Nephrol Dial Transplant (2020) 35: i13–i23 doi: 10.1093/ndt/gfz237 Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease REVIEW Jose Luis Górriz 1,2, Juan F. Navarro-González2,3,4, Alberto Ortiz2,5, Ander Vergara6,7, Julio Nu~ nez8,9, Conxita Jacobs-Cachá6,7, Alberto Martı́nez-Castelao2,10 and Maria Jose Soler 2,6,7 1 Hospital Clı́nico Universitario de Valencia, Universitat de València, INCLIVA, GEENDIAB, Valencia, Spain, 2REDINREN, Madrid, Spain, 3 Unidad de Investigación y Servicio de Nefrologı́a, Hospital Universitario Nuestra Se~ nora de Candelaria, Santa Cruz de Tenerife, Spain, 4 Instituto de Tecnologı́as Biomédicas, Universidad de La Laguna, GEENDIAB, Santa Cruz de Tenerife, Spain, 5IIS-Fundación Jimenez Diaz UAM and School of Medicine, UAM, GEENDIAB, Madrid, Spain, 6Department of Nephrology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, 7Nephrology Research Group, Vall d’Hebron Research Institute (VHIR), GEENDIAB, Barcelona, Spain, 8Department of Cardiology, Hospital Clı́nico Universitario de Valencia, Universitat de Valencia, INCLIVA, Valencia, Spain, 9CIBER Cardiovascular and 10Bellvitge University Hospital, Hospitalet, GEENDIAB, Barcelona, Spain Correspondence to: Maria Jose Soler; E-mail: mjsoler01@gmail.com; Alberto Ortiz; E-mail: aortiz@fjd.es; Twitter handle: @PepaSolerR ABSTRACT Until 2016, the mainstay of DKD treatment was renin–angio- Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have tensin system (RAS) blockade [4]. From 2016, sodium-glucose clearly demonstrated their beneficial effect in diabetic kidney cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated disease (DKD) on top of the standard of care [blood glucose beneficial effects in DKD on top of the standard of care, namely control, renin–angiotensin system blockade, smoking cessation blood glucose control, RAS blockade, smoking cessation and and blood pressure (BP) control], even in patients with overt blood pressure (BP) control [5–9]. Initially, SGLT2i was devel- DKD. However, the indication of this drug class is still blood oped to lower plasma glucose in type 2 diabetes mellitus glucose lowering in type 2 diabetic patients with estimated glo- (T2DM) patients, but large randomized controlled trials merular filtration rate >45 mL/min/1.73 m2. Based on the new (RCTs) have demonstrated both renal and cardiovascular pro- evidence, several scientific societies have emphasized the prefer- tection in T2DM beyond the benefits derived from improved ential prescription of SGLT2i for patients at risk of heart failure glycaemic control. or kidney disease, but still within the limits set by health author- The renoprotective effects of SGLT2i were first observed in ities. A rapid positioning of both the European Medicines three large trials evaluating cardiovascular safety: Agency and the US Food and Drug Administration will allow Empagliflozinn, cardiovascular, Cardiovascular Outcomes, and patients with overt DKD to benefit from SGLT2i. Clinical expe- Mortality in Type 2 Diabetes (EMPA-REG OUTCOME), rience suggests that SGLT2i safety management may in part Canagliflozin and Cardiovascular and Renal Events in Type 2 mirror renin–angiotensin blockade safety management in Diabetes (CANVAS Programme), and Dapagliflozin and patients with overt DKD. This review focuses on the rationale Cardiovascular Outcomes in Type 2 Diabetes (DECLARE- for an indication of SGTL2i in DKD. We further propose clini- TIMI 58). In these studies, SGLT2i reduced albuminuria pro- cal steps for maximizing the safety of SGLT2i in DKD patients gression, prevented glomerular filtration rate (GFR) decline and on other antidiabetic, BP or diuretic medication. decreased the incidence of renal replacement therapy in T2DM patients without overt DKD [5, 6, 8]. Three further trials ad- Keywords: chronic renal failure, diabetic kidney disease, dress the kidney effects of SGLT2i on patients with overt DKD: ESRD, SGLT2 inhibitors, type 2 diabetes Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE), Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney INTRODUCTION Disease (DAPA-CKD), and the Study of Heart and Kidney Diabetic kidney disease (DKD) is the most frequent cause of Protection With Empagliflozin (EMPA-KIDNEY). In April end-stage kidney disease (ESKD) in developed countries [1–3]. 2019, the CREDENCE trial’s striking results on kidney and 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 i13 heart protection were published [7]. In concordance with afferent arterioles. The signalling reduction leads to afferent ar- DAPA-CKD results, some authors suggest the potential use of teriole vasodilation, increases intraglomerular pressure and SGLT2i on top of RAS blockade in the early stages of DKD, causes hyperfiltration. Naþ/Hþ exchanger isoform 3 (NHE3) is when T2DM patients mainly exhibit hyperfiltration and mild a proximal tubule Naþ transporter closely regulated by glucose albuminuria. With this approach, one expects that the cardiore- metabolism and SGLT transporters, which makes it sensitive to nal protective effect of this treatment will be offered as preven- SGLT2i [22]. In Otsuka Long-Evans Tokushima Fatty diabetic tion