# Uric Acid and SGLT2 Inhibition With Empagliflozin in Heart Failure With Preserved Ejection Fraction

Wolfram Doehner, Stefan D Anker, Javed Butler, Faiez Zannad, Gerasimos Filippatos, Andrew J.S. Coats, João Pedro Ferreira, Ingrid Henrichmoeller, Martina Brueckmann, Elke Schueler, et al.

► To cite this version:

Wolfram Doehner, Stefan D Anker, Javed Butler, Faiez Zannad, Gerasimos Filippatos, et al. Uric Acid and SGLT2 Inhibition With Empagliflozin in Heart Failure With Preserved Ejection Fraction. JACC: Heart Failure, 2024, 12 (12), pp.2057-2070. 10.1016/j.jchf.2024.08.020. hal-04790633

HAL Id: hal-04790633

https://hal.univ-lorraine.fr/hal-04790633v1

Submitted on 19 Nov 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Uric Acid and SGLT2 Inhibition With Empagliflozin in Heart Failure With Preserved Ejection Fraction

## The EMPEROR-Preserved Trial

Wolfram Doehner, MD, PhD,ª Stefan D. Anker, MD, PhD,ª Javed Butler, MD, MPH, MBA,ᵇ,c Faiez Zannad, MD, PhD,ᵈ Gerasimos Filippatos, MD,ᵉ Andrew J.S. Coats, DM,ᵉ João Pedro Ferreira, MD, PhD,ᵈ,g Ingrid Henrichmoeller, MD, h,i Martina Brueckmann, MD, h,j Elke Schueler, DIPL MATH, k Stuart J. Pocock, PhD, l James L. Januzzi, MD, m Milton Packer, MDn,o

ABSTRACT

**BACKGROUND** Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcome in patients with heart failure (HF) and reduce serum uric acid (SUA). The relevance of this metabolic effect in patients with heart failure with preserved ejection fraction (HFpEF) is unclear.

**OBJECTIVES** The authors investigated the effect of empagliflozin on SUA levels in relation to the therapeutic efficacy in patients with HFpEF.

**METHODS** This post hoc analysis of the EMPEROR-Preserved (EMPagliflozin outcome Trial in Patients With chrOnic heart Failure With Preserved Ejection Fraction; NCT03057951) trial assessed the clinical effect of SUA reduction in relation to the outcome endpoints of the trial (composite primary outcome of cardiovascular mortality or hospitalization for HF, its individual components, and all-cause mortality in patients with HFpEF).

**RESULTS** Hyperuricemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) was prevalent in 49% of patients. Elevated SUA (highest tertile SUA 8.8 ± 1.4 g/dL) was associated with advanced HF severity and with higher risk of adverse outcome (primary endpoint HR: 1.23 [95% CI: 0.98-1.53]; *P* = 0.07; HF hospitalization HR: 1.42 [95% CI: 1.08-1.86]; *P* = 0.01). SUA was reduced early (after 4 weeks vs placebo –0.99 ± 0.03 mg/dL; *P* < 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of ANTIGOUT therapy) by 38% (HR: 0.62 [95% CI: 0.51-0.76]; *P* < 0.0001). The treatment benefit on the primary endpoint was not influenced by baseline SUA (HR: 0.79 [95% CI: 0.69-0.90]; *P* = 0.0004). The change in SUA was an independent correlate of the treatment benefit on the primary endpoint (*P* = 0.07).

**CONCLUSIONS** Hyperuricemia is a common complication in HFpEF and is related to advanced disease severity and adverse outcome. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricemia. (JACC Heart Fail. 2024; ■:■-■) © 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

From the ªBerlin Institute of Health - Center for Regenerative Therapies, and Department of Cardiology (CVK), Deutsches Herzzentrum der Charité and German Centre for Cardiovascular Research Partner Site Berlin, Charité - Universitätsmedizin Berlin, Berlin, Germany; ᵇBaylor Scott and White Research Institute, Dallas, Texas, USA; ᶜDepartment of Medicine, University of Mississippi School of Medicine, Jackson, Mississippi, USA; ᵈUniversité de Lorraine, INSERM, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, Inserm U1116 F-CRIN INI-CRCT, Nancy, France; ᵉNational and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece; ᵈHeart Research Institute, Sydney, New South Wales, Australia; ᶜUnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto,
ABBREVIATIONS
AND ACRONYMS

