ESC HEART FAILURE ORIGINAL RESEARCH ARTICLE ESC Heart Failure 2020; 7: 3792–3800 Published online 22 September 2020 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12965 Renal function dynamics following co‐administration of sacubitril/valsartan and empagliflozin in patients with heart failure and type 2 diabetes Rafael de la Espriella1, Antoni Bayés‐Genís2,3, Herminio Morillas4, Rafael Bravo5, Verónica Vidal6, Eduardo Núñez1, Enrique Santas1, Gema Miñana1, Juan Sanchis1,2, Lorenzo Fácila6, Francisco Torres4, Jose Luis Górriz7, Alfonso Valle4 and Julio Núñez1,2* 1 Cardiology Department, Hospital Clínico Universitario de Valencia, INCLIVA, Departamento de Medicina, Universitat de València, Valencia, Spain; 2CIBER in Cardiovascular Diseases (CIBERCV), Madrid, Spain; 3Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, and Department of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain; 4Cardiology Department, Hospital de Dénia‐MarinaSalud, Dénia, Spain; 5Cardiology Department, Hospital Costa del Sol, Marbella, Spain; 6 Cardiology Department, Hospital General de Valencia, Valencia, Spain; 7Nephrology Department, Hospital Clínico Universitario de Valencia, INCLIVA, Departamento de Medicina, Universitat de València, Valencia, Spain Abstract Aims The aim of this study was to evaluate the safety profile in terms of changes in renal function after co‐treatment with sacubitril/valsartan and empagliflozin in patients with type 2 diabetes (T2D) and heart failure with reduced ejection fraction (HFrEF). Methods and results This multicentre observational analysis included 108 patients with T2D and HFrEF treated with both agents: baseline sacubitril/valsartan (Group A; n = 43), baseline empagliflozin (Group B; n = 42), or both agents initiated simul- taneously (Group C; n = 23). The primary endpoint was estimated glomerular filtration rate (eGFR) dynamics across treatment groups. A binary characterization of worsening renal function (WRF)/improved renal function (IRF) was included in the primary endpoint. WRF and IRF were defined as an increase/decrease in serum creatinine ≥ 0.3 mg/dL or GFR ≥ 20%. Changes in quan- titative variables were evaluated using joint modelling of survival and longitudinal data (JM). Rates and their treatment differ- ences were determined by Poisson regression. The mean left ventricle ejection fraction and eGFR were 32 ± 6% and 70 ± 28 mL/min/1.73 m2, respectively. At a median follow‐up of 1.01 years (inter‐quartile range 0.71–1.50), 377 outpatient visits were recorded. Although there were differences in GFR trajectories over time within each treatment, they did not achieve statistical significance (omnibus P = 0.154). However, when these differences were contrasted among groups, there was a significant decrease in GFR in Group A as compared with Group B (P = 0.002). The contrast between Groups C and B was not significant (P = 0.430). These differences were also reflected when the rates for WRF and IRF were contrasted among treatments. Conclusions The co‐administration of sacubitril/valsartan and empagliflozin in patients with HFrEF and concomitant T2D ap- pears to be safe in terms of renal function. Keywords Heart failure with reduced ejection fraction (HFrEF); Type 2 diabetes mellitus; Sacubitril/valsartan; SGLT2i; Renal func- tion; Renal safety profile Received: 9 February 2020; Revised: 5 June 2020; Accepted: 6 August 2020 *Correspondence to: Julio Núñez, Cardiology Department, Hospital Clínico Universitario de Valencia, Av. Blasco Ibáñez 17, 46010 Valencia, Spain. Tel: +34652856689; Fax: +34963862658. Email: yulnunez@gmail.com Introduction of heart failure (HF) with reduced ejection fraction (HFrEF).1 Sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) have The angiotensin receptor neprilysin inhibitor (ARNI) also shown promise in patients with HFrEF with and without sacubitril/valsartan has become fundamental in the treatment type 2 diabetes (T2D).2 Sacubitril/valsartan and SGLT2is result ©2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any me- dium, provided the original work is properly cited and is not used for commercial purposes. Co‐administration of sacubitril/valsartan and empagliflozin 3793 in a superior renal function profile at long‐term