and not delayed to the already established DKD [10]. rats, empagliflozin decreased the tubular expression of NHE3, However, further studies in pre-diabetic patients are needed to the Naþ–Kþ–2Cl cotransporter and the epithelial Naþ chan- confirm this hypothesis. nel as compared with untreated littermates [23]. Therefore, There were initial safety concerns as SGLT2i adverse drug SGLT2i lowers glycaemia and additionally promotes natriuresis reactions (ADRs) included acute kidney injury (AKI), diabetic by inhibiting both SGLT2 activity and other Naþ transporters ketoacidosis (DKA), amputations, urinary and genital tract such as NHE3. Thus, the natriuretic effect may contribute to infections (UTIs), bladder cancer and bone fractures [11]. cardiorenal benefits by lowering arterial pressure and re- However, recent trials have downplayed these risks and the activating renal tubulo-glomerular feedback signalling from the benefit/risk balance remains positive. Interestingly, in a pooled macula densa that decreases intraglomerular pressure and analysis of 11 Phase 3 RCTs, dapagliflozin use in patients with hyperfiltration. However, prior to SGLT2i use, no other diuretic estimated GFR (eGFR) between 12 and 45 mL/min/1.73 m2 demonstrated clear cardiorenal protective effects in diabetic (CKD G3b–4) decreased the urinary albumin creatinine ratio patients although they reduced BP or volume overload. For this (UACR), BP and body weight without modulating glycated he- reason, we believe that the beneficial effects exerted by SGLT2i moglobin (HbA1c) or increasing major side effects [10]. This are the conjunction of diverse molecular mechanisms acting to- observation supports the concept of positive renal and cardiac gether. More studies on the bench side are needed to elucidate effects of SGLT2i independent from glycaemic control. the involved pathways. In this review, we describe the molecular mechanism in- Beyond the antidiabetic and natriuretic properties, studies in volved in cardiorenal protection in DKD and the current indi- non-diabetic mice and rats suggest that SGLT2i may exert addi- cations for SGLT2i treatment in DKD patients according to the tional direct kidney- or heart-protective actions [24–28]. European Medicines Agency (EMA) and the US Food and Although in some settings SGLT2i did not prevent kidney dam- Drug Administration (FDA), as well as suggestions by the sci- age, in most non-diabetic CKD models, they did decrease kidney entific community to update the indication to include overt fibrosis and inflammation [24–28]. The discrepant results may DKD. We also propose clinical practice recommendations for depend on the nature of the different insults tested: SGLT2i did the safe use of SGLT2i in DKD patients on other antidiabetic, not protect from chronic oxalosis [24] or subtotal nephrectomy hypertension and diuretic treatments. [25], while it protected from unilateral ureteral obstruction [26], ischaemia–reperfusion [27] and protein overload [28]. In cul- tured human tubular cells (HK-2), transforming growth factor NEW MOLECULAR MECHANISMS IN beta 1 (TGF-b1) upregulated SGLT2 and type IV collagen expres- CARDIORENAL PROTECTION WITH SGLT2 sion, and this was prevented by empagliflozin through nuclear INHIBITION factor-jB/Toll-like receptor 4 (NF-jB/TLR4) pathway inhibition, SGLT2i have become a promising option to treat T2DM as they thus linking a key mechanism of DKD and non-DKD CKD pro- decrease glycaemia and improve insulin resistance without pro- gression to SGLT2 [29]. Furthermore, both mice and human glo- ducing severe hypoglycaemia [12]. In a meta-analysis published merular cells also express SGLT2. Indeed, albumin upregulated by Yang et al. [13], SGLT2i was demonstrated to reduce HbA1c SGLT2 in mice with protein-overload proteinuria, in albuminuric and insulin dosage both in types 1 and 2 diabetic patients. This CKD patients and in cultured human podocytes [28]. Overall, the decrease in insulin doses could reflect an improvement in insulin available evidence of benefit in non-diabetic models supports the resistance, which is a key mediator of type 2 diabetes [14]. existence of glucose-independent nephroprotective effects, and Furthermore, it might in part explain the weight loss induced by this hypothesis will be addressed in RCTs [26–30]. this drug class. SGLT2i additionally reduces cardiovascular com- In search of further molecular targets and downstream plications and slows DKD progression [5, 6, 8, 15–17]. Diverse mediators of SGLT2i effects, the canagliflozin mechanism of experimental and clinical studies suggest that the cardiorenal action (MoA) network was explored combining cultured tubu- protection exerted by SGLT2i may be explained by mechanisms lar cell transcriptomics profiles and protein expression data independent of glycaemia and BP control. from the scientific literature. This identified 44 proteins related SGLT2 is a glucose/sodium (Naþ) cotransporter located at to the canagliflozin MoA molecular model that overlapped the apical membrane of proximal tubular cells that drives glu- with proteins in the DKD network model, and 10 of them were cose into cells