DM = diabetes mellitus

eGFR = estimated glomerular filtration rate

HF = heart failure

HFpEF = heart failure with preserved ejection fraction

HHF = hospitalization for heart failure

LVEF = left ventricular ejection fraction

NT-proBNP = N-terminal pro-B-type natriuretic peptide

SGLT2 = sodium-glucose cotransporter 2

SUA = serum uric acid

Hyperuricemia and clinical gout are common complications in patients with heart failure (HF). Hyperuricemia is related to HF severity, to the risk of hospitalization for heart failure (HHF),¹ and has been shown to be a strong prognostic marker in HF.²,³ The elevated serum levels of uric acid (SUA) in HF have been shown to result predominantly from increased metabolic turnover of purine catabolism and increased xanthine oxidase activity along with decreased renal excretion.⁴,⁵ In fact, elevated SUA levels in HF have been recognized as a biomarker of increased catabolism and of oxidative stress independent of diuretic dose or impaired kidney function.⁶ Mechanistically, elevated SUA levels reflect increased accumulation of reactive oxygen species, cytokine activation, and insulin resistance, all of which are components of HF pathophysiology.⁷ Accordingly, elevated SUA levels have been associated with a range of cardiovascular mechanisms that contribute to HF severity and progression such as myocardial remodeling, energetic and contractile efficacy, increased filling pressure, low cardiac output, endothelial dysfunction, and B-type natriuretic peptide (BNP) levels.⁵,⁸ Lastly, elevated SUA concentrations may render a patient with HF vulnerable to gout events, which are linked to worse health status, and the use of nonsteroidal anti-inflammatory drugs might interfere with ongoing HF medical therapy and cause sodium retention.

In patients with heart failure with preserved ejection fraction (HFpEF), elevated SUA levels are a common finding. However, the significance of this finding for clinical complications and outcome of patients in HFpEF is less well understood than in HF patients with reduced ejection fraction. Recent studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors effectively lower SUA levels⁹ and the risk of clinically relevant hyperuricemic events.¹⁰ Emerging evidence suggests a mediation effect of SUA lowering secondary to SGLT2

inhibitors treatment for the beneficial effect on outcomes in patients with type 2 diabetes (DM)¹¹ and in HF.¹⁰ The relevance of this observation for the overall beneficial effect of SGLT2 inhibitors in HF is not yet clear.¹²

In this study, we evaluated the clinical relevance of baseline SUA levels and SUA dynamics secondary to treatment with the SGLT2 inhibitor empagliflozin for clinical outcome and in relation to the therapeutic efficacy of empagliflozin in patients with HFpEF from the EMPEROR-Preserved (EMPagliflozin outcome Trial in Patients With chrOnic heart Failure With Preserved Ejection Fraction) trial.¹³

METHODS

**EMPEROR-PRESERVED STUDY DESIGN.** The design, study methods, and endpoints of the EMPEROR-Preserved trial have been described previously in detail.¹³,¹⁴ Briefly, EMPEROR-Preserved was a randomized, double-blind, parallel-group, placebo-controlled and event-driven trial that evaluated the effects of the SGLT2 inhibitor empagliflozin on morbidity and mortality of patients with HFpEF. The study was approved by ethical committees and was registered at ClinicalTrials.gov (NCT03057951). This post hoc analysis of the EMPEROR-Preserved study data was based on an a priori hypothesis and followed a defined analysis plan.

**STUDY PATIENTS, ASSESSMENTS, AND FOLLOW-UP.** Eligible patients included those with chronic HF (functional class II-IV) with preserved ejection fraction (ie, ejection fraction >40%) if an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of more than 300 pg/mL (in patients with sinus rhythm), or more than 900 pg/mL (in patients with atrial fibrillation) was observed. Patients were randomly assigned (double-blind, in a 1:1 ratio) to treatment with empagliflozin 10 mg once daily or placebo in addition to their usual treatments for the diagnosis. During follow-up, all treatments for HF or for other medical conditions were provided and adjusted, as clinically indicated, at the discretion of the treating physician.

Portugal; ⁸Boehringer Ingelheim International, Ingelheim, Germany; ⁹Fifth Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany; ¹⁰First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany; ¹²main analytics GmbH, Sulzbach/Taunus, Germany; ¹⁴Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom; ¹⁸Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Baim Institute for Clinical Research, Boston, Massachusetts, USA; ²Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA; and the ⁵Imperial College, London, United Kingdom.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
All randomized patients were followed at regularly planned visits throughout the duration of the trial for major outcomes and adverse events. SUA was measured (as mg/dL) for all patients in a central laboratory at baseline, at 4 and 12 weeks, and every 6 months for the duration of double-blind treatment. Hyperuricemia was defined as SUA >5.7 mg/dL for women and >7.0 mg/dL for men according to the upper limit of normal of the used assay (Roche/Hita-chi on the COBAS c platform, lower detection limit 0.5 mg/dL, coefficient of variation 0.4%, Roche Di-agnostics). The median (Q1-Q3) follow-up time was 26.2 months (18.1-33.1 months).

**STUDY OUTCOMES.** The primary endpoint was the composite of adjudicated cardiovascular death or HHF, analyzed as time to first event. The first secondary endpoint was the occurrence of all adjudicated hospitalizations for HF (first and recurrent events). Further outcomes were cardiovascular death, all-cause mortality, and time to first HHF. The effect to lower SUA was assessed in prespecified subgroups as defined in the primary analysis.¹⁴

All hospitalizations for HF and all deaths were adjudicated by a clinical event committee in a blinded manner using prespecified criteria. Clinically relevant hyperuricemia was identified as the composite of time to first event of investigator-reported episodes of gout, gouty arthritis, or gouty tophus, or the de novo initiation of SUA-lowering medication (xanthine oxidase inhibitors, uricosuric agents, or colchicine).

