Clinical Kidney Journal, 2019, vol. 12, no. 3, 313–321 doi: 10.1093/ckj/sfz070 Special Feature SPECIAL FEATURE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation and Study of Diabetic Nephropathy with Atrasentan: what was learned about the treatment of diabetic kidney disease with canagliflozin and atrasentan? Beatriz Fernandez-Fernandez1,2,3, Raul Fernandez-Prado1,2,3, Jose Luis Górriz3,4, Alberto Martinez-Castelao3,5, Juan F. Navarro-González3,6, Esteban Porrini3,7, Marı́a José Soler3,8,9 and Alberto Ortiz1,2,3 1 IIS-Fundacion Jimenez Diaz UAM and School of Medicine, UAM, Madrid, Spain, 2REDINREN, Madrid, Spain, 3 GEENDIAB, Barcelona, Spain, 4Hospital Clı́nico Universitario, Universitat de Valencia-INCLIVA, Valencia, Spain, 5Bellvitge University Hospital, Hospitalet, Barcelona, Spain, 6Unidad de Investigación y Servicio de ~ ora de Candelaria, Santa Cruz de Tenerife, Spain, 7Instituto de Nefrologı́a, Hospital Universitario Nuestra Sen Tecnologı́as Biomédicas, Hospital Universitario de Canarias, Universidad de La Laguna, Santa Cruz de Tenerife, Spain, 8Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain and 9Nephrology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain Correspondence and offprint requests to: Alberto Ortiz; E-mail: aortiz@fjd.es; Twitter handle: @PepaSolerR ABSTRACT In April 2019, two major Phase 3 randomized clinical trials were published that assessed primary renal outcomes in diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) tested an already available antidiabetic drug, canagliflozin, and the Study of Diabetic Nephropathy with Atrasentan (SONAR) tested a novel molecule, the endothelin-1 receptor blocker atrasentan, both on top of renin–angiotensin system blockade. Both trials demonstrated significant nephroprotection in patients with overt DKD (albuminuria >300 mg/g urinary creatinine) for combined primary endpoints of end-stage kidney disease (ESKD), doubling of serum creatinine or death from renal or cardiovascular causes in CREDENCE {hazard ratio [HR] 0.70 [95% confidence interval (CI) 0.59–0.82]} and ESKD and doubling of serum creatinine in SONAR [HR 0.65 (95% CI 0.49–0.88)]. Canagliflozin also decreased the secondary renal endpoint ESKD, doubling of serum creatinine or renal death [HR 0.66 (95% CI 0.53–0.81)], which was similar in nature and impact to the primary endpoint in SONAR. In addition, canagliflozin decreased a secondary endpoint of cardiovascular death or hospitalization for heart failure [HR 0.69 (95% CI 0.57–0.83)], Received: 8.5.2019; Editorial decision: 8.5.2019 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 313 314 | B. Fernandez-Fernandez et al. whereas atrasentan had no significant impact on a secondary cardiovascular composite endpoint or on hospital admissions for heart failure and, despite restrictive exclusion criteria, there was a non-significant trend towards more frequent episodes of heart failure. Based on these results, canagliflozin will likely be approved for the indication of treating DKD in T2DM and the estimated glomerular filtration rate threshold for prescribing it will be lifted, whereas the future and place of atrasentan in the treatment of DKD remain unclear. Keywords: albuminuria, atrasentan, canagliflozin, chronic kidney disease, diabetic kidney disease, endothelin, sodium-glucose cotransporter-2 (SGLT2) inhibitor April 2019 saw the publication of positive results from two ma- century in some developed countries [12]. DKD is a key contrib- jor Phase 3 randomized clinical trials (RCTs) assessing primary utor to mortality from CKD and the most frequent cause of need renal outcomes in diabetic kidney disease (DKD) of type 2 diabe- for RRT worldwide [13]. According to Global Burden of Disease tes mellitus (T2DM) patients. The approach was very different: data, DKD was the cause of >425 000 deaths in 2017, an increase The Canagliflozin and Renal Events in Diabetes with of 37% in the last decade, and accounted for 35% of deaths from Established Nephropathy Clinical Evaluation (CREDENCE) tested CKD worldwide [14]. T2DM was responsible for >80% of these an already available antidiabetic drug, canagliflozin [1] and the DKD deaths [14]. This illustrates the insufficient implementa- Study of Diabetic Nephropathy with Atrasentan (SONAR) tested tion or