together with Naþ. It is responsible for the reab- involved in DKD progression [31]. Assessment of these in sorption of 90% of the filtered glucose load [18–20]. In diabetic plasma from diabetic patients with UACR > 1.7 mg/mmol in- patients, the increase in filtered glucose enhances SGLT2 activ- cluded in the efficacy and safety of canagliflozin versus glime- ity, which worsens glycaemic control and promotes Naþ load- piride in patients with type 2 diabetes inadequately controlled ing, impairing BP control [21]. Moreover, proximal tubular with metformin (CANTATA-SU trial) identified four candi- Naþ reabsorption results in decreased Naþ availability at distal date factors [tumour necrosis factor receptor 1 (TNFR1), tubules and reduces macula densa adenosine signalling to interleukin (IL)-6, matrix metalloproteinase 7 (MMP-7) and i14 J.L. Górriz et al. fibronectin 1 (FN1)] that were decreased by canagliflozin, sup- to intolerance or in addition to other medicinal products for the porting the concept that SGLT2i may modulate inflammatory treatment of diabetes, although dapagliflozin may also be used and fibrosis processes in DKD [31, 32]. In addition, the effects in T1DM (Table 2) [47–51]. Recently, the EMA recognized the of two SGLT2i (empagliflozin and canagliflozin) and TGF-b1 positive effect of dapagliflozin on cardiovascular events. on gene expression in two human proximal tubular cell lines However, the US FDA was the first to acknowledge the specific were studied [33]. All 94 genes, mainly related to extracellular indications in T2DM patients with cardiovascular disease matrix organization, which were upregulated by TGF-b1 and (CVD) to reduce major adverse cardiovascular events (MACEs) downregulated by the two SGLT2i were identified. Three of for canagliflozin and to reduce cardiovascular death for empa- these genes [thrombospondin 1 (THBS1), tenascin C (TNC) gliflozin, based on RCT results (Tables 1 and 2) [47–51]. While and platelet-derived growth factor subunit B (PDGF-B)] re- the US FDA specifically warns against the use of any SGLT2i in lated to renal fibrosis and CKD progression were then validated T1DM, the EMA admits the use of dapagliflozin for this indica- on mRNA expression in both cell lines, proving that SGLT2i is tion. Overall, the FDA appears to have moved faster than the able to suppress these genes. EMA in response to cardiovascular safety trial results and Cardioprotection by SGLT2i has been widely attributed to clearly distinguishes between specific indications for each drug the improved glycaemia and BP control [34]. However, a direct as per RCT results (Figure 1A). The rapid response is likely re- effect on the heart cannot be disregarded since there is an ongo- lated to the FDA request for these trials, and an indication for ing controversy on whether SGLT2 is expressed in the heart [35– the treatment of DKD is undergoing priority review. In con- 39]. Recent data support direct effects on the heart since empa- trast, the EMA does not state large differences between the three gliflozin improved high glucose-induced cardiomyocyte dys- drugs either in indication or in the use according to eGFR data. function [40]. Empagliflozin also ameliorated cardiac function There are additional differences between major regulatory in pressure overload-induced heart failure in mice [41] and agencies regarding SGLT2i contraindications for DKD patients delayed ischaemic contracture in isolated mouse hearts in an with decreased eGFR (Table 3 and Figure 1B). insulin-dependent manner [42]. This last effect may depend Since 2016, scientific societies have also suggested the role of on direct inhibition of the Naþ/Hþ transporter NHE1 as SGLT2i in patients with T2DM and specific comorbidities. empagliflozin interacts with its Naþ-binding domain [42, 43]. Table 2 summarizes some of the key position manuscripts. NHE1 and NHE3 belong to the same family of Naþ/Hþ trans- Overall, scientific societies recommend considering SGLT2is as porters. NHE1 is virtually ubiquitously expressed and is re- preferential agents to treat T2DM on top of metformin when sponsible for intracellular pH maintenance, while NHE3 patients have atherosclerotic CVD, heart failure or DKD. expression is restricted to epithelial tissues where it also con- Contrary to the FDA, which provides different regulatory ad- tributes to transepithelial transport [44]. As mentioned before, vice for each drug according to specific cardiovascular safety in kidney tubules, NHE3 activity depends on SGLT2-mediated trial results, scientific societies usually use the generic term glucose transport [22]. It may be speculated that a similar ‘SGLT2i’ or ‘SGLT2i with evidence of cardiovascular or renal mechanism applies to NHE1 in the heart [22, 40]. Thus, cardi- protection’. Additionally, given the striking benefit over heart oprotection by SGLT2i may also depend on direct inhibition failure hospitalization, the preferential use of SGLT2i for of local SGLT2. Finally, empagliflozin increased glucose trans- patients with heart failure is suggested or recommended, al- porter-1 (GLUT-1) mediated glucose transport in isolated car- though this was