follow‐up Endpoints as compared with enalapril and placebo, respectively.3–6 However, both treatments may cause short‐term renal The primary endpoint of the study was the safety profile dysfunction.5,7 in terms of changes in renal function as represented by Renal function after concomitant administration of the eGFR after co‐treatment with sacubitril/valsartan and sacubitril/valsartan and SGLT2i in patients with HFrEF and empagliflozin. A binary characterization of worsening renal T2D is currently uncertain. Here, we evaluated renal function (WRF)/improved renal function (IRF) was included function dynamics during concomitant treatment with in the primary endpoint. WRF was defined as an increased se- sacubitril/valsartan and empagliflozin in addition to contem- rum creatinine ≥ 0.3 mg/dL or decreased GFR ≥ 20%. IRF was porary treatment in a cohort of consecutive ambulatory defined as a decrease in creatinine ≥ 0.3 or an increase in patients with HFrEF and T2D. GFR ≥ 20%. A sensitivity analysis evaluating the trajectory of creatinine clearance (Cockcroft–Gault formula) were also analysed. Methods Statistical analysis Study design and patients Continuous variables were expressed as means (±1 SD) or medians [inter‐quartile range (IQR)] and discrete variables This is a consecutive multicentre observational study of as percentages. Comparisons of means, medians, and fre- 108 patients with chronic HFrEF and T2D who received quencies among treatment groups were carried out with empagliflozin and sacubitril/valsartan in addition to standard one‐way ANOVA, Kruskal–Wallis test, and χ 2, respectively. treatment. Only patients receiving sacubitril/valsartan and Because the treatment groups of interest were assembled empagliflozin, according to the European Medicines Agency after the baseline visit, most of the analyses included the data approved indication and current guidelines, were included beginning at the first follow‐up visit; data on variables mea- in this analysis. All patients were treated with renin– sured at baseline were used as covariates in the regression angiotensin system (RAS) inhibitors before starting models. Changes in quantitative variables were evaluated sacubitril/valsartan. Patients were included from 1 March using linear mixed regression, with random slopes on partici- 2017 to 1 December 2018, from four dedicated HF clinics pant ID, random coefficient on continuous follow‐up time, at tertiary hospitals in Spain. The timing for initiation, combi- and unstructured covariance. These models included as nation, and up‐titration of these two drugs was left to fixed effects the interaction of treatment group with time the discretion of the patient’s physician by following (modelled as 4 df RCS), the baseline value of the longitudinal established recommendations. At the baseline visit, 43 pa- outcome tested, and the following baseline variables tients were already being treated with sacubitril/valsartan (age, eGFR, length of prior exposure to each treatment, and empagliflozin (Group A), 42 were already being treated left ventricular ejection fraction, serum sodium, and with empagliflozin and sacubitril/valsartan (Group B), and treatment with beta‐blockers and aldosterone receptor 23 patients were prescribed both drugs simultaneously blockers). In addition, furosemide‐equivalent dose (FED) and (Group C). All patients were treated with both empagliflozin sacubitril/valsartan and empagliflozin doses were added as and sacubitril/valsartan after the baseline visit. time‐specific covariates (time varying). For binary WRF/IRF, incidence rates and the treatment ratio were estimated by Poisson regression analysis. Stata 15.1 (Stata Statistical Soft- ware, Release 15 [2017]; StataCorp LP, College Station, TX, Clinical monitoring USA) was used for the analyses. Ambulatory follow‐up was performed in the HF units of each centre. At each clinical visit (baseline and follow‐up), we recorded demographic information, medical history Results [New York Heart Association (NYHA) class], vital signs (systolic blood pressures and heart rate), 12‐lead electrocardiogram The mean age of the total cohort at baseline was results, standard laboratory data, and concomitant changes 69 ± 9 years (range 73–80 