the lack of effective therapeutic approaches [15]. A criti- a novel molecule, the endothelin-1 receptor blocker atrasentan cal analysis of currently available therapies and recent results [2]. We now discuss what these results will mean in the near fu- from RCTs suggests that suboptimal efficacy of current ture for the practicing nephrologist, as they will likely result in a approaches does play a key role in the dismal outcome of DKD dramatic paradigm change in the management of DKD. Thus, in patients. the past 20 years, only renin–angiotensin system (RAS) blockers have shown a nephroprotective effect on DKD as a primary end- point in a placebo-controlled RCT, whereas numerous other tri- WHAT IS THE CURRENT TREATMENT FOR als have failed to demonstrate a benefit [3, 4]. DKD? Hyperglycaemia is the driving force for the development of dia- WHAT IS DKD? betic complications, and tight glycaemic control prevents the development of micro- and macrovascular complications [16]. A recent consensus conference considered DKD as chronic kid- However, once kidney injury has occurred, additional injury ney disease (CKD) attributable to diabetes, where CKD is defined pathways are recruited and optimal kidney care requires the by an estimated glomerular filtration rate (eGFR) <60 mL/min/ combination of antidiabetic with nephroprotective medication. 1.73 m2 or a urinary albumin:creatinine ratio (UACR) 30 mg/g Nephroprotection based on antiproteinuric therapy with RAS creatinine [5, 6]. Thus DKD is usually a clinical diagnosis not blockers is the current standard of therapy for non-pregnant di- confirmed by kidney biopsy. Pathological features of DKD may abetic patients with either hypertension or pathological albu- be present in the absence of and may precede pathological albu- minuria [17]. Angiotensin-converting enzyme inhibitors (ACEis) minuria [7]. The terms DKD and diabetic nephropathy are fre- or angiotensin receptor blockers (ARBs) are indicated for neph- quently used interchangeably, although it has been argued that roprotection. However, their beneficial nephroprotective effect diabetic nephropathy should be reserved for those patients with has only been demonstrated as secondary prevention, and histopathological confirmation of the diagnosis [7]. However, di- American Diabetes Association (ADA) guidelines still do not rec- abetic patients may also have non-diabetic causes of CKD, espe- ommend ACEis or ARBs for primary prevention of CKD in dia- cially if reduced eGFR coexists with normoalbuminuria and betic patients with normal blood pressure or UACR <30 mg/g additional red flags. A diagnosis of DKD implies both an in- and normal eGFR [17]. Dual RAS blockade with ACEis, ARBs or creased risk of end-stage renal disease (ESRD) ultimately requir- aliskiren is formally contraindicated following RCT-derived con- ing renal replacement therapy (RRT) and an increased risk of cerns about the efficacy and safety of these combinations [18, premature death, mainly due to cardiovascular disease [8]. The 19]. Key RAS blockade trials for DKD in T2DM, such as Reduction classical clinical spectrum of DKD consists of the progression of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with from microalbuminuria (UACR 30–300 mg/g, currently termed the Angiotensin II Antagonist Losartan (RENAAL; losartan ver- A2 albuminuria) to macroalbuminuria (UACR >300 mg/g, cur- sus placebo) or the Irbesartan Diabetic Nephropathy Trial rently termed A3 albuminuria). While 25–35% of DKD patients (IDNT; irbesartan versus placebo or amlodipine) enrolled have decreased renal function despite normoalbuminuria patients with overt DKD (UACR >300 mg/g) (Figure 1) and ob- (UACR <30 mg/g, currently termed as A1 albuminuria) or micro- served a risk reduction for doubling of serum creatinine or ESRD albuminuria [9], those with A3 albuminuria (overt DKD) are at versus placebo (Figure 2A and B), but the residual risk was still the highest risk of progression and premature death and should in the range of 6.0–8.0/100 patient-years for individual end- be targeted by trials of novel therapeutic approaches on top of points and 11/100 patient-years for the combined endpoint of the current state of the art [10, 11]. doubling of serum creatinine or ESRD (Figure 2C) [3, 4]. Thus, de- spite the