not a primary outcome of cardiovascular safety diomyocytes [45], and this could also contribute to SGLT2i trials. Scientific societies fall short of recommending the use of cardioprotection. SGLT2i outside the eGFR limits provided by regulatory author- In summary, there is evidence that SGLT2i exert pleiotropic ities (Table 3). It is likely that the range of eGFR at which cana- tissue-protective effects via different mechanisms (Supplementary gliflozin can be prescribed will expand in the near future, given data, Figure S1): (i) reduction of glycaemia, BP and volume over- the renal benefit observed in the CREDENCE trial of canagliflo- load; (ii) SGLT2 inhibition in kidney tubules leading to improved zin versus placebo in patients with overt DKD, in which metabolic control, natriuresis and decreased hyperfiltration; (iii) patients were enrolled with eGFR 30 mL/min/1.73 m2, and local SGLT2 inhibition in other organs, such as the heart [40, 41] canagliflozin was not stopped until renal replacement therapy or the pancreas [46]; and (iv) SGLT2-independent interference was initiated (Supplementary data, Figure S2A). We believe with Naþ/Hþ transporters. that this supports an indication of canagliflozin at any eGFR value in non-dialysis patients, always with the caveat that initia- tion of SGLT2i may decrease the baseline eGFR as it decreases WHEN TO START SGLT2 IN DIABETIC hyperfiltration. In this regard, in T2DM patients with DKD, PATIENTS? canagliflozin decreased the relative risk of a composite primary As of June 2019, regulatory and scientific society statements outcome of ESKD (dialysis, transplantation or a sustained esti- and recommendations on the indications and timing of SGLT2i mated GFR of < 15 mL/min/1.73 m2), doubling of the serum prescriptions differ. This likely reflects the different processing creatinine level or death from renal or cardiovascular causes by timelines for the wealth of recent information from high cardio- 30% versus placebo [hazard ratio (HR) ¼ 0.70; 95% confidence vascular risk and DKD RCTs (Table 1) [5–8, 15]. The EMA cur- interval (CI) 0.59–0.82; P ¼ 0.00001] [7]. More specifically, a rent indication for SGLT2i is the treatment of insufficiently hard component of the composite, the residual risk of ESKD was controlled T2DM as an adjunct to diet and exercise, either as reduced to 2/100 patient-years of follow-up (Supplementary monotherapy when metformin is considered inappropriate due data, Figure S2B). Taken together with beneficial effects over SGLT2 in diabetic kidney disease i15 pre-specified renal outcomes such as incident or worsening 0.53d (0.43–0.66) 0.60b (0.47–0.77) 0.68c (0.54–0.86) 0.54f (0.40–0.75) nephropathy (progression to macroalbuminuria, doubling of se- HR (95% CI) rum creatinine, initiation of renal replacement therapy or death outcome Renal from renal disease) and incident albuminuria in patients with milder or no evidence of DKD in cardiovascular safety trials [5, 17], overall data point to a nephroprotective effect at different stages of DKD that warrants preferential use of SGLT2i to treat 0.67 (0.52–0.87) 0.61 (0.47–0.80) 0.73 (0.61–0.88) 0.65 (0.50–0.85) hospitalization HR (95% CI) Heart failure T2DM patients from very early in the course of DKD, and even before its occurrence to prevent or delay it. The kidney outcomes success of SGLT2i trials for T2DM has set the stage for addi- tional trials enrolling non-T2DM patients [30]. 0.87 (0.72–1.06) 0.78 (0.55–1.00) 0.98 (0.82–1.17) 0.62 (0.49–0.77) HR (95% CI) CV death SGLT2 AND DKD: PROS AND CONS Three large cardiovascular safety trials—EMPA-REG OUTCOME, the CANVAS programme and DECLARE-TIMI 58—demonstrated that SGLT2i reduced albuminuria progres- sion, prevented GFR decline and decreased the incidence of HR (95% CI) Not different Not different Not different Not different Stroke/AMI renal replacement therapy [5, 8, 11, 15, 17, 52]. However, these were secondary endpoints and few patients had moderate-to- severe DKD (Table 1), so information on patients with A3 albu- minuria or GFR <60 mL/min/1.73 m2 was limited. Two ongoing 0.86* (0.75–0.97) 0.86* (0.74–0.99) 0.80 (0.55–1.00) 0.93 (0.84–1.03) (DAPA-CKD and EMPA-KIDNEY) and one just completed MACE HR (95% CI) (CREDENCE) RCTs test with different SGLT2i for primary renal endpoints in patients with overt DKD. The CREDENCE trial evaluated the impact of SGLT2 inhibition (canagliflozin 100 mg daily) against placebo in patients with T2DM and DKD defined as UACR >300 mg/g with eGFR from 30 to 90 mL/min/1.73 m2 Doubling of serum creatinine with eGFR  45 mL/min/1.73 m2, initiation of renal replacement therapy or death from renal disease. 