years); 75% of patients were male, in HF therapy. Standard laboratory data included serum 63.9% had ischaemic heart disease, 58.7% had a history of a creatinine, estimated glomerular filtration rate (eGFR) as previous admission for acute HF, and 71.3% of patients were determined by CKD‐EPI, haemoglobin, sodium, and potas- NYHA II. The mean left ventricular ejection fraction, eGFR, sium at all visits. creatinine, BUN, and systolic blood pressure was 32 ± 6%, ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965 3794 R. de la Espriella et al. 70 ± 28 mL/min/1.73 m2, 1.18 ± 0.42 mg/dL, 26.5 ± 13 mg/dL, Sacubitril/valsartan was up‐titrated in 27 patients during and 128 ± 21 mmHg, respectively. The median NT‐proBNP the follow‐up. After up‐titration, the follow‐up visit oc- was 1795 pg/mL (IQR 715–4234). At baseline, most of the pa- curred at a median of 66 (IQR 30–163) days. The propor- tients were receiving loop diuretics (80.6%), beta‐blockers tion of patients taking medium (100 mg b.i.d.) and (96.3%), and mineralocorticoid receptor antagonists (79.6%). higher doses (200 mg b.i.d.) of sacubitril/valsartan in- Detailed baseline characteristics for all patients are presented creased during follow‐up (P = 0.001) without differences in Table 1. No significant differences were found across treat- among groups (P = 0.112; Figure S1). No differences ment groups. The time on treatment (length of exposure) were found for doses of empagliflozin during the with sacubitril/valsartan (Group A) and empagliflozin (Group follow‐up in the whole sample (mean dose = 10 mg q.d.; B) was 133 (60–253) and 100 days (47–210), respectively. P = 0.379) and across treatment groups (interaction P‐ value = 0.896). During follow‐up, WRF occurred in six (22.2%) patients in Treatment titration during follow‐up and adverse whom sacubitril/valsartan was up‐titrated and in 26 (32.1%) events in whom it was not (P = 0.330). No patient experienced an eGFR decrease ≥50%, development of end‐stage renal dis- This study included 120.8 person‐years of follow‐up or a total ease, or death due to renal failure. of 382 patient‐visits. At a median follow‐up of 1.01 years (IQR Sacubitril/valsartan was down‐titrated in three (2.8%) pa- 0.71–1.50), there was a median of three visits per patient tients. The reason for down‐titration was symptomatic hypo- (range 2–15). After baseline, the first, second, and third visits tension in two (1.8%) patients and WRF in one patient (0.9%). occurred at a median of 38.5 (IQR 23–119), 143 (IQR 68–232), However, the drug was not withdrawn in any of these and 245 days (IQR 146–313), respectively. patients. Table 1 Baseline characteristics across treatment groups Empagliflozin first Sacubitril/valsartan Characteristic None (n = 23) (n = 42) first (n = 43) Total (n = 108) P‐value Age, years 69 ± 10 70 ± 9 68 ± 9 69 ± 9 0.599 Male sex, n (%) 18 (78.3) 30 (71.4) 33 (76.7) 81 (75.0) 0.784 Clinical features of heart failure Ischaemic aetiology, n (%) 14 (60.9) 26 (61.9) 29 (67.4) 69 (63.9) 0.820 Left ventricular ejection fraction, % 31 ± 6 32 ± 6 32 ± 6 32 ± 6 0.887 NT‐proBNP, pg/mL* 2145 (1483; 4609) 2117 (662; 4731) 1600 (628; 3136) 1795 (715; 4234) 0.283 CA125, U/mL* 44 (14; 114) 38 (14; 92) 44 (21; 66) 42 (15; 84) 0.875 NYHA functional class, n (%) 0.699 I 0 (0.0) 2 (4.8) 3 (7.0) 5 (4.6) II 16 (69.6) 30 (71.4) 31 (72.1) 77 (71.3) III 7 (30.4) 9 (21.4) 9 (20.9) 25 (23.1) IV 0 (0.0) 1 (2.4) 0 (0.0) 1 (0.9) Heart rate, mmHg, 68 ± 10 73 ± 15 76 ± 14 73 ± 14 0.102 Systolic blood pressure, mmHg 127 ± 23 128 ± 22 129 ± 18 128 ± 21 0.946 Creatinine, mg/dL 1.25 ± 0.51 1.18 ± 0.39 1.13 ± 0.39 1.18 ± 0.42 0.540 2 Estimated GFR, mL/min/1.73 m 64.4 ± 20.6 68.3 ± 27.9 74.1 ± 31.0 69.8 ± 27.9 0.374 Medical history, n (%) Hypertension 21 (91.3) 33 (78.6) 36 (83.7) 90 (83.3) 0.418 Ischaemic heart disease 14 (60.9) 25 (59.5) 30 (69.8) 69 (63.9) 0.582 Atrial fibrillation 8 (34.8) 17 (40.5) 16 (37.2) 41 (38.0) 0.895 Prior admission for AHF, n (%) 13 (56.5) 17 (40.5) 14 (32.6) 44 (40.7) 0.168 Background therapy, n (%) Mineralocorticoid receptor 18 (78.3) 33 (78.6) 35 (81.4) 86 (79.6) 0.933 antagonist Beta‐blocker 22 (95.7) 42 (100.0) 40 (93.0) 104 (96.3) 0.231 Ivabradine 9 (39.1) 12 (28.6) 7 (16.3) 28 (25.9) 0.115 Implantable