current standard of care, the residual risk for CKD pro- gression is still substantial, in line with the global statistics for WHAT IS THE BURDEN OF DKD? mortality from CKD and DKD. In recent years, several clinical CKD is one of the fastest growing causes of death worldwide. It trials assessing new molecules, such as paricalcitol, aliskiren, is estimated that, at the current pace of growth, it will become sulodexide and bardoxolone, have failed to demonstrate a reno- the second most frequent cause of death before the end of the protective effect on DKD [24–27]. Novel therapies for DKD | 315 FIGURE 1: CKD G (GFR) and A (albuminuria) categories of patients enrolled in RCTs for current DKD therapies, cardiovascular SGLT2i trials, CANVAS and SONAR. Data from references [1, 2, 4, 20–23]. Data presented as mean 6 SD and albuminuria data as median (IQR). The percentage of patients with eGFR <60 mL/min/1.73 m2 was 25.9, 22.7 and 9.11% in EMPA-REG, CANVAS and DECLARE, respectively. For albuminuria >300 mg/g, the percentages were 11, 7.1 and 6.8%, respectively. WHAT IS THE CURRENT ANTIDIABETIC DRUG SGLT2i if HbA1c was on target. If the SGLT2 is contraindicated, then a glucagon-like peptide-1 (GLP-1) receptor agonist shown OF CHOICE FOR PATIENTS WITH DKD? to reduce CKD progression may be considered. The recommen- Regarding the optimal antidiabetic drugs to prevent DKD in dia- dation is based on secondary outcome results of the cardiovas- betic patients or to prevent DKD progression once it has devel- cular outcomes trials EMPA-REG OUTCOME (empagliflozin; oped, the recommendations are evolving rapidly. As recently as Empagliflozin Cardiovascular Outcome Event Trial in Type 2 2015, the European Renal Best Practice recommended metfor- Diabetes Mellitus Patients), CANVAS Program (canagliflozin; min in a dose adapted to renal function as a first-line agent in CANagliflozin cardioVascular Assessment Study), LEADER (lira- DKD patients with eGFR <45/mL/min/1.73 m2 [28, 29], despite a glutide; Liraglutide Effect and Action in Diabetes: Evaluation of formal European Medicines Agency (EMA) contraindication for Cardiovascular Outcome Results) and SUSTAIN 6 (semaglutide; eGFR <30 mL/min/1.73 m2 that extends to <45 mL/min/1.73 m2 Trial to Evaluate Cardiovascular and Other Long-term for fixed-dose combinations of metformin with sodium–glucose Outcomes With Semaglutide in Subjects With Type 2 Diabetes) cotransporter (SGLT) inhibitors (SGLT2is) [30]. The recommen- [17, 20, 32–35]. Thus only SGLT2i and GLP-1 receptor agonist dation to use metformin as a first-line agent whenever not con- have shown any nephroprotective effect beyond their glucose- traindicated is in line with the Standards of Medical Care in lowering effect, albeit up to CREDENCE, as secondary endpoints Diabetes of the ADA 2018, which additionally recommended not in populations not necessarily having DKD [36]. The ADA-EASD to initiate metformin if eGFR <45 mL/min/1.73 m2 and to stop it document does not provide a GFR threshold for the indication if eGFR <30 mL/min/1.73 m2 and added no further advice for of SGLT2i, given that it differs for different regions, but acknowl- patients with DKD regarding the choice of antidiabetic agent edged the existence of such thresholds. Thus they recom- [31], as well as with the 2018 Consensus Report by the ADA and mended considering SGLT2i to lower glucose when metformin the European Association for the Study of Diabetes (EASD) for failed or could not be used or on top of metformin in patients haemoglobin A1c (HbA1c) goals, treatments and lifestyle man- with a DKD diagnosis based on albuminuria but, essentially, agement for T2DM patients with and without complications with preserved renal function, given the explicit caveats on the [32]. However, this report, published at the end of 2018, clearly use of SGLT2i in patients with low eGFR. Thus, based on the evi- differentiated patients with CKD from non-complicated T2DM dence available in 2018, they recommend considering SGLT2i to patients and recommended metformin as a first-line agent to lower serum glucose for albuminuric DKD patients with rela- lower glucose in patients with T2DM and CKD without contrain- tively preserved renal function based on the potential nephro- dications and to consider adding an SGLT2i if