12.3 (6.65–42.1) 927 (463–1833) Not availablee Not available [1, 7]. CREDENCE was stopped prematurely because the pre- (mg/g)a UACR specified efficacy criteria for early cessation were reached, thus AMI, acute myocardial infarction; MACE, composite of cardiovascular death, myocardial infarction or ischaemic stroke. providing evidence of renal and heart protection in a population Composite of 40% reduction in eGFR to <60 mL/min/1.73 m2, end-stage kidney disease or death from renal cause. partly excluded from prior RCTs [53]. Regarding safety, rates of adverse events were similar between groups, with the exception (mL/min/1.73 m2) of DKA (2.2 versus 0.2 events per 1000 patient-years in canagli- Dialysis for at least 30 days, kidney transplantation or eGFR < 15 mL/min/1.73 m2 for at least 30 days. flozin and placebo patients, respectively) and genital mycotic in- eGFR 76.5 56.2 85.2 74 fection—especially, in male patients—which were more frequent in the canagliflozin group. Despite the increasing evidence of SGLT2i efficacy in DKD, the use of this drug class is still limited to patients with eGFR CVD (% of Composite of 40% reduction in eGFR, renal replacement therapy or renal death. >45 mL/min/1.73 m2. This restriction may be ascribed to two patients) 65.6 50.4 40.6 99.1 main reasons: (i) SGLT2i were designed as antidiabetic drugs Table 1. Key cardiovascular safety and CKD trials of SGLT2i and their antidiabetic effects depend on the magnitude of gly- cosuria, which is limited in patients with decreased GFR [54]; CV safety CV safety CV safety and (ii) given the mechanism of action, there was no rationale DKD Trial type for their use as antidiabetic agents in patients with an eGFR <45 mL/min/1.73 m2. Accordingly, they were not even tested in large numbers of patients with low eGFR, until now. DECLARE-TIMI [8] OUTCOME [5, 15] Although exploratory trials had evaluated the efficacy and CREDENCE [7] CANVAS [6] EMPA-REG UACR  30 mg/g in 40% of participants. safety of SGLT2i in established DKD [54], their clinical impact Trial was low, as the sample size was small, the duration short and re- nal outcomes were not assessed. Interestingly, a meta-analysis Median (interquartile range). of 4000 patients with eGFR from 45 to 60 mL/min/1.73 m2 *P < 0.05 for superiority. from 11 RCTs demonstrated consistent positive effects of dapa- gliflozin on BP, body weight, haematocrit, albuminuria, eGFR, Empagliflozin Dapagliflozin Canagliflozin bicarbonate, pulse pressure and uric acid. CREDENCE con- firmed kidney and cardiovascular benefits for patients starting Drug canagliflozin in overt DKD patients (G3a and G3b, eGFR >30 mL/min/1.73 m2) that maintained therapy up to the d b a c e f i16 J.L. Górriz et al. SGLT2 in diabetic kidney disease Table 2. Indications (EMA, FDA) or recommendations (ADA-EASD, ESC, EURECA-m and DIABESITY) for the use of SGLT2i Drug EMA (as of FDA (as of June 2019) ADA-EASD 2018 [50] ESC 2016 [49] EURECA-m and DIABESITY CREDENCE-based likely June 2019) [48] 2019 [51] future suggestions [47] SGLT2i Canagliflozin T2DM T2DM controlb In T2DM, metformin as first line. SGLT2i should Recommendation: add Indication to treat controla To reduce risk of SGLT2i as next step when: be consid- SGLT2i if T2DM and DKD T2DM with CKD MACEs in T2DM HbA1C not on target or on ered early in when: independently from with established target using a second drug that the course of HbA1c not on target on glycaemia control CVDc is not an GLP-1RA and athero- T2DM metformin; or Dapagliflozin T1DMd and T2DM controlb sclerotic CVD (on par with patients with HbA1c on target and met- ? T2DMa con- GLP-1RA) or heart failure or CVD (Class formin not tolerated or trol and to DKD predominate (not if II, level B) contraindicated; or reduce risk eGFR under local authorized HbA1C on target with one of cardiovas- eGFR) agent, consider switch to cular effects SGLT2i Empagliflozin T2DMa T2DM controlb ? control To reduce risk of CV death in T2DM with established CVDe CREDENCE based likely future suggestions reflect the authors views regarding potential future guidelines of EMA indications based on the results of the CREDENCE trial. These should be considered hypothetical and may not reflect the eventual decisions by these bodies a Adults with insufficiently controlled T2DM as an adjunct to diet and exercise, either as monotherapy when metformin is considered inappropriate due to intolerance or in addition to other medicinal products for the treatment of diabetes. b As an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. c To reduce the risk of MACE in adult patients with T2DM and established CVD. d Adults with insufficiently controlled T1DM as an adjunct to insulin in patients with body mass index 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. e To reduce the risk of cardiovascular death in adult patients with T2DM and established CVD. American Diabetes Association-European Association for the Study of Diabetes (ADA-EASD), European Society of Cardiology (ESC), European Renal and Cardiovascular Medicine (EURECA-m) and Diabetes and Obesity in Renal Disease (DIABESITY) are European Renal Association (ERA-EDTA) working groups. i17 A Regulatory status of SGLT2i as of June 2019 bladder cancer [58] and bone fractures [59]. The most consis- tent associations have been with DKA, UTI and genital infec- Canagliflozin Dapagliflozin Empagliflozin tions. From 2015 to 2018, the FDA has issued six warnings Indication to about ADRs linked to SGLT2i. A review on the safety profile of treat T2DM SGLT2i that selected 27 studies for risk analysis concluded that Indication to reduce causality assessment disclosed a correlation between SGLT2i CV