cardioverter‐defibrillator 3 (13.0) 7 (16.7) 12 (27.9) 22 (20.4) 0.270 Cardiac resynchronization therapy 2 (8.7) 5 (11.9) 3 (7.0) 10 (9.3) 0.732 Loop diuretics 20 (87.0) 37 (88.1) 30 (69.8) 87 (80.6) 0.070 Thiazides 2 (8.7) 3 (7.1) 5 (11.6) 10 (9.3) 0.771 Metformin 19 (82.6) 22 (52.4) 31 (72.1) 72 (66.7) 0.029 GFR was estimated using the Modification of Diet in Renal Disease Study (MDRD) formula. Continuous variables are expressed as mean ± standard deviation, unless otherwise specified. AHF, acute heart failure; CA125, antigen carbohydrate 125; GFR, glomerular filtration rate; NT‐proBNP, amino‐terminal pro‐brain natri- uretic peptide; NYHA, New York Heart Association. * Values expressed as median (inter‐quartile range). ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965 Co‐administration of sacubitril/valsartan and empagliflozin 3795 Sacubitril/valsartan was withdrawn in one patient owing to 6 months) and a later plateau or decrease. The slope for symptomatic hypotension. Empagliflozin was stopped in the Group B trajectory was statistically significant different seven patients, mainly owing to urinary/genital tract infection from 0 (flat slope). Group C, on the other hand, showed (n = 4). In the other three cases treated with empagliflozin, a consistent increase over the entire follow‐up (Figure 1). the reason for withdrawal was not recorded. Analysis of differences between groups (using Group B as When modelled over time, the FED decreased in all groups a reference) over the continuum of the follow‐up showed (mainly during the first 6 months), without significant differ- a significant decrease in eGFR for Group A (Figure 2A). ential effect across treatment groups (Figure S2). Neither The overall trajectory comparing Group B vs. C showed loop diuretics nor thiazides were prescribed in 21 patients no significant differences (Figure 2B). Similar trajectories at follow‐up. In 22 patients (20.4%), loop diuretic doses were among treatments groups were found when creatinine down‐titrated at least once (12.8%, 21.7%, and 30.4% for clearance was evaluated (Figure S3). Likewise, we did not Groups A, B, and C, respectively; P = 0.239). find significant changes in blood urea nitrogen and serum During the entire follow‐up, six deaths (5.6%), nine (8.3%) sodium Figures S4 and S5). admissions for acute HF, and seven visits to the emergency room (6.5%) were recorded. No differences were found among the treatment groups (Table S1). Worsening and improved renal function During the entire follow‐up, 45 and 38 episodes of Changes in renal function WRF and IRF were recorded in 33 (30.6%) and 23 (21.3%) patients, respectively. Mean crude rates for WRF and Overall trajectory by treatment group IRF are presented in Figure 3A and B, respectively. The slope of the GFR trajectories for Groups A and B Overall, patients belonging to Group A had the highest showed a bimodal response with an early increase (first rates of WRF1. Conversely, Group B had the lowest and Figure 1 Continuous changes in eGFR across treatment groups. Group A: patients on stable sacubitril/valsartan treatment in which empagliflozin was initiated. Group B: patients on stable empagliflozin treatment in which sacubitril/valsartan was initiated. Group C: naïve patients in which sacubitril/ 2 valsartan and empagliflozin were initiated simultaneously. eGFR, glomerular filtration rate (mL/min/1.73 m ). eGFR was determined by CKD‐EPI formula. ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965 3796 R. de la Espriella et al. Figure 2 Changes in renal function compared between groups. Group A: patients on stable sacubitril/valsartan treatment in which empagliflozin was initiated. Group B: patients on stable empagliflozin treatment in which sacubitril/valsartan was initiated. Group C: naïve patients in which sacubitril/ valsartan and empagliflozin were initiated simultaneously. Group B was used as a reference. highest rates for WRF and IRF, respectively. Intermediate Compared with Group B, and assuming a constant effect rates were found in Group C. No patients met the WRF2 over the follow‐up, patients in the Group A showed a signifi- criteria. cant increase in the risk of WRF1 (IRR = 2.36, 95% CI: 1.03– Figure 3 Renal function trajectories across treatment groups. (A) Worsening renal function (WRF) rate. (B) Improved renal function (IRF) rate. Group A: patients on stable sacubitril/valsartan treatment in which empagliflozin was initiated. Group B: patients on stable empagliflozin treatment in which sacubitril/valsartan was initiated. Group C: naïve patients in which sacubitril/valsartan and empagliflozin were initiated simultaneously. ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965 Co‐administration of sacubitril/valsartan and empagliflozin 3797 5.43; P = 0.043). No significant differences were found for sacubitril/valsartan in those already being treated with Group C (IRR = 2.02, 95% CI: 0.88–4.67; P = 0.097). Likewise, empagliflozin was associated with IRF. An intermediate risk and compared with Group B, patients belonging to Group A of WRF was found when both treatments were initiated showed a lower risk of IRF (IRR = 0.20, 95% CI: 0.05–0.83; simultaneously. P = 0.027) without differences for Group C (IRR = 0.86, 95% These findings suggest that the combined ARNI‐SGLT2 CI: 0.32–2.28; P = 0.767). inhibition appears to have a similar renal safety profile (at mid‐term) as previously reported when both treatments are used separately.3,4,6,8 Our results are somehow reassuring Discussion considering that these two treatments seem to have inde- pendent and additive benefits when used in combination. In this observational multicentre registry, we found that Notably, the present findings do not apply to other HF sce- co‐administration of sacubitril/valsartan and empagliflozin in narios (e.g. patients with more than mild renal dysfunction, patients with chronic HFrEF, T2D, and normal or mildly re- no T2D, and acute HF syndromes) in which we should likely duced renal function (eGFR > 60 mL/min/1.73 m2) did not be more conservative and vigilant. translate into significant and clinically relevant changes in eGFR. None of the patients in this cohort had a >50% de- crease in eGFR during the follow‐up. When examined contin- Combined administration of empagliflozin and uously using smaller changes in renal function parameters sacubitril/valsartan: friend or foe for the kidney (increase/decrease in creatinine ≥ 0.3 or decrease/increase in GFR ≥ 20%), we found that the higher risk of WRF was at- Given the observational nature of this study, we can tributable to empagliflozin initiation in those already being only speculate how empagliflozin and sacubitril/valsartan treated with sacubitril/valsartan. Conversely, initiation of exerted their effects on kidney function (Figure 4). Both Figure 4 Hypothesized renal haemodynamic effects of co‐administration of SGLT2i and sacubitril/valsartan in patients with HFrEF and T2D. Group A: patients on stable sacubitril/valsartan treatment in which empagliflozin was initiated. SGLT2i causes pre‐glomerular vasoconstriction via TGF activation with a coinciding drop in intra‐glomerular pressures. A post‐glomerular vasodilatation effect via adenosine A2 receptor activation has also been sug- gested. Group B: patients on stable empagliflozin treatment in which sacubitril/valsartan was initiated. NPs decrease pre‐glomerular vascular resistance and may counteract the vasoconstrictive action of SGLT2 inhibition on the pre‐glomerular arteriole. Group C: naïve patients in which sacubitril/ valsartan and empagliflozin were initiated simultaneously. An intermediate effect on afferent arteriole tone could be expected by the concomitant ad- ministration of both treatments. A1R, adenosine type 1 receptor; A2R, adenosine type 1 receptor; ARBs, angiotensin receptor blockers; FF, filtration fraction; GFR, glomerular filtration rate; IRF, improved renal function; NPs, natriuretic peptides; RBF, renal blood flow; TGF, tubuloglomerular feedback; WRF, worsening renal function. ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965 3798 R. de la Espriella et al. SGLT2 and neprilysin receptors are abundantly expressed in parameter for detecting early renal function changes16,20 the kidneys. Additionally, the cohort was primarily composed of ambula- Several explanations are possible for the early slight tory patients with chronic HFrEF, concomitant T2D, and decrease in eGFR after empagliflozin initiation in patients normal or mildly reduced renal function. Therefore, it is already being treated with ARNI. First, it may be related to unclear how the results will apply to the broader HF popula- an adenosine‐mediated increase in afferent pre‐glomerular tion, those without T2D, and patients with higher degrees arteriolar resistance with a coinciding decrease in of renal impairment. Finally, we did not measure other surro- intra‐glomerular pressure.9,10 Second, recent findings suggest gates of renal haemodynamic and urine parameters that a predominant vasodilatory effect of SGLT2is on efferent ar- may be useful to explain these results. Therefore, all the terioles mediated by adenosine A2 receptor activation when conclusions are merely speculative and only allow us to the potential for pre‐glomerular vasoconstriction has already generate hypothesis about the underlying mechanism behind been achieved.11 The authors observed that eGFR was ac- these findings. companied by stable, or even reduced, pre‐glomerular vascu- lar resistance, suggesting that post‐glomerular vasodilation explains the acute decrease in eGFR after SGLT2i initiation.11 Conclusions Third, in addition to the aforementioned glomerular haemo- dynamic effects, a reduction in proximal tubular sodium reab- The co‐administration of sacubitril/valsartan and sorption together with enhanced tubular flow secondary to empagliflozin in ambulatory patients with chronic HFrEF, osmotic diuresis may increase substrate availability in the dis- T2D, and normal or mildly reduced renal function appears tal nephron.12,13 Accordingly, SGLT2is may work synergisti- to be safe in terms of renal function. A better renal function cally with more distal diuretics, potentiating diuresis and profile emerged when sacubitril/valsartan was added to natriuresis.14 This aspect is relevant, as 80% of patients were empagliflozin. Further studies are needed to unravel the receiving loop diuretics at baseline. An alternative explana- potential synergistic effect of both treatments in terms of tion could be related to plasma volume contraction rather cardiorenal outcomes. than ‘true’ WRF15,16; we observed FED reductions in all groups, mainly during the first 6 months of follow‐up. In contrast, eGFR slightly improved when sacubitril/valsartan was added to patients who were already Conflict of Interest treated with empagliflozin. Natriuretic peptides (NPs) are The authors have no other funding, financial relationships, or known to reduce pre‐glomerular vascular resistance and conflicts of interest to disclose relative to this work. may also increase the filtration surface area by relaxing glo- merular mesangial cells.17 However, the renal effects of these peptides are markedly attenuated in HF because renal neprilysin activity and protein expression levels are upregu- Funding lated in this syndrome.18 Accordingly, neprilysin inhibition by sacubitril/valsartan may boost the effects of NPs on This work was supported in part by grants from glomerular haemodynamic. The immediate increase in uri- CentrodeInvestigación Biomédica en Red Enfermedades nary albumin/creatinine ratio observed in PARADIGM‐HF af- Cardiovasculares (CIBER CV) (grant numbers 16/11/00420 ter initiation of sacubitril/valsartan, with normalization to and 16/11/00403). pre‐screening values following discontinuation, clearly sug- gests a haemodynamic effect.3 Therefore, the observed im- provement in eGFR in our cohort after the introduction of Supporting information sacubitril/valsartan suggests that it may counteract the vaso- constrictive action of empagliflozin on the pre‐glomerular ar- Additional supporting information may be found online in the teriole. In addition, sacubitril/valsartan promptly reduces Supporting Information section at the end of the article. cardiac filling pressures and promotes left ventricular reverse remodelling,7,19 which may also have contributed to en- Figure S1. Sacubitril valsartan dose pattern at follow‐up. hanced renal blood flow. Group A: patients on stable sacubitril/valsartan treatment in which empagliflozin was initiated. Group B: patients on stable Limitations empagliflozin treatment in which sacubitril/valsartan was ini- As an observational study, causality cannot be