HbA1c targets protective effects, but stopped short of recommending SGLT2i were not achieved or replacing a second antidiabetic drug for an to treat DKD. A European Renal and Cardiovascular medicine 316 | B. Fernandez-Fernandez et al. A B C FIGURE 2: Efficacy of nephroprotective therapies. (A) Relative risk or HR for primary endpoint (IDNT and RENAAL: doubling of the serum creatinine concentration, ESRD or death; CANVAS: doubling of the serum creatinine concentration, ESRD or cardiovascular or renal death). SONAR was omitted because the primary endpoint did not include death. (B) Relative risk or HR for key renal endpoints explored in all the trials. The original IDNT manuscript did not provide the combined doubling of the se- rum creatinine concentration and ESRD endpoint. (C) Residual risk for key renal endpoints. In IDNT, the residual risk per 100 person-years was estimated from mean follow-up and percentage of patients with events. Data from references [2–4]. The comparator for RENAAL and IDNT was placebo/absence of RAS blockade, whereas the comparator for CREDENCE and SONAR was placebo þ RAS blockade. and DIABESITY consensus statement are aligned with the ADA- EASD consensus report [37]. Despite the recommendations on WHAT ARE SGLT2IS? oral antidiabetics, insulin is still commonly used in T2DM, espe- SGLT2is are the newest class of oral agents to treat T2DM. These cially as eGFR decreases [38, 39]. drugs block the SGLT2 cotransporter involved in 90% of glucose Novel therapies for DKD | 317 A B FIGURE 3: Cardiovascular safety of SGLT2i and atrasentan. Data from (A) cardiovascular outcome trials enrolling T2DM patients at high cardiovascular risk (CANVAS Program, DECLARE-TIMI and EMPA-REG OUTCOME) [20, 33, 40] and (B) trials enrolling patients with DKD (CANVAS and SONAR) [2, 20] are presented. MACE: major car- diovascular events: cardiovascular death, myocardial infarction or stroke. reabsorption in the proximal renal tubule, resulting in increased this regard, scientific society guidelines and consensus docu- urinary glucose excretion and lower blood glucose levels [37]. In ments have moved faster than regulatory authorities by recom- cardiovascular safety trials enrolling patients at high cardiovas- mending considering SGLT2i preferentially to treat diabetes in cular risk (Figure 1), the SGLT2is canagliflozin, dapagliflozin and patients with DKD and will likely continue to advance in this empagliflozin reduced cardiovascular risk (Figure 3A) and also major paradigm change by making recommendations on their incident or worsening nephropathy as secondary or post hoc kid- role in the treatment of DKD, not just of T2DM. ney outcomes [20, 33, 37, 40, 41]. WHAT WAS THE EVIDENCE BASE TO ARE SGLT2IS INDICATED FOR THE TREATMENT INDICATE SGLT2I IN PATIENTS WITH DKD OF DKD? PATIENTS PRIOR TO CREDENCE? Not as of April 2019. The EMA lists as indications for SGLT2i the Before CREDENCE, cardiovascular outcomes trials of SGLT2is treatment of adults with T2DM in monotherapy or combination used to lower glucose had enrolled patients at a high cardiovas- therapy and (for dapagliflozin) also for type 1 diabetes mellitus cular risk [20, 33, 40]. These included a significant number of (T1DM) in combination with insulin (Table 1) [42–44]. There is patients with DKD defined as either eGFR 30–60 mL/min/1.73 m2 no mention of specific indications for DKD patients or to treat or UACR >30 mg/g: as an example, in EMPA-REG OUTCOME, 40% DKD. On the contrary, there is a warning for starting these drugs of patients had pathological albuminuria and an additional 20% in DKD patients that fulfil the eGFR criterion for CKD (SGLT2i had eGFR 30–60 mL/min/1.73 m2 with normoalbuminuria [45]. not to be initiated when eGFR <60 mL/min/1.73 m2). This warn- However, only 11% had baseline albuminuria >300 mg/g. As a ing is based on the lower antidiabetic effect of the drugs when consequence, the mean levels of eGFR and median levels of renal function is decreased as well as on concerns about volume UACR for the full SGLT2i cardiovascular cohort were not in the depletion. This warning is expected to change soon once the DKD range (Figure 1). In addition to significantly lower cardio- regulatory authorities examine the results from CREDENCE. In vascular events as defined by at least