Clinical Kidney Journal, 2020, vol. 13, no. 5, 728–733 doi: 10.1093/ckj/sfaa198 Advance Access Publication Date: 9 October 2020 Editorial Comment EDITORIAL COMMENT SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia Beatriz Fernandez-Fernandez1,2, Pantelis Sarafidis3, Mehmet Kanbay4,5, Juan F. Navarro-González2,6, Marı́a José Soler2,7,8, Jose Luis Górriz2,9 and Alberto Ortiz1,2 1 IIS-Fundacion Jimenez Diaz and School of Medicine, Universidad Autónoma de Madrid, Grupo Espan ~ ol de Estudio de la Nefropatia Diabetica, Madrid, Spain, 2Spanish Renal Research Network, Madrid, Spain, 3 Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece, 4 Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey, 5 Bellvitge University Hospital, Hospitalet, Grupo Espan ~ ol de Estudio de la Nefropatia Diabetica, Barcelona, Spain, 6Unidad de Investigación y Servicio de Nefrologı́a, Hospital Universitario Nuestra Sen ~ ora de Candelaria, 7 Grupo Espan ~ ol de Estudio de la Nefropatia Diabetica, Santa Cruz de Tenerife, Spain, Department of Nephrology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, 8 Nephrology Research Group, Vall d’Hebron Research Institute , Grupo Espan ~ ol de Estudio de la Nefropatia Diabetica, Barcelona, Spain and 9Hospital Clı́nico Universitario, INCLIVA, Universitat de Valencia, Grupo Espan ~ ol de Estudio de la Nefropatia Diabetica, Valencia, Spain Correspondence to: Alberto Ortiz; E-mail: aortiz@fjd.es, Jose Luis Górriz; E-mail: jlgorriz@gmail.com ABSTRACT Abstract. Sodium–glucose co-transporter-2 (SGLT2) inhibitors decreased cardiovascular (CV) events and improved renal outcomes in CV safety studies in type 2 diabetes melitus (T2DM) patients at high CV risk. Canagliflozin also improved kidney outcomes in diabetic kidney disease in the Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluationtrial. More recently, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial showed that dapagliflozin improved CV outcomes in patients with HF with or without diabetes. Protection from HF in non- diabetics was confirmed for empagliflozin in the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial. A meta-analysis of DAPA-HF and EMPEROR-Reduced confirmed reductions in all-cause and CV death and the combined risk of CV death or worsening HF, as well as in the composite renal endpoint fhazard ratio [HR] 0.62 [95% confidence interval (CI) 0.43–0.90]g without differences based on the presence of diabetes or baseline estimated glomerular filtration rate (eGFR). Moreover, the Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (DAPA-CKD) showed that dapagliflozin as an add-on over renin–angiotensin system blockade in patients with chronic kidney disease (CKD; with or without T2DM) reduced the HR for the primary endpoint (time to the first occurrence of 50% eGFR decline, end-stage kidney disease or renal or CV death) to 0.61 (95% CI 0.51–0.72) and for the secondary endpoints of worsening renal function or death from kidney failure [HR 0.56 (95% CI 0.45–0.68)], hospitalization for HF or CV death [HR 0.71 (95% CI 0.55–0.92)] and Received: 1.9.2020; Editorial decision: 1.9.2020 C The Author(s) 2020. 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 728 SGLT2 inhibitors for CKD | 729 all-cause mortality [HR 0.69 (95% CI 0.53–0.88)]. These beneficial effects were consistent in patients with and without T2DM. In conclusion, SGLT2 inhibitors offer CV and kidney protection in both diabetic and non-diabetic CKD and, additionally, improve glycaemic control in T2DM, making them first-line therapy for CKD independent from diabetic status. Keywords: chronic kidney disease, clinical trials, mortality, outcomes, SGLT2 inhibitor Chronic kidney disease (CKD) is one of the fastest-growing [HR 0.80 (95% CI 0.67–0.95), P ¼ 0.01] and hospitalization for heart global causes of death, projected to become the fifth leading failure [HF; HR 0.61 (95% CI 0.47–0.80), P < 0.001], thus confirming global cause of death by 2040, while in countries with long life in a CKD population the benefits observed in patients at high expectancy it may become the second leading cause of death CV risk. Interestingly, while the antidiabetic effect of SGLT2 before the end of the century [1, 2]. Diabetic