inferred. Addi- tiated. Group C: naïve patients in which sacubitril/valsartan tional limitations of this study are the limited sample size, and empagliflozin were initiated simultaneously. which is prone to bias because of unmeasured confounding, Figure S2. Furosemide‐equivalent dose pattern during the first and eGFR may not be the most accurate and sensitive 6‐months in the whole sample (A), without significant differenetial ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965 Co‐administration of sacubitril/valsartan and empagliflozin 3799 effect acroos teratment groups (B). Group A: patients on stable Figure S4. Continuous changes in BUN across treatment groups. Group sacubitril/valsartan treatment in which empagliflozin was initiated. A: patients on stable sacubitril/valsartan treatment in which Group B: patients on stable empagliflozin treatment in which empagliflozin was initiated. Group B: patients on stable empagliflozin sacubitril/valsartan was initiated. Group C: naïve patients in which treatment in which sacubitril/valsartan was initiated. Group C: naïve sacubitril/valsartan and empagliflozin were initiated simultaneously. patients in which sacubitril/valsartan and empagliflozin were initiated Table S1. Adverse events across treatment groups simultaneously. BUN, blood urea nitrogen Figure S3. Predicted Cockroft‐Gault formula trajectories. Group A: pa- Figure S5. Continuous changes in serum sodium across treatment tients on stable sacubitril/valsartan treatment in which empagliflozin groups. Group A: patients on stable sacubitril/valsartan treatment in was initiated. Group B: patients on stable empagliflozin treatment in which empagliflozin was initiated. Group B: patients on stable which sacubitril/valsartan was initiated. Group C: naïve patients in empagliflozin treatment in which sacubitril/valsartan was initiated. which sacubitril/valsartan and empagliflozin were initiated Group C: naïve patients in which sacubitril/valsartan and empagliflozin simultaneously. were initiated simultaneously. References 1. Burnett H, Earley A, Voors AA, Senni M, from the EMPA‐REG OUTCOME Trial. 12. Mullens W, Damman K, Harjola V‐P, McMurray JJV, Deschaseaux C, Cope S. Circ Heart Fail 2019; 12: e005875. Mebazaa A, Brunner‐La Rocca H‐P, Mar- Thirty years of evidence on the efficacy 6. Kluger AY, Tecson KM, Lee AY, Lerma tens P, Testani JM, Tang WHW, Orso F, of drug treatments for chronic heart fail- EV, Rangaswami J, Lepor NE, Cobble Rossignol P, Metra M, Filippatos G, ure with reduced ejection fraction: a net- ME, McCullough PA. Class effects of Seferovic PM, Ruschitzka F, Coats AJ. work meta‐analysis. Circ Heart Fail 2017; SGLT2 inhibitors on cardiorenal out- The use of diuretics in heart failure with 10: e003529. comes. Cardiovasc Diabetol 2019; 18: 99. congestion—a position statement from 2. McMurray JJV, Solomon SD, Inzucchi 7. Velazquez EJ, Morrow DA, DeVore AD, the Heart Failure Association of the Eu- SE, Køber L, Kosiborod MN, Martinez Duffy CI, Ambrosy AP, McCague K, ropean Society of Cardiology: Diuretics FA, Ponikowski P, Sabatine MS, Anand Rocha R, Braunwald E. Angiotensin– in heart failure. Eur J Heart Fail 2019; IS, Bělohlávek J, Böhm M, Chiang C‐E, neprilysin inhibition in acute decompen- 21: 137–155. Chopra VK, de Boer RA, Desai AS, Diez sated heart failure. N Engl J Med 2019; 13. Wanner C. EMPA‐REG OUTCOME: the M, Drozdz J, Dukát A, Ge J, Howlett 380: 539–548. nephrologist’s point of view. Am J Med JG, Katova T, Kitakaze M, Ljungman 8. Zelniker TA, Wiviott SD, Raz I, Im K, 2017; 130: S63–S72. CEA, Merkely B, Nicolau JC, O’Meara Goodrich EL, Bonaca MP, Mosenzon O, 14. Mullens W, Verbrugge FH, Nijst P, Mar- E, Petrie MC, Vinh PN, Schou M, Kato ET, Cahn A, Furtado RHM, Bhatt tens P, Tartaglia K, Theunissen E, Tereshchenko S, Verma S, Held C, DL, Leiter LA, McGuire DK, Wilding Bruckers L, Droogne W, Troisfontaines DeMets D, Docherty KF, Jhund PS, JPH, Sabatine MS. SGLT2 inhibitors for P, Damman K, Lassus J, Mebazaa A, Bengtsson O, Sjöstrand M, Langkilde primary and secondary prevention of Filippatos G, Ruschitzka F, Dupont M. AM, DAPA‐HF Trial Committees and In- cardiovascular and renal outcomes in Rationale and design of the ADVOR (Ac- vestigators. Dapagliflozin in patients type 2 diabetes: a systematic review etazolamide in Decompensated Heart with heart failure and reduced ejection and meta‐analysis of cardiovascular Failure with Volume Overload) trial: ac- fraction. N Engl J Med 2019; 381: outcome trials. Lancet 2019; 393: etazolamide in decompensated heart 1995–2008. 