one primary endpoint 318 | B. Fernandez-Fernandez et al. Table 1. SGLT2i and atrasentan current (15 April 2019) indications canagliflozin to treat DKD. CREDENCE randomized 4401 T2DM and use in renal disease by the EMA [42–44] patients with DKD to canagliflozin or placebo and followed them for a median of 2.62 years in an event-driven trial Indications (Figure 1) [2]. It was terminated early because of the evidence of Canagliflozin, dapagliflozin and empagliflozin: adults with insuffi- benefit in a pre-specified interim analysis. The key result is a ciently controlled T2DM as an adjunct to diet and exercise, either risk reduction of 30% in the canagliflozin group for the compos- as monotherapy when metformin is considered inappropriate due to intolerance or in addition to other medicinal products for the ite primary renal outcome, and what is more relevant, these treatment of diabetes. results were obtained in subjects with eGFR 30–90 mL/min/1.73 Dapagliflozin: adults with insufficiently controlled T1DM as an ad- m2 and UACR 300–5000 mg/g [2]. It should be noted that patients junct to insulin in patients with BMI 27 kg/m2, when insulin were enrolled with an eGFR up to 30 mL/min/1.73 m2, thus po- alone does not provide adequate glycaemic control despite opti- tentially expanding a putative canagliflozin indication ‘treat- mal insulin therapy. ment of DKD’ outside the eGFR limits of the current EMA Atrasentan: no indication, experimental drug. statement that canagliflozin should not be initiated when eGFR Use in renal disease patients is <60 mL/min/1.73 m2 for the indication ‘treatment of T2DM’. Canagliflozin, dapagliflozin or empagliflozin should not be initi- In fact, at baseline, eGFR was 30–44 mL/min/1.73 m2 in 31% of ated in patients with an eGFR <60 mL/min/1.73 m2 and should be the patients and 45–60 mL/min/1.73 m2 in 29%. Furthermore, discontinued at a GFR persistently <45 mL/min/1.73 m2. canagliflozin was maintained until patients started RRT. Thus this trial established the efficacy for kidney protection and the safety of the use of canagliflozin at any eGFR as long as the pa- (Figure 3A), trials with empagliflozin, canagliflozin and dapagli- tient is not on RRT. flozin observed a significantly lower incidence of renal out- Canagliflozin decreased the combined primary endpoint comes defined by secondary endpoints in these mixed DKD and [ESRD, doubling of serum creatinine or death from renal or car- non-DKD populations [20, 33, 40]. diovascular cause; HR 0.70 (95% CI 0.59–0.82)] and the secondary In EMPA-REG OUTCOME, empagliflozin significantly reduced renal endpoint ESRD, doubling of serum creatinine or renal incident or worsening nephropathy (defined as decreasing renal death [HR 0.66 (95% CI 0.53–0.81)] (Figure 2B). In addition, cana- function, developing UACR > 300 mg/g, doubling of serum creat- gliflozin decreased the secondary endpoint of cardiovascular inine or developing ESRD or death from ESRD) by almost 40% death or hospitalization for heart failure [HR 0.69 (95% CI 0.57– {hazard ratio [HR] 0.61 [95% confidence interval (CI) 0.53–0.70]} 0.83)] (Figure 3B). [33, 41]. In the CANVAS Program, canagliflozin patients devel- Overall, canagliflozin was safe, with both any and serious oped less macroalbuminuria than placebo patients and the adverse events significantly less frequent than for placebo [HR composite outcome (40% reduction in eGFR, RRT or renal death) 0.87 (95% CI 0.82–0.93) and HR 0.87 (95% CI 0.79–0.97), respec- was less frequent in canagliflozin than in placebo patients [HR tively]. Some adverse effects that raised concerns in prior cana- 0.60 (95% CI 0.47–0.77)] [20]. The Multicenter Trial to Evaluate gliflozin trials were not increased in frequency [HR 1.11 (95% CI the Effect of Dapagliflozin on the Incidence of Cardiovascular 0.79–1.56) for amputation and HR 0.98 (95% CI 0.70–1.37) for frac- Events (DECLARE-TIMI) was published later in 2019. Patients ture], whereas the HR for diabetic ketoacidosis was 10, although randomized to dapagliflozin had a 47% lower incidence of the the absolute risk was low (11/2200 patients). composite renal outcome [decrease of at least 40% in eGFR to A perspective on the combined cardiovascular and renal <60 mL/min/1.73 m2, ESRD or death from renal causes: HR 0.53 effects of