**STATISTICAL ANALYSES.** Baseline characteristics are presented as frequencies and percentages for categorical variables and mean ± SD or median (IQR) for continuous variables. For descriptive and outcome analyses, the study population was grouped into tertiles of SUA, with thresholds defined separately for men and women. For men, the values used to define tertiles were 5.9 mg/dL and 7.5 mg/dL; for women, the corresponding values were 5.4 mg/dL and 6.9 mg/dL. Sex-specific tertiles were combined to present the analyses of tertiles for the entire population. Differences in baseline characteristics were evaluated using ordinal regression likelihood ratio test. Incidence rates are presented as rates per 100 patient-years of follow-up.

Cox proportional models were used to calculate HRs for prespecified outcomes in relation to baseline SUA using the lowest SUA tertile as the reference. This analysis was restricted to the placebo group to exclude any potential effect of empagliflozin. The relationship between baseline SUA as continuous variable and outcomes was analyzed after

multivariate adjustment similar to the Cox model, using a restricted cubic spline-regression model (using 4 knots at the 5th, 35th, 65th, and 95th percentiles). Time-to-event analyses for the effect of empagliflozin vs placebo were performed using the Cox model of the randomized population (intention-to-treat principle), adjusted for age, left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR) (by Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI]), sex, geographical region, DM status, baseline SUA tertiles, and SUA tertiles × treatment interaction. For the analysis of HF events (first and repeated events), between-group differences were assessed using a joint frailty model, with cardiovascular death as competing risks and using the same covariates as for the primary endpoint. We carried out an additional analysis of the Cox model, which included baseline SUA and the change of SUA at the 4-week post-randomization visit as additional covariates (landmark analysis) to assess a potential contributing effect of change in SUA using the same Cox model as for the primary analysis but considering only time after the visit at week 4. Patients with missing SUA data at baseline or week 4 visit, or patients with an event during the first 4 weeks were excluded from this analysis.

Changes from baseline SUA laboratory measurements were assessed using a mixed model for repeated measures, which included age, baseline eGFR, and LVEF as linear covariates and sex, region, individual last projected visit based on dates of randomization and trial closure, and baseline DM status as fixed effects, along with interaction terms for baseline SUA tertile by visit and for baseline SUA tertile by visit by treatment. All *P* values reported are 2-sided; no adjustment was made for multiplicity of comparisons. All analyses were performed with SAS, version 9.4 (SAS Institute).