kidney disease inhibitors decreases as eGFR decreases, since the total amount (DKD) is the most common cause of CKD and, together with age- of glucose excreted decreases, the CV and kidney benefit is still ing, hypertension and obesity, is thought to be a key contributor observed at the lower end of the eGFR spectrum of patients en- to the increasing prevalence and mortality from CKD. Indeed, rolled in major clinical trials [9]. Furthermore, although there is hypertension is currently the second most common cause of discussion about the precise mechanisms responsible for kid- CKD. Of note, >90% of patients with diabetes and almost all ney and heart protection by SGLT2 inhibitors, these drugs re- patients with diabetic CKD are also hypertensive. In this situa- duce intraglomerular pressure in individuals with and without tion, drugs that improve glycaemic control and simultaneously diabetes, as glycosuria is also observed in non-diabetic individu- decrease blood pressure and weight would be welcomed. als, since plasma glucose is continuously filtered by glomeruli Furthermore, since one of the key features of CKD is increased and reabsorbed completely by proximal tubules independent of cardiovascular (CV) mortality [3], if such drugs also decrease CV the presence of diabetes [10]. Besides decreasing single nephron events and mortality, they could go a long way towards decreas- GFR and promoting natriuresis, this mechanism decreases the ing the health impact of CKD. Finally, the current cornerstone of proximal tubular workload, thus protecting tubules that may al- CKD therapy and one of the cornerstones of CV disease therapy ready be compromised by decreased oxygen availability be- is blockade of the renin–angiotensin system (RAS), but the asso- cause of the capillary rarefaction characteristics of CKD [11, 12]. ciated trend towards hyperkalaemia limits their optimal use in Based on these results and considerations, more recent ran- everyday practice [4]. Thus it would be helpful if such drugs domized controlled trials (RCTs) enrolled both diabetic and non- would help control hyperkalaemia. For several years now we diabetic patients with either HF or CKD (Figure 1). have known that sodium–glucose co-transporter-2 (SGLT2) inhibitors possess many of these characteristics. Recent and ac- cumulating evidence suggests that they may also decrease the SGLT2 INHIBITORS IMPROVE CV OUTCOMES significant residual CV and renal risk for diabetic and non- ALSO IN NON-DIABETIC PATIENTS WITH HF diabetic CKD patients treated by the current standard of RAS The first large Phase 3 trial of SGLT2 inhibitors enrolling non- blockade. diabetic patients in addition to diabetics was the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA- SGLT2 INHIBITORS IMPROVE KIDNEY AND CV OUTCOMES IN T2DM 90 DECLARE In CV safety trials, SGLT2 inhibitors improved CV outcomes in 80 CANVAS patients with type 2 diabetes mellitus (T2DM) [5]. Moreover, as EMPA-REG antidiabetic drugs, they improved metabolic control. In addi- 70 DAPA-HF eGFR (mL/min/1.73 m2) tion, they decreased blood pressure and weight, likely because 60 EMPEROR-reduced they promote the urinary excretion of sodium and calories from CREDENCE glucose since SGLT2 reabsorbs both from the glomerular ultra- 50 IDNT filtrate. This iso-osmotic diuresis also leads to improved control DAPA-CKD 40 RENAAL of hyperkalaemia. On top of these advantages, CV safety trials suggested a nephroprotective effect of SGLT2 inhibitors in 30 Cardiovascular safety trials T2DM patients at high CV risk (reviewed in Górriz et al. [6]). Heart failure trials 20 CKD trials Nephroprotection was clearly confirmed for T2DM patients with 10 CKD trials, RAS blockade DKD in the Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation (CREDENCE) trial [6–8]. In 0 patients with an estimated glomerular filtration rate (eGFR) of 1 10 100 1000 10 000 30–<90 mL/min/1.73 m2 and a urinary albumin:creatinine ratio UACR (log mg/g) (UACR) of 300–5000 mg/g on RAS blockade, canagliflozin reduced FIGURE 1: Baseline kidney characteristics for RCTs assessing RAS blockade in by 30% the relative risk of a composite primary outcome of end- CKD as well as RCTs assessing different aspects