canagliflozin in DKD patients is provided by the mea- (95% CI: 0.430.66)] [40]. However, the incidence of ESRD in the gre advances in cardiovascular outcomes provided by the intro- control population was low (e.g. 0.2/100 patient-years) in EMPA- duction of RAS blockade. In IDNT (irbesartan), a secondary REG OUTCOME [41]. cardiovascular outcome of cardiovascular death, myocardial in- In EMPA-REG OUTCOME, 7.7% of the patients had an eGFR farction, heart failure resulting in hospitalization, stroke or <45 mL/min/1.73 m2 and in the CANVAS Program, 5.5%. In both lower limb amputation was not significantly different from pla- studies, the cardiovascular and renal benefits were observed in cebo [HR 0.91 (95% CI 0.72–1.14)] [4]. In RENAAL (losartan), there both patients with normal and reduced eGFR. were no significant differences for a similar secondary cardio- Thus hypothesis-generating evidence had been gathered vascular outcome (cardiovascular death, myocardial infarction prior to CREDENCE from secondary endpoints of cardiovascular or unstable angina, stroke, first hospitalization for heart failure outcomes trials that were very suggestive of a drug class neph- or coronary or peripheral revascularization, risk reduction 10%; roprotective effect for SGLT2is. Furthermore, the cardiovascular P ¼ 0.26) [3]. However, irbesartan reduced the incidence of con- and renal benefits of SGLT2is appear to extend to DKD patients gestive heart failure necessitating hospitalization by 23% and with eGFR in the 30–60 mL/min/1.73 m2 range. But this hypothe- there was a non-significant trend (P ¼ 0.08) for a reduction of sis had not been formally tested in an RCT with primary renal this outcome for losartan. outcomes nor in a full cohort of DKD patients, which is the nov- elty of CREDENCE. IS THERE BIOLOGICAL PLAUSIBILITY FOR CANAGLIFLOZIN BEING NEPHROPROTECTIVE WHAT WAS LEARNED FROM THE CREDENCE ONCE EGFR IS <60 mL/MIN/1.73 M2? TRIAL TESTING CANAGLIFLOZIN TO TREAT The EMA states that SGLT2i should not be initiated at low eGFR DKD? as the degree of glycosuria and antidiabetic efficacy is lower The results of the CREDENCE trial were published in April 2019. when less glucose is filtered by glomeruli. However, there are This is the first RCT of any SGLT2i in which the whole study several solid hypotheses that may explain nephroprotection population had DKD and the primary endpoint was renal, thus even when the antidiabetic effect is mild [37]. Foremost among providing solid evidence for a novel therapeutic indication for these is a single-nephron impact on glomerular hyperfiltration Novel therapies for DKD | 319 related to tubuloglomerular feedback inducing afferent arteriole hospital admissions for heart failure [HR 1.33 (95% CI 0.85–2.07)] vasoconstriction, thus complementing efferent arteriole vasodi- or deaths (Figure 3B). Still, there were significantly more epi- lation by RAS blockade and further lowering intraglomerular sodes of fluid retention (36.6% versus 32.3%, P ¼ 0.022), but not pressure, glomerular hyperfiltration and albuminuria [37]. The of cardiac failure (5.5% versus 3.9%, P ¼ 0.064). tubuloglomerular feedback would be triggered by increased so- dium availability in the distal nephron, as SGLT2 inhibition pre- vents both sodium and glucose reabsorption in proximal HOW WILL THIS NEW KNOWLEDGE IMPACT tubules. CLINICAL PRACTICE? THE NEW ERA OF Additional mechanisms of action have been proposed for the cardiovascular and nephroprotective effects that exceed SGLT2I/RAS BLOCKADE FOR DKD those of other antidiabetic drugs with a greater impact on glu- The impact of CREDENCE is expected to be more immediate cose control as summarized recently [37]. These may include than that of SONAR. In our view, CREDENCE sets the stage for but are not limited to lowering body weight, blood pressure, uric an indication of canagliflozin for the treatment of DKD as the acid, plasma volume and proximal tubular cell glucotoxicity, combination of canagliflozin and RAS blockade achieved a very oxidative stress, inflammation and oxygen consumption and low residual renal risk (Figure 2C). This would result in a major increasing natriuresis, haemoglobin levels and insulin sensitiv- paradigm change from using SGLT2is to treat T2DM to using ity [37]. them to treat DKD, independent