**DATA-SHARING STATEMENT.** To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and after secondary analyses in peer-reviewed journals and regulatory and reimbursement activities are completed, normally within 1 year after the marketing application has been
<table><caption>TABLE 1 Clinical Characteristics of Patients According to Serum Uric Acid Tertiles</caption><thead><tr><th></th><th>Tertile 1<br>(n = 1,938)</th><th>Tertile 2<br>(n = 1,998)</th><th>Tertile 3<br>(n = 1,988)</th><th>P Value<br>for Trend</th></tr></thead><tbody><tr><td>Serum uric acid, mg/dL</td><td>4.65 ± 0.79</td><td>6.41 ± 0.54</td><td>8.79 ± 1.40</td><td></td></tr><tr><td>Age, y</td><td>72.1 ± 9.0</td><td>71.6 ± 9.4</td><td>72.0 ± 9.8</td><td>0.8148</td></tr><tr><td>Female</td><td>873 (45.0)</td><td>894 (44.7)</td><td>886 (44.6)</td><td>0.7632</td></tr><tr><td>Race</td><td></td><td></td><td></td><td>0.0097</td></tr><tr><td>White</td><td>1,458 (75.2)</td><td>1,535 (76.8)</td><td>1,494 (75.2)</td><td></td></tr><tr><td>Black</td><td>69 (3.6)</td><td>78 (3.9)</td><td>109 (5.5)</td><td></td></tr><tr><td>Asian</td><td>275 (14.2)</td><td>277 (13.9)</td><td>270 (13.6)</td><td></td></tr><tr><td>Other, including mixed races</td><td>135 (7.0)</td><td>108 (5.4)</td><td>114 (5.7)</td><td></td></tr><tr><td>Missing</td><td>1 (0.1)</td><td>0</td><td>1 (0.1)</td><td></td></tr><tr><td>Region</td><td></td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>North America</td><td>200 (10.3)</td><td>207 (10.4)</td><td>301 (15.1)</td><td></td></tr><tr><td>Latin America</td><td>566 (29.2)</td><td>482 (24.1)</td><td>442 (22.2)</td><td></td></tr><tr><td>Europe</td><td>851 (43.9)</td><td>957 (47.9)</td><td>856 (43.1)</td><td></td></tr><tr><td>Asia</td><td>232 (12.0)</td><td>240 (12.0)</td><td>213 (10.7)</td><td></td></tr><tr><td>Other</td><td>89 (4.6)</td><td>112 (5.6)</td><td>176 (8.9)</td><td></td></tr><tr><td>NYHA functional class</td><td></td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>II</td><td>1,663 (85.8)</td><td>1,685 (84.3)</td><td>1,487 (74.8)</td><td></td></tr><tr><td>III</td><td>272 (14.0)</td><td>308 (15.4)</td><td>488 (24.5)</td><td></td></tr><tr><td>IV</td><td>2 (0.1)</td><td>3 (0.2)</td><td>12 (0.6)</td><td></td></tr><tr><td>Body mass index, kg/m²</td><td>28.7 ± 5.6</td><td>29.8 ± 5.8</td><td>30.9 ± 6.0</td><td>&lt;0.0001</td></tr><tr><td>≥30 kg/m²</td><td>714 (36.8)</td><td>898 (44.9)</td><td>1,045 (52.6)</td><td>&lt;0.0001</td></tr><tr><td>Heart rate, beats/min</td><td>70.1 ± 11.7</td><td>70.0 ± 11.4</td><td>71.0 ± 12.5</td><td>0.0110</td></tr><tr><td>Systolic blood pressure, mm Hg</td><td>132.5 ± 15.3</td><td>132.5 ± 15.6</td><td>130.5 ± 16.1</td><td>&lt;0.0001</td></tr><tr><td>LVEF, %</td><td>54.4 ± 8.7</td><td>54.0 ± 8.9</td><td>54.7 ± 8.7</td><td>0.2386</td></tr><tr><td>NT-proBNP, pg/mL</td><td>815 (446-1,513)</td><td>937 (484-1,620)</td><td>1,199 (591-2,096)</td><td>&lt;0.0001<sup>a</sup></td></tr><tr><td>Hospitalization for HF in last 12 mo</td><td>349 (18.0)</td><td>414 (20.7)</td><td>599 (30.1)</td><td>&lt;0.0001</td></tr><tr><td>Atrial fibrillation<sup>b</sup></td><td>901 (46.5)</td><td>1,013 (50.7)</td><td>1,117 (56.2)</td><td>&lt;0.0001</td></tr><tr><td>Hypertension</td><td>1,734 (89.5)</td><td>1,813 (90.7)</td><td>1,820 (91.5)</td><td>0.0258</td></tr><tr><td>Diabetes</td><td>909 (46.9)</td><td>943 (47.2)</td><td>1,050 (52.8)</td><td>0.0002</td></tr><tr><td>History of gout</td><td>116 (6.0)</td><td>97 (4.9)</td><td>157 (7.9)</td><td>0.0099</td></tr><tr><td>Antigout medication</td><td>426 (22.0)</td><td>338 (16.9)</td><td>249 (12.5)</td><td>&lt;0.0001</td></tr><tr><td>eGFR, mL/min/1.73 m²</td><td>67.5 ± 19.3</td><td>62.1 ± 18.5</td><td>52.6 ± 18.8</td><td>&lt;0.0001</td></tr><tr><td>&lt;60 mL/min/1.73 m²</td><td>670 (34.6)</td><td>947 (47.4)</td><td>1,335 (67.2)</td><td>&lt;0.0001</td></tr><tr><td>Device therapy</td><td></td><td></td><td></td><td></td></tr><tr><td>Implantable cardioverter-defibrillator<sup>c</sup></td><td>78 (4.0)</td><td>75 (3.8)</td><td>74 (3.7)</td><td>0.6225</td></tr><tr><td>Cardiac resynchronization therapy<sup>d</sup></td><td>7 (0.4)</td><td>6 (0.3)</td><td>10 (0.5)</td><td>0.4568</td></tr><tr><td>HF medication</td><td></td><td></td><td></td><td></td></tr><tr><td>Beta-blocker</td><td>1,641 (84.7)</td><td>1,744 (87.3)</td><td>1,731 (87.1)</td><td>0.0287</td></tr><tr><td>ACEI</td><td>769 (39.7)</td><td>819 (41.0)</td><td>796 (40.0)</td><td>0.8254</td></tr><tr><td>ARB without neprilysin inhibition</td><td>750 (38.7)</td><td>795 (39.8)</td><td>749 (37.7)</td><td>0.5024</td></tr><tr><td>ARNI</td><td>37 (1.9)</td><td>44 (2.2)</td><td>48 (2.4)</td><td>0.2794</td></tr><tr><td>Loop diuretics</td><td>1,082 (55.8)</td><td>1,314 (65.8)</td><td>1,615 (81.2)</td><td>&lt;0.0001</td></tr><tr><td>Thiazides diuretics</td><td>373 (19.2)</td><td>417 (20.9)</td><td>439 (22.1)</td><td>0.0287</td></tr><tr><td>MRA</td><td>602 (31.1)</td><td>772 (38.6)</td><td>844 (42.5)</td><td>&lt;0.0001</td></tr></tbody></table>

Values are mean ± SD or n (%), except as noted. Tertiles: male: T1: 5.9 mg/dL, T2: 7.5 mg/dL; female: T1: 5.4 mg/dL, T2: 6.9 mg/dL. <sup>a</sup>Based on log-transformed results.

<sup>b</sup>Defined as atrial fibrillation reported in any electrocardiogram before treatment intake or history of atrial fibrillation reported in medical history. <sup>c</sup>Implantable cardioverter defibrillator with or without cardiac resynchronization therapy. <sup>d</sup>Cardiac resynchronization therapy with or without a defibrillator.