of SGLT2 inhibitors: CV safety in stage kidney disease (dialysis, transplantation or a sustained T2DM, kidney protection in T2DM, HF outcomes in HF patients with and without eGFR of <15 mL/min/1.73 m2), doubling of the serum creatinine T2DM and kidney protection in CKD patients with and without T2DM. RCTs assessing patients with and without T2DM are labeled in red. The following level or death from renal or CV causes fhazard ratio [HR] 0.70 SGLT2 inhibitors were tested: canagliflozin (CANVAS and CREDENCE), dapagli- [95% confidence interval (CI) 0.59–0.82]g. This risk reduction was flozin (DECLARE, DAPA-HF and DAPA-CKD) and empagliflozin (EMPA-REG and consistent for the different components of the primary end- EMPEROR-reduced). No baseline albuminuria data were available for DAPA-HF point as well as for CV death, myocardial infarction or stroke and EMPEROR-reduced. 730 | B. Fernandez-Fernandez et al. CREDENCE Cardiovascular death DAPA-CKD CREDENCE All-cause death DAPA-CKD EMPEROR-reduced no-DM EMPEROR-reduced DM DAPA-HF no-DM DAPA-HF DM Cardiovascular death or hospitalization for heart failure CREDENCE DAPA-CKD CREDENCE DAPA-CKD DM Primary combined DAPA-CKD No-DM kidney endpoint DAPA-CKD DM and non-DM patients 0 0.2 0.4 0.6 0.8 1.0 Non-DM patients Hazard ratio vs. placebo DM patients FIGURE 2: Key outcomes of RCTs assessing SGLT2 inhibitors in patients with HF or CKD. Results are presented for the full population, which in some RCTs (DAPA-HF, DAPA-CKD and EMPEROR-reduced) was comprised of patients with T2DM and non-diabetic individuals and separately for diabetics and non-diabetics. The primary combined kidney endpoint in CREDENCE and DAPA-CKD consisted of CKD progression, as assessed by a doubling of serum creatinine (CREDENCE) or 50% eGFR de- cline (DAPA-CKD), end-stage kidney disease, renal death or CV death. The endpoint of CV death or hospitalization for HF was the primary endpoint in HF trials (DAPA- HF and EMPEROR-reduced). The following SGLT2 inhibitors were tested: canagliflozin (CREDENCE), dapagliflozin (DAPA-HF and DAPA-CKD) and empagliflozin (EMPEROR-reduced). HF) trial [13]. DAPA-HF enrolled 4744 patients with HF and low Dapagliflozin on Renal Outcomes and Cardiovascular Mortality ejection fraction with or without diabetes with an eGFR 30 mL/ in Patients With Chronic Kidney Disease (DAPA-CKD) tested min/1.73 m2. Over a median of 18.2 months, the HR for the pri- dapagliflozin in patients with CKD [16]. In addition, a meta- mary composite outcome of worsening HF or CV death was 0.74 analysis of the EMPEROR-Reduced and DAPA-HF trials has been (95% CI 0.65–0.85) (Figure 2). A reduction of worsening HF [HR published [17], as well as a small crossover RCT of dapagliflozin 0.70 (95% CI 0.59–0.83)], death from CV causes [HR 0.82 (95% CI in non-diabetic CKD (DIAMOND) [18]. 0.69–0.98)] and all-cause death [HR 0.83 (95% CI 0.71–0.97)] was The EMPEROR-Reduced trial enrolled 3730 patients with HF noted. Findings were similar for patients with or without diabe- and an eGFR 20 mL/min/1.73 m2 who were followed for a me- tes (HR of primary outcome 0.75 and 0.73, respectively). dian of 16 months [15]. It essentially reproduced the beneficial However, serum creatinine increased more up to 8 months in findings observed in DAPA-HF, with an HR for the primary end- patients on dapagliflozin (0.07 6 0.24 versus 0.04 6 0.25 mg/dL; point of worsening HF or CV death of 0.75 (95% CI 0.65–0.86) P < 0.007). Given the short follow-up, this may be attributed to (Figure 2), although the decrease in CV or all-cause mortality did decreased glomerular hyperfiltration. Indeed, a post hoc analysis not reach statistical significance. A careful analysis should ad- disclosed that the slope of the eGFR assessed from Day 14 after dress the reason for this discrepancy regarding the impact on the introduction of dapagliflozin was 1.09 (95% CI 1.41 to mortality between the two HF trials of SGLT2 inhibitors. Again, 0.78) mL/min/1.73 m2/year for dapagliflozin versus 2.87 (95% there was no difference between diabetic and non-diabetic CI 3.19 to 2.55) for placebo (P < 0.01), while the risk of dou- patients for the primary outcome (HR 0.72 and 0.78, respec- bling of serum creatinine was reduced