from any antidiabetic effect. Furthermore, it should expand the indication of canagliflozin to patients with eGFR below the current limits of 60 mL/min/1.73 WHAT IS ATRASENTAN? m2 for initiation and 45 mL/min/1.73 m2 for maintenance. Indeed, since the drug was not stopped until patients initiated Endothelin-1 is a vasoactive peptide with cytokine-like proper- RRT, there should be no limits for canagliflozin prescription ties shown to contribute to the pathogenesis of DKD in preclini- based on eGFR. It is likely that CREDENCE evidenced a nephro- cal studies [46]. Atrasentan is a selective endothelin receptor protective class effect, but regulatory indications for other type A (ETA) antagonist initially studied for the potential treat- SGLT2is for DKD will likely await the results of RCTs with simi- ment of cancer [47]. However, clinical development for cancer lar primary endpoints. This new knowledge will likely open the was discontinued. Early success with ETA antagonists in de- door for testing SGLT2i/RAS blockade for nephroprotection in creasing albuminuria in DKD patients was marred by volume T1DM as well as in other forms of CKD. The later will be ex- overload, which led to the termination of RCTs with avosentan plored by the EMPA-KIDNEY (The Study of Heart and Kidney for nephroprotection due to an excess of heart failure episodes Protection With Empagliflozin; NCT03594110) and DAPA-CKD (A [48]. The SONAR Phase 3 RCT explored nephroprotection by Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes atrasentan in DKD and incorporated an innovation to prior tri- and Cardiovascular Mortality in Patients With Chronic Kidney als: the exclusion of patients at risk of heart failure. This was Disease; NCT03036150) [49]. An improved understanding of done in two sequential steps: exclusion of patients with base- nephroprotective effects obtained from clinical studies may line brain natriuretic peptide (BNP) >200 pg/mL or a history of also help advance the field of CKD therapy. In this regard, a re- heart failure or of severe peripheral oedema, followed by an en- cent RCT disclosed evidence of proximal tubular cell protection richment period that selected patients for albuminuria response by dapagliflozin [50]. plus lack of substantial fluid retention (an increase in body- The impact of SONAR on the regulatory fate and eventual weight 3 kg and a BNP increase to 300 pg/mL) once on atra- clinical use of atrasentan is less clear. On the one hand, SONAR sentan [2]. In our opinion, these sequential steps to improve has clearly demonstrated that atrasentan preserves renal func- safety may severely compromise the external validity of the tion in addition to decreasing albuminuria. However, this was results and their use in routine clinical practice. shown against the old benchmark of RAS blockade, and the field has shifted towards a new benchmark of RAS blockade plus SGLT2i. Thus, even if atrasentan is approved for a DKD indica- WHAT WAS LEARNED FROM THE SONAR tion, its current role in clinical practice would be unclear. On the TRIAL TESTING ATRASENTAN TO TREAT DKD? other hand, the particular design of the SONAR trial, and espe- SONAR randomized 2648 adults with T2DM, an eGFR 25–75 mL/ cially the need for a first BNP determination at baseline and a min/1.73 m2 and a UACR 300–5000 mg/g on RAS blockade to second measurement in the enrichment period, can represent a atrasentan or placebo and followed them for a median of serious hindrance to the widespread use of atrasentan in dia- 2.2 years [2] (Figure 1). The trial was event-driven and was ter- betic patients. In addition, nephroprotection afforded by atra- minated prematurely when it was predicted that the pre-speci- sentan was not associated with cardiovascular benefit, even fied number of events would not be reached. The primary after multiple baseline and early exclusions based on cardiovas- composite renal outcome of doubling of serum creatinine or cular safety. This again benchmarks negatively with current ESRD was reached in 6.0% of atrasentan and 7.9% of placebo drugs such as SGLT2is that provide both kidney and cardiovas- patients with an HR of 0.65 (95% CI 0.49–0.88; P ¼ 0.0047) cular benefit. However, there is the distinct possibility that the (Figure 2B). The difference was also significant