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BMI = body mass index; eGFR = estimated glomerular filtration rate; HF = heart failure; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro-B-type natriuretic peptide; SUA = serum uric acid.
<table><caption>TABLE 2 Risk of Endpoints According to SUA Levels in the Placebo Group</caption><thead><tr><th></th><th>Events</th><th>Incidence/100 PY (95% CI)</th><th>HR (95% CI)</th><th>P Value</th><th>P Value (Trend Test)</th></tr></thead><tbody><tr><td>First HHF or CV death</td><td></td><td></td><td></td><td></td><td>0.0421</td></tr><tr><td>SUA tertile 1, Ref. (n = 975)</td><td>147 (15.1)</td><td>7.53 (6.36-8.80)</td><td></td><td></td><td></td></tr><tr><td>SUA tertile 2 (n = 966)</td><td>132 (13.7)</td><td>6.69 (5.60-7.88)</td><td>0.82 (0.65-1.04)</td><td>0.1090</td><td></td></tr><tr><td>SUA tertile 3 (n = 1,018)</td><td>226 (22.2)</td><td>11.82 (10.33-13.41)</td><td>1.23 (0.98-1.53)</td><td>0.0703</td><td></td></tr><tr><td>Time to first HHF</td><td></td><td></td><td></td><td></td><td>0.0044</td></tr><tr><td>SUA tertile 1, Ref. (n = 975)</td><td>89 (9.1)</td><td>4.56 (3.66-5.55)</td><td></td><td></td><td></td></tr><tr><td>SUA tertile 2 (n = 966)</td><td>84 (8.7)</td><td>4.26 (3.39-5.21)</td><td>0.84 (0.62-1.14)</td><td>0.2632</td><td></td></tr><tr><td>SUA tertile 3 (n = 1,018)</td><td>174 (17.1)</td><td>9.10 (7.80-10.50)</td><td>1.42 (1.08-1.86)</td><td>0.0124</td><td></td></tr><tr><td>Total number of HHF<sup>a</sup></td><td></td><td></td><td></td><td></td><td>0.0004</td></tr><tr><td>SUA tertile 1, Ref. (n = 975)</td><td>131</td><td></td><td></td><td></td><td></td></tr><tr><td>SUA tertile 2 (n = 966)</td><td>124</td><td></td><td>0.88 (0.63-1.22)</td><td>0.4370</td><td></td></tr><tr><td>SUA tertile 3 (n = 1,018)</td><td>281</td><td></td><td>1.69 (1.23-2.32)</td><td>0.0011</td><td></td></tr><tr><td>CV death</td><td></td><td></td><td></td><td></td><td>0.1420</td></tr><tr><td>SUA tertile 1, Ref. (n = 975)</td><td>76 (7.8)</td><td>3.66 (2.88-4.52)</td><td></td><td></td><td></td></tr><tr><td>SUA tertile 2 (n = 966)</td><td>66 (6.8)</td><td>3.15 (2.44-3.95)</td><td>0.87 (0.62-1.22)</td><td>0.4142</td><td></td></tr><tr><td>SUA tertile 3 (n = 1,018)</td><td>100 (9.8)</td><td>4.62 (3.76-5.57)</td><td>1.26 (0.91-1.73)</td><td>0.1590</td><td></td></tr><tr><td>All-cause mortality</td><td></td><td></td><td></td><td></td><td>0.1314</td></tr><tr><td>SUA tertile 1, Ref. (n = 975)</td><td>132 (13.5)</td><td>6.35 (5.31-7.48)</td><td></td><td></td><td></td></tr><tr><td>SUA tertile 2 (n = 966)</td><td>114 (11.8)</td><td>5.44 (4.49-6.48)</td><td>0.86 (0.67-1.11)</td><td>0.2384</td><td></td></tr><tr><td>SUA tertile 3 (n = 1,018)</td><td>176 (17.3)</td><td>8.14 (6.98-9.38)</td><td>1.19 (0.93-1.52)</td><td>0.1573</td><td></td></tr><tr><td>Clinically relevant hyperuricemia</td><td></td><td></td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>SUA tertile 1, Ref. (n = 774)</td><td>14 (1.8)</td><td>0.97 (0.53-1.54)</td><td></td><td></td><td></td></tr><tr><td>SUA tertile 2 (n = 805)</td><td>40 (5.0)</td><td>2.67 (1.90-3.55)</td><td>2.56 (1.39-4.72)</td><td>0.0026</td><td></td></tr><tr><td>SUA tertile 3 (n = 879)</td><td>176 (20.0)</td><td>12.93 (11.09-14.91)</td><td>10.50 (5.98-18.41)</td><td>&lt;0.0001</td><td></td></tr></tbody></table>

Values are n (%), unless otherwise indicated. Based on a Cox regression model with terms for age, baseline eGFR, and baseline LVEF as linear covariates and region, diabetes status, sex, and baseline uric acid as fixed factors. aJoint Frailty Model including the same factors as for the Cox regression model.