death in T2DM and DKA and UTI [60]. A systematic review and meta-analysis with CVD of RCT that included SGLT2i up to May 2018 [61] selected 109 Indication to reduce reports on SGLT2i, mainly dapagliflozin, canagliflozin, empa- MACE in T2DM gliflozin and ipragliflozin. When compared with placebo, with CVD* SGLT2i decreased the risk of AKI (RR ¼ 0.59; 95% CI 0.39– Indication to reduce Undergoing 0.89; I2 ¼ 0.0%), while no difference was found for DKA (RR ¼ priority CKD progression/ESKD in T2DM with CVD review 0.66; 95% CI 0.30–1.45, I2 ¼ 0.0%), UTI (RR ¼ 1.02; 95% CI 0.95–1.09, I2 ¼ 0.0%) or bone fracture (RR ¼ 0.87; 95% CI Indication to reduce 0.69–1.09, I2 ¼ 1.3%). Three studies reported on amputation, MACE and CKD in T2DM with one finding a significantly increased risk. Subgroup analy- sis did show an increased risk of UTI with dapagliflozin only B eGFR and use of SGLT2i as of June 2019 (RR ¼ 1.21; 95% CI 1.02–1.43, I2 ¼ 0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture. The eGFR Canagliflozin Dapagliflozin Empagliflozin (ml/min/1.73m2) authors concluded that evidence from RCTs did not suggest an increased risk of harm with SGLT2i as a class over placebo or > 60 active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited pre- 45 cision, and, therefore, clinically important ADRs could not be 30 ruled out. In the CANVAS programme, 10 142 T2DM patients were 15 randomly allocated to canagliflozin 100 or 300 mg/day or pla- *Includes cardiovascular death EMA cebo [18]. Canagliflozin was associated with a significant dou- FDA bling in the risk for amputations, mainly toe and metatarsal FIGURE 1: (A) Regulatory status regarding indications of SGLT2i as amputations (6.3 versus 3.4 cases per 1000 patient-years, HR ¼ of June 2019. The FDA differentiates between the indications of the 1.97, 95% CI 1.41–2.75) [62]. The risk was similar for ischaemic three SGLT2i according to T2DM patient characteristics, while the and infective aetiologies and for 100 and 300 mg doses. Overall EMA does not. In contrast, EMA allows the use of dapagliflozin in amputation risk was strongly associated with baseline history of T1DM, while the FDA warns against the use of any of these drugs in prior amputation (major or minor) (HR ¼ 21.31, 95% CI T1DM. (B) Regulatory status regarding use in individuals with de- 15.40–29.49) and other established risk factors. No interactions creased eGFR of SGLT2i as of June 2019. Language such as ‘contra- between randomized treatment and participant characteristics indicated’ or ‘should not be used’ has been considered equivalent. Discontinuous line represents the situation in which the drug was explained the effect of canagliflozin on amputation risk. For ev- initiated prior to the deterioration of renal function. Based on the ery clinical subgroup studied, numbers of amputation events results of the CREDENCE trial [7], we anticipate that at least for projected were smaller than the numbers of MACE averted canagliflozin, usage will be allowed in the near future up to the initia- (HR ¼ 1.97). Additionally, no differences in the incidence tion of renal replacement therapy. of amputations were observed in the CREDENCE RCT in patients with DKD randomized to 100 mg/day canagliflozin. start of dialysis [7]. This evidence should be sufficient for the Interestingly, when CREDENCE was started the amputations approval of the use of this drug class or at least of canagliflozin warning regarding the CANVAS study was already released, in patients with eGFR <45 mL/min/1.73 m2. and investigators were aware of this ADR. However, no differ- The overall safety record of SGLT2i in patients with ences regarding baseline peripheral artery disease between the moderate-to-severe DKD has been positive [17, 54]. Adverse two studies were observed. In the DECLARE study, comparing events were more frequent in patients receiving higher doses of dapagliflozin versus placebo added to standard care in 17 160 this drug class. However, in CREDENCE, a low canagliflozin patients followed for a median of 4.2 years, there were no differ- dose of 100 mg/day was nephroprotective and safe, suggesting ences in the incidence of amputations, stroke or fractures, with that lower SGLT2i doses achieved renal and heart protection in a significant increase of UTI or genital infections and DKA. patients with overt DKD, with eGFR <45 mL/min/1.73 m2 Moreover, there was a lower risk of hypoglycaemia, AKI and (mean eGFR 56 mL/min/1.73 m2) [7]. bladder cancer in the dapagliflozin-treated group (Supplementary data, Tables S1 and S2) [8]. To clarify whether the amputation SAFETY OF SGLT2i: IS THERE A CLASS risk could be a class effect of SGLT2i, a thorough collection of pro- EFFECT? spective data on amputations and other foot-related complica- Potential ADRs of SGLT2i include AKI [55], DKA [56], foot tions is required in all ongoing and future long-term randomized and toe amputations [17], UTI and genital infections [57], clinical trials (e.g. DAPA-CKD, Dapagliflozin in Patients with i18 J.L. Górriz et al. CREDENCE based likely future suggestions reflect the author’s views regarding potential future guidelines of EMA indications