for doubling of combined nephroprotection afforded by atrasentan and SGLT2i serum creatinine [HR 0.61 (95% CI 0.43–0.87)] but not for ESRD on top of RAS blockade further reduces the residual risk and [HR 0.73 (95% CI 0.53–1.01)], despite a greater number of ESRD that additionally the combination offsets any potential deleteri- than doubling of serum creatinine events. ous effect of atrasentan on heart failure. Nevertheless, as attrac- Atrasentan, used under the conditions of the trial, was found tive as this hypothesis might seem, it requires formal to be safe but, at the same time, it did not provide a cardiovas- assessment in new, specifically designed RCTs. In addition, al- cular advantage. There were no significant differences in a sec- though T1DM was not explored in SONAR, T1DM patients may ondary cardiovascular composite endpoint (cardiovascular be a niche for atrasentan, given the potential for ketoacidosis death, non-fatal myocardial infarction or non-fatal stroke) or in with SGLT2is in these patients. 320 | B. Fernandez-Fernandez et al. FUNDING on therapies on top of renin angiotensin system blockade. J Clin Med 2015; 4: 1325–1347 Research by the authors is funded by FIS/Fondos FEDER 11. Fernandez-Fernandez B, Ortiz A, Gomez-Guerrero C et al. (PI16/02057, PI16/01814. PI17/00257, ISCIII-RETIC REDinREN Therapeutic approaches to diabetic nephropathy–beyond RD016/0009), Sociedad Espan ~ ola de Nefrologı́a, FRIAT, the RAS. Nat Rev Nephrol 2014; 10: 325–346 Comunidad de Madrid en Biomedicina B2017/BMD-3686 12. Ortiz A, Sanchez-Nin ~ o MD, Crespo-Barrio M et al. The CIFRA2-CM. E.P. is a researcher in the Ramón y Cajal Spanish Society of Nephrology (SENEFRO) commentary to Program. the Spain GBD 2016 report: keeping chronic kidney disease out of sight of health authorities will only magnify the prob- lem. Nefrologia 2019; 39: 29–34 CONFLICT OF INTEREST STATEMENT 13. Kramer A, Pippias M, Noordzij M et al. The European Renal A.O. is a consultant for Sanofi Genzyme and has received Association–European Dialysis and Transplant Association speaker fees or travel support from Amicus, Amgen, Fresenius (ERA-EDTA) Registry annual report 2015: a summary. Clin Medical Care, Menarini, Kyowa Kirin, Alexion, Otsuka and Vifor Kidney J 2018; 11: 108–122 Fresenius Medical Care Renal Pharma. J.F.N.G. has served as a 14. GBD 2017 Causes of Death Collaborators. Global, regional, consultant and has received speaker fees or travel support from and national age-sex-specific mortality for 282 causes of AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Esteve, death in 195 countries and territories, 1980-2017: a system- Genzyme, Lilly, Novartis, Servier, Shire and Vifor Fresenius atic analysis for the Global Burden of Disease Study 2017. Medical Care Renal Pharma. J.L.G. has received fees for giving Lancet 2018; 392: 1736–1788 talks from AstraZeneca, Boehringer Ingelheim, Janssen, 15. Ortiz A. Translational nephrology: what translational re- Mundipharma, Novartis, Novo Nordisk, Otsuka and Vifor search is and a bird’s-eye view on translational research in Pharma. M.J.S. has received speaker fees or travel support from nephrology. Clin Kidney J 2015; 8: 14–22 Otsuka, Menarini, AstraZeneca, Boehringer Ingelheim, Janssen, 16. American Diabetes Association. 6. Glycemic targets: stand- Mundipharma, Novartis, Eli Lilly, Esteve and Novo Nordisk. ards of medical care in diabetes—2019. Diabetes Care 2019; B.F.F. has received speaker fees or travel support from Abbvie, 42(Suppl 1): S61–S70 AstraZeneca, Boehringer Ingelheim, Esteve, Menarini, 17. American Diabetes Association. 11. Microvascular complica- Mundipharma, Novartis and Novo Nordisk. tions and foot care: standards of medical care in diabetes— 2019. Diabetes Care 2019; 42(Suppl 1): S124–S138 18. Esteras R, Perez-Gomez MV, Rodriguez-Osorio L et al. REFERENCES Combination use of medicines from two classes of renin- 1. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal angiotensin system blocking agents: risk of hyperkalemia, outcomes in type 2 diabetes and nephropathy. N Engl J Med hypotension, and impaired renal function. Ther Adv Drug Saf 2019. doi: 10.1056/NEJMoa1811744 2015; 6: 166–176 2. Heerspink HJL, Parving H-H, Andress DL et al. Atrasentan 19. 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