CV = cardiovascular; HHF = heart failure hospitalization; PY = patient-years; Ref. = Reference; other abbreviations as in Table 1.

granted by major regulatory authorities. Researchers may use the link¹⁵ to request access to study data.

## RESULTS

**BASELINE CHARACTERISTICS.** Of the 5,988 patients randomized in the EMPEROR preserved trial, 5,924 patients (98.9%) with a baseline assessment of SUA were included in this analysis. Mean SUA was 6.86 ± 1.93 mg/dL in men and 6.35 ± 1.94 mg/dL in women. Hyperuricemia was observed in 49% of patients. The treatment groups were comparable for baseline SUA (placebo 6.65 ± 1.95 mg/dL vs empagliflozin 6.62 ± 1.96 mg/dL) and for prevalence of hyperuricemia (placebo 48.7% vs empagliflozin 48.3%).

Clinical characteristics of patients grouped in tertiles of SUA are shown in Table 1. Using gender-specific tertiles, the sex distribution was similar in all tertiles. Elevated SUA (highest tertile mean SUA 8.8 ± 1.4 mg/dL) was associated with more advanced severity of HF as indicated by NYHA functional class,

NT-proBNP concentration, or the frequency of HHF in the last 12 months. Certain comorbidities (ie, atrial fibrillation, hypertension, DM, impaired renal function, and obesity) were more prevalent among patients with elevated SUA. The use of diuretic agents and mineralocorticoid receptor antagonists increased as SUA increased.

**ASSOCIATION OF URIC ACID WITH CLINICAL OUTCOMES WITHIN PLACEBO.** Elevated SUA (highest tertile) was associated with a higher risk for the primary endpoint (HR: 1.23 [95% CI: 0.98-1.53]; *P* = 0.07) and an increased risk of hospitalization (first-time HHF HR: 1.42 [95% CI: 1.08-1.86]; *P* = 0.01; recurrent HHF: HR: 1.69 [95% CI: 1.23-2.32]; *P* < 0.01, as compared with the lowest tertile) (Table 2). When analyzed by tertiles, elevated SUA was not associated with increased mortality (cardiovascular and all-cause mortality). When SUA was analyzed as a continuous variable, a J-shaped relationship was observed with adverse outcome being associated with higher SUA levels, but
FIGURE 1 Relationship Between Baseline SUA and Outcomes

<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

Relationship between baseline serum uric acid (SUA) as continuous variable and outcomes in the placebo arm of the EMPEROR-Preserved study (EMPagliflozin outcome Trial in Patients With chronic heart Failure With Preserved Ejection Fraction) cohort (n = 2,959). HRs (solid gray line) with 95% CIs are shown for the first hospitalization for heart failure (HHF) or cardiovascular (CV) death (A), first-time HHF (B), cardiovascular death (C), and all-cause mortality (D), using cubic splines (4 knots), multivariate adjusted analysis.

not with low SUA levels, for all endpoints (Figure 1). Cumulative incidence curves for the composite primary endpoint, first hospitalization and CV death, between SUA tertiles are shown in Supplemental Figure 1.

The rate of clinically relevant hyperuricemic events in the placebo-treated patients was more than 10 times higher in the highest SUA tertile, as compared with the lowest SUA tertile (incidence per 100 patient-years: 12.9 [95% CI: 11.1-14.9] vs 1.0 [95% CI: 0.5-1.5]) (Table 2).

**EFFECT OF EMPAGLIFLOZIN ON URIC ACID LEVELS AND CLINICAL HYPERURICEMIC EVENTS.** Treatment with empagliflozin resulted in a significant reduction of SUA within 4 weeks of therapy (mean reduction vs placebo: -0.99 ± 0.03 mg/dL; *P* < 0.0001) (Figure 2), and the magnitude of the treatment effect remained stable throughout the treatment period. The reduction of SUA levels at week 4 in patients treated with empagliflozin was more pronounced with higher

baseline SUA (adjusted mean change from baseline ± SE; tertile 1: -0.77 ± 0.05 mg/dL, tertile 2: -1.00 ± 0.05 mg/dL, tertile 3: -1.18 ± 0.05 mg/dL; *P* value for trend <0.0001). The SUA-lowering effect of empagliflozin was consistent across prespecified subgroups, including patients with severely impaired kidney function, although the magnitude of SUA reduction was smaller in patients with more advanced impairment of kidney function (trend test for eGFR subgroups: *P* < 0.0001) (Table 3). Further, an interaction was observed between the degree of SUA change and comorbidity of DM where the reduction of SUA was more pronounced in patients without DM (*P* < 0.0001). A subanalysis was performed to identify characteristics of patients treated with empagliflozin with no or ineffective SUA reduction (nonresponders, defined as a reduction of SUA of <0.2 mg/dL) vs patients with more pronounced SUA reduction from baseline to week 4. Results are presented in Supplemental Table 1. A significant difference was observed between nonresponders and responders for
<figure><img src="image_6.png" /><figcaption>FIGURE 2 Treatment Effect of Empagliflozin or Placebo on SUA Levels</figcaption></figure>

Treatment effect of empagliflozin or placebo on serum uric acid (SUA) levels, reduction from baseline.

the presence of DM comorbidity and impaired renal function. There was, however, no difference between nonresponders and responders regarding measures of HF severity (including NYHA functional class, NT-proBNP, LVEF, HF disease duration, HHF in the last 12 months, or medical treatment for HF). There was also no difference for gout treatment or history of gout between nonresponders and responders.