based on the results of the CREDENCE trial. These should be considered hypothetical and may not reflect the eventual Use at any GFR not yet on di- Heart Failure and Reduced Ejection Fraction (DAPA-HF) and alysis for kidney and car- CREDENCE-based likely future DECLARE with dapagliflozin; EMPagliflozin outcomE tRial in diovascular protection Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced); and Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes suggestions Mellitus Participants With Vascular Disease (VERTIS CV) with ? ? ertugliflozin). Recently, the use of SGLT2i has been also associated with SGLT2i were used in EMPA-REG to eGFR 30, but current indica- OUTCOME and CANVAS up Fournier gangrene, a rare urologic emergency characterized and canagliflozin and >60 for tion is >45 for empagliflozin EURECA-m and DIABESITY by necrotizing infection of the external genitalia, perineum and perianal region. The FDA identified 55 unique cases of Fournier gangrene in patients receiving SGLT2i between 1 March 2013 and 31 January 2019. Age ranged from 33 to dapagliflozin’ 87 years; 39 were men and 16 were women. Time to onset af- ter SGLT2i initiation ranged from 5 days to 49 months. All 2019 [51] patients had DKA (n ¼ 8), sepsis or septic shock (n ¼ 9) and AKI (n ¼ 4). Eight patients had faecal diversion surgery, two developed necrotizing fascitis of a lower extremity that re- quired amputation and one required a lower extremity by- pass procedure because of gangrenous toes. Three patients ESC 2016 [49] died. For comparison, the FDA identified 19 Fournier gan- No mention grene cases associated with other antidiabetic agents be- tween 1984 and 31 January 2019: metformin (n ¼ 8), insulin decisions by these bodies. eGFR in mL/min/1.73 m2. EMA, ADA-EASD, ESCEURECA-m and DIABESITY are ERA-EDTA working groups. glargine (n ¼ 6), short-acting insulin (n ¼ 2), sitagliptin plus metformin (n ¼ 2), and dulaglutide (n ¼ 1). These patients ranged in age from 42 to 79 years; 12 were men and 7 were ADA-EASD 2018 [50] women. Two patients died [63]. These findings merit further varies with agent and local health Authorized eGFR research. In conclusion, genital infections are probably the most fre- authority quent and documented ADR of the SGLT2i. Other potential ADRs are less consistent and variable data can be found in differ- ent RCTs and meta-analysis. Given the similar molecular struc- ture of the available SGLT2i, it is plausible that ADRs observed FDA (as of May 2019) until now are a class effect. The discrepancies observed in the Should not be initi- Should not be initi- Contraindicated if Contraindicated if Contraindicated if published RCTs may be ascribed to the differences in patient characteristics as well as in evolving clinical experience with these eGFR <30 eGFR <60 eGFR <30 eGFR <45 eGFR <30 ated when ated when agents rather than to differences between specific SGLT2i. [44] CLINICAL RECOMMENDATIONS FOR THE Table 3. Use of SGLT2i in patients DKD: impact of eGFR USE OF SGLT2 INHIBITORS IN DKD persistently <45 Should not be ini- Should be discon- A multifactorial intervention is still the best therapeutic ap- EMA (as of May tinued at GFR tiated when proach to T2DM with or without DKD. These include imple- eGFR <60 2019) [47] menting lifestyle interventions, promoting weight loss (healthy diet and exercise) in obese patients, reducing low- density lipoprotein cholesterol levels using statins, treating BP preferentially with RAS blockade and improving glycae- mic control [51, 64]. For the latter objective, metformin is Empagliflozin Dapagliflozin Canagliflozin still considered the first pharmacological option if tolerated, although safety and prescribed doses should be revised if eGFR is 30–60 mL/min/1.73 m2 and the fact sheet recom- mends stopping the drug when eGFR falls below 30 mL/min/ 1.73 m2 [65], although this is a debated issue. Recent consen- SGLT2i sus documents have addressed the place of SGLT2i and glu- Drug cagon-like peptide-1 receptor agonists (GLP-1RAs), in light of cardiovascular and renal outcomes trials [51, 64, 66]. SGLT2 in diabetic kidney disease i19 Recommendations for SGLT2 inhibitors use Other antidiabetic drug or insulin treatment? Yes No Insulin+ or SU++ Other antidiabetic drugs → Consider reducing dose if HbA1c <8.5% -metformin, GLP-1 RAs, DPP-4i or glinides- or documented hypoglycemic events. → Dose adjustment not usually required. Diuretic treatment? Yes No → Consider reducing dose in elderly patients or patients with low water intake. Antihypertensive treatment? Yes No → Consider reducing dose in elderly patients, BP <140/80 mmHg or documented hypotensive symptoms. → Prescribe SGLT2 inhibitor, informing the patient about possible adverse events and recommendations. þ FIGURE 2: Recommendations before starting treatment with SGLT2i. A decrease of 20% of the insulin dose is recommended, especially if there are previously reported hypoglycaemic events or the eGFR is <60 mL/min/1.73 m2. þþSulphonylureas (SU) should be withdrawn if eGFR falls below 45 mL/min/1.73 m2. DPP-4i, dipeptidyl peptidase 4 inhibitor GLP-1 RAs, glucagon-like peptide-1 receptor agonists. Adapted