with the SGLT2 inhibitor tively). With regards to renal outcomes, the mean slope of the [HR 0.56 (95% CI 0.39–0.83)] and the difference between placebo eGFR was lower in patients on empagliflozin (–0.55 6 0.23 versus and dapagliflozin increased with time [14]. Additionally, similar –2.28 6 0.23 mL/min/1.73 m2/year; P < 0.001) and in another pre- cardiac protection was observed for patients with eGFR <60 or specified analysis the HR for a composite renal outcome (dialy- 60 mL/min/1.73 m2; the HR for the primary outcome was 0.72 sis or renal transplantation or a sustained reduction of eGFR (0.59–0.86) and 0.76 (0.63–0.92), respectively [13]. defined in several ways according to baseline eGFR) was 0.50 (95% CI 0.32–0.77), although this outcome was uncommon, oc- SGLT2 INHIBITORS IMPROVE KIDNEY curring in 3.1% of placebo patients. It is of interest that the EMPEROR-Reduced trial lowered the eGFR threshold at which OUTCOMES IN NON-DIABETIC PATIENTS SGLT2 inhibitors offer CV and kidney benefit to 20 mL/min/ WITH HF 1.73 m2. In August 2020, the results of two new trials testing SGLT2 The meta-analysis of the EMPEROR-Reduced and DAPA-HF inhibitors in diabetic and non-diabetic patients with HF or CKD trials confirmed the CV and renal benefits [17]. Of interest, a re- were reported [15, 16]. The EMPagliflozin outcomE tRial in duction in the risk of worsening HF or CV death was also ob- Patients With chrOnic heaRt Failure With Reduced Ejection served in patients with CKD and eGFR <60 mL/min/1.73 m2 [HR Fraction (EMPEROR-Reduced) trial tested empagliflozin in 0.77 (95% CI 0.68–0.88)] and in the elderly [HR for those 75 years patients with HF [15], while the Study to Evaluate the Effect of of age 0.77 (95% CI 0.64–0.92)] and was similar for diabetic [HR SGLT2 inhibitors for CKD | 731 0.74 (95% CI 0.65–0.84)] and non-diabetic [HR 0.75 (95% CI 0.65– (500–3500 mg/24 h) CKD patients with a mean eGFR of 0.87)] individuals. However, the most interesting analysis was 58 6 23 mL/min/1.73 m2 were randomly assigned to dapagliflo- related to safety: the incidence of severe hypoglycaemia, frac- zin–placebo or placebo–dapagliflozin. Although a transient re- tures, ketoacidosis, lower limb amputation and Fournier’s gan- duction in eGFR of –6.6 mL/min/1.73 m2 (95% CI –9.0 to –4.2; grene was minimal (0.7% for every individual event except for P < 0.0001) was observed at Week 6 on dapagliflozin, there was fractures, which was 2.7%) and did not differ between SGLT2 no impact on proteinuria [difference in proteinuria change from inhibitors and placebo. baseline between dapagliflozin and placebo of 0.9% (95% CI – 16.6–22.1; P ¼ 0.93)], thus dissociating a haemodynamic impact on eGFR from an impact on proteinuria. Results on albuminuria SGLT2 INHIBITORS ADDITIONALLY IMPROVE and proteinuria for non-diabetic patients enrolled in DAPA-CKD KIDNEY AND CV OUTCOMES IN NON-DIABETIC are awaited, as this may provide clues as to the mechanism of PATIENTS WITH CKD nephroprotection afforded by SGLT2 inhibitors. The most interesting data relate to DAPA-CKD trial [16, 19, 20]. As in the case of the other large trial with a primary kidney end- CRYSTAL BALL SGLT2-INOMICS point (CREDENCE) [8], DAPA-CKD was stopped early for over- whelming efficacy. DAPA-CKD enrolled 4304 CKD patients with In conclusion, SGLT2 inhibitors appear to be primarily nephro- an eGFR of 25–75 mL/min/1.73 m2 and albuminuria of 200– protective and cardioprotective agents that additionally im- 5000 mg/g, 2906 (68%) of them with T2DM, with a mean age of prove glycaemic control in those T2DM patients who have 62 years and a median follow-up of 2.4 years [16, 20]. The mean better preserved kidney function. Large RCTs in diabetic and baseline eGFR was 43.1 (standard deviation 12.4) mL/min/ non-diabetic CKD patients on RAS blockade have shown that 1.73 m2 and 14.5% of patients had an eGFR <30 mL/min/1.73 m2. they slow kidney disease progression, decrease CV events and The median baseline albuminuria was 949 mg/g and 90% of improve survival independent of the presence of diabetes. Thus patients had albuminuria >300 mg/g. The cause of CKD was the benefits appear to extend beyond diabetes to include ischaemic/hypertensive nephropathy in 