Treatment with empagliflozin reduced the risk of clinically relevant hyperuricemic events by 38% (HR: 0.62 [95% CI: 0.51-0.76]; *P* < 0.0001) (Figure 3). Analyzing the components of clinically relevant hyperuricemia separately showed that the risk reduction was comparable for both individual components (initiation of antihyperuricemic medication HR: 0.62 [95% CI: 0.50-0.76]; *P* < 0.0001; gout events HR: 0.60 [95% CI: 0.43-0.83]; *P* = 0.0024) (Supplemental Table 2). The effect of empagliflozin to reduce hyperuricemic events was constant when the cohort was stratified for baseline SUA levels (Figure 4) or for a history of gout (Supplemental Table 3).

### EFFICACY OF EMPAGLIFLOZIN IN RELATION TO SUA LEVELS AND DYNAMICS.
The beneficial effect of empagliflozin on the primary composite endpoint and on the risk of HHF was independent of baseline SUA, and the magnitude of the effect was comparable

across the SUA tertiles (all trend *P* > 0.1) (Figure 4). When SUA at baseline was included in the Cox model as a continuous variable, the beneficial effect of empagliflozin on the primary composite outcome was independent of SUA (HR: 0.79 [95% CI: 0.69-0.90]; *P* < 0.001).

A potential contributing effect from the SUA-lowering characteristic of empagliflozin (within 4 weeks after treatment start) for the clinical outcome benefit of empagliflozin was observed using a landmark analysis, considering only events occurring from week 4 onwards (n = 5,696, 96.2% of the entire study population). The change in SUA levels showed an incremental association of SUA reduction with the treatment effect for the primary endpoint (Supplemental Table 4).