31–39. failure with volume overload. Eur J 3. Damman K, Gori M, Claggett B, Jhund 9. Kidokoro K, Cherney DZI, Bozovic A, Heart Fail 2018; 20: 1591–1600. PS, Senni M, Lefkowitz MP, Prescott Nagasu H, Satoh M, Kanda E, Sasaki T, 15. Sokolski M, Zymliński R, Biegus J, MF, Shi VC, Rouleau JL, Swedberg K, Kashihara N. Evaluation of glomerular Siwołowski P, Nawrocka‐Millward S, Zile MR, Packer M, Desai AS, Solomon hemodynamic function by empagliflozin Todd J, Yerramilli MR, Estis J, SD, McMurray JJV. Renal effects in diabetic mice using in vivo imaging. Jankowska EA, Banasiak W, Ponikowski and associated outcomes during Circulation 2019; 140: 303–315. P. Urinary levels of novel kidney bio- angiotensin‐neprilysin inhibition in 10. Kuriyama S. Protection of the kidney markers and risk of true worsening renal heart failure. JACC Heart Failure 2018; with sodium–glucose cotransporter 2 in- function and mortality in patients with 6: 489–498. hibitors: potential mechanisms raised by acute heart failure: kidney biomarkers 4. Packer M, Claggett B, Lefkowitz MP, the large‐scaled randomized control tri- and risk of true worsening renal func- McMurray JJV, Rouleau JL, Solomon als. Clin Exp Nephrol 2019; 23: 304–312. tion and mortality in AHF. Eur J Heart SD, Zile MR. Effect of neprilysin inhibi- 11. van Bommel EJM, Muskiet MHA, van Fail 2017; 19: 760–767. tion on renal function in patients with Baar MJB, Tonneijck L, Smits MM, 16. Ahmad T, Jackson K, Rao VS, Tang type 2 diabetes and chronic heart Emanuel AL, Bozovic A, Danser AHJ, WHW, Brisco‐Bacik MA, Chen HH, failure who are receiving target doses Geurts F, Hoorn EJ, Touw DJ, Larsen Felker GM, Hernandez AF, O’Connor of inhibitors of the renin–angiotensin EL, Poulsen HE, Kramer MHH, CM, Sabbisetti VS, Bonventre JV, Wilson system: a secondary analysis of the Nieuwdorp M, Joles JA, van Raalte DH. FP, Coca SG, Testani JM. Worsening re- PARADIGM‐HF trial. Lancet Diab The renal hemodynamic effects of the nal function in patients with acute heart Endocrinol 2018; 6: 547–554. SGLT2 inhibitor dapagliflozin are failure undergoing aggressive diuresis is 5. Butler J, Zannad F, Fitchett D, Zinman B, caused by post‐glomerular vasodilata- not associated with tubular injury. Circu- Koitka‐Weber A, von Eynatten M, tion rather than pre‐glomerular vaso- lation 2018; 137: 2016–2028. Zwiener I, George J, Brueckmann M, constriction in metformin‐treated 17. Brenner BM, Ballermann BJ, Gunning Cheung AK, Wanner C. Empagliflozin patients with type 2 diabetes in the ME, Zeidel ML. Diverse biological ac- improves kidney outcomes in patients randomized, double‐blind RED trial. tions of atrial natriuretic peptide. Physiol with or without heart failure: insights Kidney Int 2019: S0085253819309913. Rev 1990; 70: 665–699. ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965 3800 R. de la Espriella et al. 18. Knecht M, Pagel I, Langenickel T, Philipp Williamson KM, Solomon SD, for the Milo O, Teerlink JR, Givertz MM, S, Scheuermann‐Freestone M, Willnow PROVE‐HF Investigators. Association of O’Connor CM, Dittrich HC, Bloomfield T, Bruemmer D, Graf K, Dietz R, change in N‐terminal pro–B‐type natri- DM, Voors AA, Davison BA. Prognostic Willenbrock R. Increased expression of uretic peptide following initiation of significance of creatinine increases dur- renal neutral endopeptidase in severe sacubitril‐valsartan treatment with car- ing an acute heart failure admission in heart failure. Life Sci 2002; 71: diac structure and function in patients patients with and without residual con- 2701–2712. with heart failure with reduced ejection gestion: a post hoc analysis of the 19. Januzzi JL, Prescott MF, Butler J, Felker fraction. JAMA 2019; 322: 1085. PROTECT data. Circ Heart Fail 2018; GM, Maisel AS, McCague K, Camacho 20. Metra M, Cotter G, Senger S, Edwards C, 11: e004644. A, Piña IL, Rocha RA, Shah AM, Cleland JG, Ponikowski P, Cursack GC, ESC Heart Failure 2020; 7: 3792–3800 DOI: 10.1002/ehf2.12965