16%, immunoglobulin patients with the second (hypertension/vascular nephropathy) A (IgA) nephropathy in 6% and focal segmental glomeruloscle- and third (glomerulonephritis) most common causes of CKD, al- rosis in 3% and it had been confirmed by biopsy in 20% of though subgroup analyses are awaited to confirm this. patients. An overwhelming majority (97%) were on RAS block- Additionally, and at least for HF, the benefits extend to old age, ade. Dapagliflozin reduced the risk of the primary combined again pending detailed analysis of CKD trials. Finally, in more endpoint of >50% eGFR decline, onset of ESRD or renal or CV recent trials, SGLT2 inhibitors appear safer than in initial trials, death [HR 0.61 (95% CI 0.51–0.72)] (Figure 2). The number needed likely because of better physician handling of SGLT2 inhibitors to treat to avoid one primary event was low at 19. The benefit of and concomitant drug prescription. In fact, they are as safe or dapagliflozin on the primary endpoint was consistent in even safer for certain adverse effects as a placebo. A further RCT of SGLT2 inhibitors in diabetics and non-diabetics with CKD is patients with and without T2DM [HR 0.64 (95% CI 0.52–0.79) and ongoing, testing empagliflozin. The Study of Heart and Kidney 0.50 (0.35–0.72), respectively; P for interaction ¼ 0.24]. It was also Protection With Empagliflozin (EMPA-KIDNEY) will be a larger observed in patients with an eGFR <45 or >45 mL/min/1.73 m2 trial that will also enroll patients with Type 1 diabetes (T1DM) in and with albuminuria <1000 or >1000 mg/g, i.e. in patients with different stages of CKD and different severity of albuminuria. Overall, the results were in the range found for canagliflozin in T1DM T2DM Non-DM CREDENCE in DKD [8]. There were no statistically significant dif- ferences in DAPA-CKD in the primary endpoint between dia- betics and non-diabetics, however, the HR was 22% lower for Heart failure non-diabetics. Thus the kidney benefit afforded by dapagliflozin was at least as large in patients with non-DKD (including Non- ischaemic/hypertensive nephropathy, IgA nephropathy and fo- albuminuric CKD CKD cal segmental glomerulosclerosis, among others) than in DKD. Additionally, dapagliflozin reduced all three secondary end- points compared with placebo: worsening renal function or High CV risk death from kidney failure [HR 0.56 (95% CI 0.45–0.68)], hospitali- FIGURE 3: Current status and key future developments in the study of SGLT2 zation for HF or CV death [HR 0.71 (95% CI 0.55–0.92)] and all- inhibitors and CV and kidney benefit. Coloured parts indicate populations in cause mortality [HR 0.69 (95% CI 0.53–0.88)]. Dapagliflozin was whom cardio- and nephroprotection have been demonstrated for SGLT2 inhibi- also found to be safe in patients with CKD, with no differences tors: dark red for high CV risk, light brown for CKD and light red for HF. Thus col- compared with placebo in the incidence of severe hypoglycae- ours highlight high CV risk, HF and CKD patients and their overlaps within the mia, fractures, ketoacidosis and lower limb amputation, which T2DM and the non-diabetic populations. Additionally, non-albuminuric CKD is indicated in green when CV and kidney benefit has been demonstrated in large were all uncommon. Diabetic ketoacidosis was not reported in clinical trials, as for non-albuminuric CKD in T2DM patients within HF and high any patient randomized to dapagliflozin and occurred in two CV risk trials or non-diabetic patients with HF. However, no data are available patients in the placebo group, while severe hypoglycaemia was regarding CV or kidney benefit in non-diabetic patients with CKD and an ab- not observed in patients without T2DM. Data on urinary tract sence of HF, thus a white (non-coloured) spot is placed over patients with non- infections were not presented. In this regard, data from major albuminuric CKD who are not diabetic and do not have HF. Additionally, there is outcome trials suggest that SGLT2 inhibitors are not associated no information on potential CV or renal benefits in T1DM patients. EMPA-REG will expand data from currently available trial results by exploring T1DM and with an increased risk of urinary tract infections [21]. non-albuminuric CKD in persons without diabetes. Of note, CV and kidney ben- An interesting piece of information is provided by the efit has been observed up to now for populations with an eGFR 20 mL/min/ DIAMOND trial, although it had a small sample size and short 1.73 m2 in the context of HF and EMPA-REG will also enroll CKD patients with an follow-up [18]. In this crossover trial, 53 non-diabetic proteinuric eGFR 20 mL/min/1.73 m2. 