglomerular pressure. In fact, SGLT2 inhibitors demon- T2D patients at high cardiovascular risk was associated with strated a similar pattern of change in renal function to that ob- slower progression of kidney disease and lower rates of clini- served with ACEi or ARBs, where a short-term decrease of cally relevant renal events as compared with placebo over a me- glomerular filtration rate is followed by stabilization over time dian follow-up period of 3.1 years [16]. Subsequently, Heerspink [12]. This initial reduction is also reversible when the drug is et al. [11] demonstrated that canagliflozin slowed renal disease discontinued. Other plausible mechanisms that have been pro- progression over >2 years of follow-up in T2D patients indepen- posed to contribute to SGLT2 inhibitor renoprotection are lower- dently of its glycaemic effects. Recently, dapagliflozin adminis- ing of blood pressure, weight loss, amelioration of the volume tration was associated with robust reductions in hospitalization overload and glycaemic control itself (Figure 1). However, it is for heart failure and progression of renal disease, regardless of still not clear whether these drugs also exert direct protective baseline atherosclerotic risk category or history of heart failure effects on the kidney. To determine whether SGLT2 inhibitors [10]. These promising outcomes have to be confirmed in future have a renoprotective effect independent from glycaemia and trials with renal progression as the primary endpoint that enrol blood pressure control, some clinical trials are ongoing to assess (or are currently enrolling) patients with more advanced CKD its effect on non-diabetic CKD patients. such as Canagliflozin and Renal Endpoints in Diabetes with Diabetic mice and rat models seem to respond to SGLT2 Established Nephropathy Clinical Evaluation, a study to evalu- inhibitors similarly to humans in terms of glycaemia and body ate the effect of dapagliflozin on renal outcomes and cardiovas- weight control [21]. In addition, the experimental models of dia- cular mortality in patients with CKD and the study of heart and betic nephropathy also showed the cardiorenal protection phe- kidney protection with empagliflozin [17]. In the current study, notype [22–25]. In contrast, in non-diabetic CKD experimental Satirapoj et al. [18] have shown in a randomized controlled trial models, the results are unclear. Some studies were not able to that dapagliflozin treatment decreases urinary kidney injury demonstrate that SGLT2 inhibitors prevented kidney damage molecule 1 (uKIM-1) levels. In concordance, Dekkers et al. [19] in [26, 27], whereas others demonstrated clear renoprotective a post hoc analysis also demonstrated a decrease of uKIM-1 after effects [28–32]. In mice with tubular damage induced by chronic dapagliflozin treatment. These results suggest that SGLT2 oxalosis, empagliflozin did not improve renal function or fibro- inhibitors exert renoprotection by different mechanisms such sis [26]. In concordance, dapagliflozin did not improve the 324 | A. Vergara et al. glomerular filtration rate in the subtotal nephrectomy model of well as to explain how and in which specific non-diabetic kid- glomerulosclerosis in the rat [27]. However, in a rat model of ney diseases they could be effective. kidney damage induced by unilateral ureteral obstruction, SGLT2 inhibition decreased kidney fibrosis and inflammation biomarkers, such as transforming growth factor-beta 1 (TGF-b1), ACKNOWLEDGEMENTS alpha smooth muscle actin (a-SMA) or fibronectin. Moreover, The authors are current recipients of research grants from they exhibited a downregulation of the inflammatory Nuclear the FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII, factor kappa B/Toll-like receptor 4 (NF-jB/TLR4) signalling path- PI17/00257 and REDINREN, RD16/0009/0030. A.V. performed way, as well as a partial recovery of tubular klotho levels sug- gesting that empagliflozin may have a protective effect against this work within the basis of the Doctorate of Medicine of inflammation and fibrosis [30]. Panchapakesan et al. showed the Autonomous University of Barcelona (UAB). similar results in cultured proximal tubular cells where empa- gliflozin attenuated the NF-jB/TLR4 pathway. They also demon- strated that SLGT2 expression was not only induced by high CONFLICT OF INTEREST STATEMENT Downloaded from https://academic.oup.com/ckj/article/12/3/322/5370330 by guest on 11 February 2022 glucose levels, but also by the profibrotic factor TGF-b1 [28]. In a M.J.S. reports conflict of interest with NovoNordisk, Janssen, mouse model, luseogliflozin prevented fibrosis after kidney in- Boehringer, Eli Lilly, AstraZeneca, Abbvie and Esteve, out- jury induced by