from reference [68]. These documents consider SGLT2i and GLP-1RAs as sec- insulin, which is already associated with an increased risk of ond-line therapy in both DKD with unmet glycaemic control hypoglycaemia in CKD [54, 67]. Combination with other anti- (HbA1c >7%) and for controlled DKD patients (HbA1c <7%). diabetic drugs, such as GLP-1RAs or metformin, has a much Specifically, consensus documents recommend the use of lower risk of hypoglycaemic events [69]. Because of the diuretic SGLT2i in T2DM patients with established CVD or DKD. These effect, doses of other diuretic medications should also be revised changes shift the focus of this drug prescription from glycaemic and in many cases decreased when starting SGLT2i in DKD control to improved kidney and cardiovascular outcomes. patients (Figure 2). In elderly or frail patients, who may have a The mechanistic effect of this drug class, including natriure- lower water intake or access, SGLT2i therapy should be carefully sis and glycosuria, guides the concomitant use of other drugs initiated and closely monitored. and suggests some preventive measures to increase safety when The routine risk management strategy for SGLT2i is very initiating SGLT2i treatment in patients with CKD on other similar to that for RAS blockers, which is familiar for both antidiabetic drugs or diuretics. Thus, the lower antidiabetic effi- patients and physicians. Thus, patients on SGLT2i treatment cacy of SGLT2i at low eGFR may require a combination with should be advised to temporarily discontinue the drug if acutely other antidiabetic agents [67]. Severe hypoglycaemia is rarely ill, especially in the presence of vomiting, diarrhoea or de- described with the use of SGLT2i and is usually associated with creased water intake, to avoid dehydration and volume deple- the add-on therapy to other hypoglycaemic drugs [54, 67]. tion. Similarly, SGLT2i should be transiently withdrawn during To prevent hypoglycaemic events in DKD patients, other anti- acute infections, fever, surgery and other insulin counter- diabetic drugs should be titrated, reduced or withdrawn before regulatory states to prevent DKA [67, 70]. DKA is a rare but se- starting SGLT2i (Figure 2). This recommendation is particularly vere complication of SGLT2i treatment that, unlike classic important in DKD patients on sulphonylureas (SU) and/or on DKA, is usually associated with mild-to-moderate serum i20 J.L. Górriz et al. glucose elevations. DKA may be precipitated by fasting, alcohol Biomedicina B2017/BMD-3686 CIFRA2-CM, and CIBER intake, excessive reduction of insulin doses, dehydration or CV 16/11/00420. acute processes, although some cases remain unexplained [71]. To avoid DKA, SGLT2i should be initiated at the lowest dose CONFLICT OF INTEREST STATEMENT possible when blood ketone levels are <0.6 mmol/L [72]. Moreover, it is not advisable to start this drug class in patients A.O. has received speaker fees from Sanofi-Genzyme, Amgen, with an already known low reservoir of endogenous insulin or Fresenius Medical Care, Mundipharma, Amicus and Freeline. low C-peptide. It is recommended that patients self-monitor M.J.S. has received speaker fees or travel support from capillary blood ketones when DKA is suspected, but urine Otsuka, Menarini, Astrazeneca, Boehringer Ingelheim, ketones monitoring would be enough. SGLT2i therapy should Janssen, Mundipharma, Novartis, Eli Lilly, Esteve and be discontinued if ketone levels increase. Proper education is Novonordisk. J.F.N.-G. has served as a consultant, and has re- important for both the patient and the clinician to be fully ceived speaker fees or travel support from Abbvie, Amgen, aware of factors impacting ketone levels and the protocol to fol- AstraZeneca, Boehringer Ingelheim, Esteve, Genzyme, Lilly, low if ketone levels increase. In concordance, a nephrologist Novartis, Servier, Shire and Vifor Fresenius Medical Care should suspect euglycaemic DKA when called as consultant in Renal Pharma. J.L.G. has received fees for giving talks from: the emergency department for a severe metabolic acidosis with Astrazeneca, Boehringer Ingelheim, Janssen, Mundipharma, high anion gap in a diabetic patient under SGLT2i therapy. Novartis, Novonordisk, Otsuka and Vifor Pharma. A.M.C. SGLT2i may be not initiated if hypovolaemia or peripheral vas- has received speaker fees from Boëhringer-Ingelheim, Lilly, cular disease is present or in older frail patients. Merck Sharp Dhôme and Novo-Nordisk. REFERENCES CONCLUSIONS 1. Fernandez-Fernandez B, Fernandez-Prado R, Górriz JL et al. Canagliflozin In conclusion, emerging evidence derived from RCTs and and renal events in diabetes with established nephropathy clinical evaluation meta-analyses point to cardioprotective and nephroprotective and study of diabetic nephropathy with atrasentan: what was learned about effects of SGLT2i that are maintained in patients with full- the treatment of diabetic kidney disease with canagliflozin and atrasentan? blown DKD with baseline eGFR up to 30 mL/min/1.73 m2. The Clin Kidney J 2019; 12: 313–321 2. Kramer A, Pippias M, Noordzij M et al. 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