732 | B. Fernandez-Fernandez et al. addition to T2DM and non-diabetics and will have a lower eGFR research support for an investigator-initiated study from entry criteria (20–90 mL/min/1.73 m2) than other CKD trials and AstraZeneca. J.L.G. has served as a consultant for Boehringer will not require pathological albuminuria to enroll patients with Ingelheim, Mundipharma, AstraZeneca, Novo Nordisk and has low eGFR (20–<45 mL/min/1.73 m2), potentially expanding the received speaker honoraria from Boehringer Ingelheim, population that benefits from SGLT2 inhibition if it meets the Mundipharma, AstraZeneca, Novo Nordisk, Novartis and Eli primary endpoint [9] (Figure 3). Of note, nephroprotection was Lilly. M.J.S. is a consultant for Novo Nordisk and received also observed in HF trials in which pathological albuminuria speaker fees from Janssen, Boehringer Ingelheim, Eli Lilly, was not an inclusion requirement. What is next? AstraZeneca, Mundipharma, Fresenius Medical Care and Esteve. Guidelines should be updated to include SGLT2 inhibitor as B.F.F. reports speaker fees or travel support from AbbVie, first-line nephroprotective therapy on top of RAS blockade for AstraZeneca, Boehringer Ingelheim, Esteve, Menarini, any CKD, or at least for the causes of CKD tested in DAPA-CKD. Mundipharma, Novartis and Novo Nordisk, outside the submit- Further RCTs focused on specific causes of CKD should confirm ted work. their efficacy in those, likely starting with IgA nephropathy and focal segmental glomerulosclerosis, which, although present in REFERENCES the DAPA-CKD trials, were clearly underrepresented. In this re- gard, the whole therapeutic approach to IgA nephropathy is be- 1. Foreman KJ, Marquez N, Dolgert A et al. 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The potential for im- proving cardio-renal outcomes by sodium-glucose co-trans- CONFLICT OF INTEREST STATEMENT porter-2 inhibition in people with chronic kidney disease: a A.O. is a consultant for Sanofi Genzyme and has received rationale for the EMPA-KIDNEY study. Clin Kidney J 2018; 11: speaker fees or travel support from AstraZeneca, Amicus, 749–761 Amgen, Fresenius Medical Care, Menarini, Kyowa Kirin, 10. Ferrannini E, Baldi S, Frascerra S et al. Shift to fatty substrate Alexion, Otsuka and Vifor Fresenius Medical Care Renal Pharma utilization in response to sodium-glucose cotransporter 2 in- and is director of the Catedra Mundipharma-UAM of DKD. hibition in subjects without diabetes and patients with type J.F.N.G. has served as a consultant and has received speaker 2 diabetes. Diabetes 2016; 65: 1190–1195 fees or travel support from AbbVie, Amgen, AstraZeneca, 11. Satirapoj B, Korkiatpitak P, Supasyndh O. 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Presented at the European Society of 20. Wheeler DC, Stefansson BV, Batiushin M et al. The Cardiology Congress, August 29, 2020; https://esc2020.escar Dapagliflozin and Prevention of Adverse outcomes in dio.org/detail/video/ref: S31328?_ga¼2.107325186. Chronic Kidney Disease (DAPA-CKD) trial: baseline charac- 1440733159.1598629931-849659886.1598629931 (30 August teristics. Nephrol Dial Transplant 2020; 10.1093/ndt/gfaa234 2020, date last accessed) 21. Sarafidis PA, Ortiz A. The risk for urinary tract infections 15. Packer M, Anker SD, Butler J et al. Cardiovascular and renal with sodium-glucose cotransporter 2 inhibitors: no longer a outcomes with empagliflozin in heart failure. N Engl J Med cause of concern? Clin Kidney J 2019; 13: 24–26 2020; doi: 10.1056/NEJMoa2022190 22. Bakris GL, Agarwal R, Anker SD et al.Design and baseline 16. Heerspink HL. Dapagliflozin in patients with chronic kidney characteristics of the Finerenone in Reducing Kidney Failure disease DAPA-CKD. 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