ischaemia–reperfusion. Increased expression of side of the submitted work. vascular endothelial growth factor A (VEGF-A) in the kidneys of these animals was also observed. Both the decrease of fibrosis and the VEGF-A overexpression were suppressed when luseogli- flozin was associated with sunitinib—a VEGF receptor inhibitor. REFERENCES These results suggest that the protective effects of luseogliflozin 1. Xie Y, Bowe B, Mokdad AH et al. Analysis of the Global were in part mediated by the VEGF-A pathway [29]. In a murine Burden of Disease study highlights the global, regional, and protein-overload proteinuria model, dapagliflozin reduced pro- national trends of chronic kidney disease epidemiology teinuria and glomerular damage in a similar way to lisinopril— from 1990 to 2016. Kidney Int 2018; 94: 567–581 an ACEi. In the in vivo model and in cultured cells, bovine serum 2. Patel A, MacMahon S, Chalmers J et al.; ADVANCE albumin upregulated SGLT2 expression in podocytes in an NF- Collaborative Group. Intensive blood glucose control and jB-dependent manner. This induced cytoskeleton changes that vascular outcomes in patients with type 2 diabetes. N Engl J reverted with the administration of dapagliflozin. Interestingly, Med 2008; 358: 2560–2572 SGLT2 inhibition may directly target the podocytes and contrib- 3. Palazzolo G, Albanese NN, DI Cara G et al. Proteomic analysis ute to maintain the actin cytoskeleton architecture [31]. of exosome-like vesicles derived from breast cancer cells. Hyperglycaemia-induced senescence and oxidative stress on Anticancer Res 2012; 32: 847–860 the tubular cells have also been related to glucose overload. In a 4. Gerstein HC, Miller ME, Byington RP et al.; Action to Control type 1 diabetic rat model, senescence was mediated by SGLT2 Cardiovascular Risk in Diabetes Study Group. Effects of in- and p-21 [32]. Moreover, in cultured tubular cells, high glucose tensive glucose lowering in type 2 diabetes. N Engl J Med concentrations induce an inflammatory and proapoptotic state 2008; 358: 2545–2559 mainly caused by oxidative stress that was prevented by tofogli- 5. UPDS Group (UKPDS). Intensive blood-glucose control with flozin [33]. sulphonylureas or insulin compared with conventional The results obtained in non-diabetic CKD models suggest treatment and risk of complications in patients with type 2 that SGLT2 inhibitors could also have a direct beneficial effect diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) on the kidney, which would be independent of the glycaemic Group. Lancet 1998; 352: 837–853 and blood pressure control (Figure 1). Not all the biological path- 6. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of ways involved in the cardiorenal protection exerted by SGLT2 angiotensin-converting-enzyme inhibition on diabetic ne- inhibitors have been characterized. In addition to high glucose phropathy. N Engl J Med 1993; 329: 1456–1462 levels, several studies have observed SGLT2 upregulation by 7. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan profibrotic factors like TGF-b1 and protein overload. These find- on renal and cardiovascular outcomes in patients with type ings may explain the implication of this co-transporter in non- 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869 diabetic kidney disease. Furthermore, SGLT2 blockade interacts 8. Mann JFE, Anderson C, Gao P et al. Dual inhibition of the with several pathways and signalling molecules such as NF-jB/ renin–angiotensin system in high-risk diabetes and risk for TLR4, VEGF-A or klotho, suggesting that these drugs modulate stroke and other outcomes. J Hypertens 2013; 31: 414–421 inflammatory and fibrotic responses. As not all of the non- 9. Wanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and diabetic CKD animal models responded to SGLT2 inhibitors [26, progression of kidney disease in type 2 diabetes. N Engl J Med 27], it is possible that the direct effects on the kidney are depen- 2016; 375: 323–334 dent on the specific CKD experimental model studied. 10. Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and cardio- In conclusion, SGLT2 inhibitors have been shown to reduce vascular outcomes in type 2 diabetes. N Engl J Med 2019; 380: cardiovascular complications and to slow diabetic kidney dis- 347–357 ease progression in patients with T2D. Interestingly, this effect 11. Heerspink HJL, Desai M, Jardine M et al. Canagliflozin slows was also associated with decreased urinary proximal tubular in- progression of renal function decline independently of gly- jury biomarkers. Beside glycaemic and blood pressure control, cemic effects. J Am Soc Nephrol 2017; 28: 368–375 these drugs seem to exert direct renoprotective effects that may 12. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic explain the results obtained in non-diabetic models of CKD. and cardiovascular considerations of SGLT2 inhibition. Nat However, more evidence is needed to confirm the results, as Rev Nephrol 2017; 13: 11–26 Sodium-glucose cotransporter inhibitors | 325 13. Monami M, Nardini C, Mannucci E. Efficacy and safety of so- augmentation of the effects with saxagliptin, a DPP4 inhibi- dium glucose co-transport-2 inhibitors in type 2 diabetes: a tor. Cardiovasc Drugs Ther 2017; 31: 119–132 meta-analysis of randomized clinical trials. Diabetes Obes 24. Tahara A, Takasu T. Prevention of progression of diabetic Metab 2014; 16: 457–466 nephropathy by the SGLT2 inhibitor ipragliflozin in unin- 14. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardio- ephrectomized type 2 diabetic mice. Eur J Pharmacol 2018; vascular outcomes, and mortality in type 2 diabetes. N Engl J 830: 68–75 Med 2015; 373: 2117–2128 25. Leng W, Ouyang X, Lei X et al. The SGLT-2 inhibitor dapagli- 15. Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and car- flozin has a therapeutic effect on atherosclerosis in diabetic diovascular and renal events in type 2 diabetes. N Engl J Med ApoE / mice. Mediators Inflamm 2016; 2016: 1–13 2017; 377: 644–657 26. Ma Q, Steiger S, Anders H-J. Sodium glucose transporter-2 in- 16. Perkovic V, de Zeeuw D, Mahaffey KW et al. Canagliflozin hibition has no renoprotective effects on non-diabetic and renal outcomes in type 2 diabetes: results from the chronic kidney disease. Physiol Rep 2017; 5: e13228 CANVAS Program randomised clinical trials. Lancet Diabetes 27. Zhang Y, Thai K, Kepecs DM et al. Sodium-glucose linked Endocrinol 2018; 6: 691–704 cotransporter-2 inhibition does not attenuate disease Downloaded from https://academic.oup.com/ckj/article/12/3/322/5370330 by guest on 11 February 2022 17. Jardine MJ, Mahaffey KW, Neal B et al. The Canagliflozin progression in the rat remnant kidney model of chronic and Renal Endpoints in Diabetes with Established kidney disease. PLoS One 2016; 11: e0144640 Nephropathy Clinical Evaluation (CREDENCE) study ratio- 28. Panchapakesan U, Pegg K, Gross S et al. Effects of SGLT2 inhi- nale, design, and baseline characteristics. Am J Nephrol bition in human kidney proximal tubular cells— 2018; 46: 462–472 renoprotection in diabetic nephropathy? PLoS One 2013; 8: 18. Satirapoj B, Korkiatpitak P, Supasyndh O. Effect of SGLT-2 in- e54442 hibitor to proximal tubular function and injury in 2 patients 29. Zhang Y, Nakano D, Guan Y et al. A sodium-glucose cotrans- with type 2 diabetes: a randomized controlled trial. Clin porter 2 inhibitor attenuates renal capillary injury and fibro- Kidney J 2019 sis by a vascular endothelial growth factor–dependent 19. Dekkers CCJ, Petrykiv S, Laverman GD et al. Effects of the pathway after renal injury in mice. Kidney Int 2018; 94: SGLT-2 inhibitor dapagliflozin on glomerular and tubular in- 524–535 jury markers. Diabetes Obes Metab 2018; 20: 1988–1993 30. Abbas NAT, El Salem A, Awad MM. Empagliflozin, SGL T2 in- 20. Herrington WG, Preiss D, Haynes R et al. The potential for im- hibitor, attenuates renal fibrosis in rats exposed to unilateral proving cardio-renal outcomes by sodium-glucose co-trans- ureteric obstruction: potential role of klotho expression. porter-2 inhibition in people with chronic kidney disease: a Naunyn Schmiedebergs Arch Pharmacol 2018; 39: 1347–1360 rationale for the EMPA-KIDNEY study. Clin Kidney J 2018; 11: 31. Cassis P, Locatelli M, Cerullo D et al. SGLT2 inhibitor dapagli- 749–761 flozin limits podocyte damage in proteinuric nondiabetic ne- 21. Liang Y, Arakawa K, Ueta K et al. Effect of canagliflozin on re- phropathy. JCI Insight 2018; 3: pii: 98720 nal threshold for glucose, glycemia, and body weight in nor- 32. Kitada K, Nakano D, Ohsaki H et al. Hyperglycemia mal and diabetic animal models. PLoS One 2012; 7: e30555 causes cellular senescence via a SGLT2- and p21- 22. Shin SJ, Chung S, Kim SJ et al. Effect of sodium-glucose co- dependent pathway in proximal tubules in the early transporter 2 inhibitor, dapagliflozin, on renal renin- stage of diabetic nephropathy. J Diabetes Complications angiotensin system in an animal model of type 2 diabetes. 2014; 28: 604–611 PLoS One 2016; 11: e0165703 33. Ishibashi Y, Matsui T, Yamagishi S. Tofogliflozin, a highly se- 23. Ye Y, Bajaj M, Yang H-C et al. SGLT-2 inhibition with dapagli- lective inhibitor of SGLT2 blocks proinflammatory and proa- flozin reduces the activation of the Nlrp3/ASC inflamma- poptotic effects of glucose overload on proximal tubular some and attenuates the development of diabetic cells partly by suppressing oxidative stress generation. Horm cardiomyopathy in mice with type 2 diabetes. Further Metab Res 2015; 48: 191–195