### DISCUSSION

The main findings from this study were: 1) in patients with HFpEF, hyperuricemia was a common finding (prevalence 49%), and elevated SUA was associated with a higher prevalence of comorbidities including atrial fibrillation, hypertension, DM, impaired renal function, and obesity; 2) elevated SUA levels were associated with more advanced HF in terms of NYHA
<table><caption>TABLE 3 The Treatment Effect of Empagliflozin to Lower SUA in Patient Subgroups</caption><thead><tr><th rowspan="2"></th><th colspan="2">Empagliflozin 10 mg</th><th colspan="2">Placebo</th><th rowspan="2">Adjusted Mean Difference (95% CI)<sup>b</sup></th><th rowspan="2">Interaction P Value</th></tr><tr><th>Baseline</th><th>Change at Wk 4<sup>a</sup></th><th>Baseline</th><th>Change at Wk 4<sup>a</sup></th></tr></thead><tbody><tr><td>History of hypertension</td><td></td><td></td><td></td><td></td><td></td><td>0.5798</td></tr><tr><td>Yes</td><td>6.63 ± 0.04</td><td>-1.03 ± 0.02</td><td>6.66 ± 0.04</td><td>-0.04 ± 0.02</td><td>-0.98 (-1.04 to -0.93)</td><td></td></tr><tr><td>No</td><td>6.59 ± 0.13</td><td>-1.14 ± 0.07</td><td>6.47 ± 0.11</td><td>-0.10 ± 0.06</td><td>-1.04 (-1.22 to -0.86)</td><td></td></tr><tr><td>Diabetes</td><td></td><td></td><td></td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>Diabetic</td><td>6.77 ± 0.05</td><td>-0.83 ± 0.03</td><td>6.77 ± 0.05</td><td>-0.04 ± 0.03</td><td>-0.80 (-0.88 to -0.72)</td><td></td></tr><tr><td>Not diabetic</td><td>6.49 ± 0.05</td><td>-1.23 ± 0.03</td><td>6.52 ± 0.05</td><td>-0.06 ± 0.03</td><td>-1.17 (-1.25 to -1.09)</td><td></td></tr><tr><td>Age, y</td><td></td><td></td><td></td><td></td><td></td><td>0.7081</td></tr><tr><td>&lt;65</td><td>6.75 ± 0.09</td><td>-1.02 ± 0.05</td><td>6.82 ± 0.08</td><td>-0.01 ± 0.04</td><td>-1.01 (-1.13 to -0.88)</td><td></td></tr><tr><td>≥65</td><td>6.59 ± 0.04</td><td>-1.04 ± 0.02</td><td>6.60 ± 0.04</td><td>-0.06 ± 0.02</td><td>-0.98 (-1.04 to -0.92)</td><td></td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td><td>0.4720</td></tr><tr><td>Male</td><td>6.86 ± 0.05</td><td>-1.05 ± 0.03</td><td>6.88 ± 0.05</td><td>-0.05 ± 0.03</td><td>-1.01 (-1.08 to -0.93)</td><td></td></tr><tr><td>Female</td><td>6.33 ± 0.05</td><td>-1.02 ± 0.03</td><td>6.36 ± 0.05</td><td>-0.05 ± 0.03</td><td>-0.97 (-1.05 to -0.88)</td><td></td></tr><tr><td>Race</td><td></td><td></td><td></td><td></td><td></td><td>0.0645</td></tr><tr><td>White</td><td>6.61 ± 0.04</td><td>-1.02 ± 0.03</td><td>6.65 ± 0.04</td><td>-0.01 ± 0.03</td><td>-1.01 (-1.07 to -0.95)</td><td></td></tr><tr><td>Black</td><td>6.96 ± 0.19</td><td>-0.87 ± 0.10</td><td>6.92 ± 0.17</td><td>0.07 ± 0.10</td><td>-0.94 (-1.21 to -0.67)</td><td></td></tr><tr><td>Asian</td><td>6.65 ± 0.10</td><td>-1.26 ± 0.09</td><td>6.69 ± 0.09</td><td>-0.24 ± 0.09</td><td>-1.01 (-1.16 to -0.87)</td><td></td></tr><tr><td>Other including mixed race</td><td>6.42 ± 0.16</td><td>-0.81 ± 0.09</td><td>6.36 ± 0.14</td><td>-0.12 ± 0.08</td><td>-0.69 (-0.92 to -0.47)</td><td></td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td></td><td></td><td></td><td></td><td></td><td>0.2584</td></tr><tr><td>&lt;30</td><td>6.40 ± 0.05</td><td>-1.01 ± 0.03</td><td>6.44 ± 0.05</td><td>-0.05 ± 0.03</td><td>-0.96 (-1.03 to -0.88)</td><td></td></tr><tr><td>≥30</td><td>6.89 ± 0.05</td><td>-1.07 ± 0.03</td><td>6.89 ± 0.05</td><td>-0.05 ± 0.03</td><td>-1.02 (-1.11 to -0.94)</td><td></td></tr><tr><td>eGFR, mL/min/1.73 m<sup>2</sup></td><td></td><td></td><td></td><td></td><td></td><td>&lt;0.0001<sup>c</sup></td></tr><tr><td>≥90</td><td>5.62 ± 0.11</td><td>-0.94 ± 0.07</td><td>6.01 ± 0.11</td><td>0.08 ± 0.07</td><td>-1.02 (-1.21 to -0.82)</td><td></td></tr><tr><td>60 to &lt;90</td><td>6.19 ± 0.05</td><td>-1.13 ± 0.03</td><td>6.14 ± 0.05</td><td>-0.01 ± 0.03</td><td>-1.12 (-1.21 to -1.04)</td><td></td></tr><tr><td>45 to &lt;60</td><td>6.77 ± 0.06</td><td>-1.04 ± 0.04</td><td>6.83 ± 0.07</td><td>-0.08 ± 0.04</td><td>-0.96 (-1.06 to -0.85)</td><td></td></tr><tr><td>30 to &lt;45</td><td>7.41 ± 0.09</td><td>-0.95 ± 0.05</td><td>7.36 ± 0.09</td><td>-0.14 ± 0.05</td><td>-0.81 (-0.94 to -0.68)</td><td></td></tr><tr><td>&lt;30</td><td>8.09 ± 0.19</td><td>-0.74 ± 0.09</td><td>8.30 ± 0.20</td><td>-0.12 ± 0.09</td><td>-0.61 (-0.86 to -0.37)</td><td></td></tr><tr><td>Cause of HF</td><td></td><td></td><td></td><td></td><td></td><td>0.4303</td></tr><tr><td>Ischemic</td><td>6.51 ± 0.06</td><td>-1.00 ± 0.03</td><td>6.56 ± 0.06</td><td>-0.04 ± 0.03</td><td>-0.96 (-1.05 to -0.86)</td><td></td></tr><tr><td>Nonischemic</td><td>6.68 ± 0.05</td><td>-1.06 ± 0.03</td><td>6.69 ± 0.04</td><td>-0.05 ± 0.02</td><td>-1.00 (-1.07 to -0.94)</td><td></td></tr><tr><td>Baseline NYHA functional class</td><td></td><td></td><td></td><td></td><td></td><td>0.1513</td></tr><tr><td>I/II</td><td>6.49 ± 0.04</td><td>-1.04 ± 0.02</td><td>6.55 ± 0.04</td><td>-0.07 ± 0.02</td><td>-0.97 (-1.03 to -0.91)</td><td></td></tr><tr><td>III/IV</td><td>7.18 ± 0.10</td><td>-1.04 ± 0.05</td><td>7.10 ± 0.10</td><td>0.03 ± 0.05</td><td>-1.08 (-1.20 to -0.95)</td><td></td></tr><tr><td>Baseline use of MRA</td><td></td><td></td><td></td><td></td><td></td><td>0.1593</td></tr><tr><td>No</td><td>6.47 ± 0.04</td><td>-1.03 ± 0.03</td><td>6.52 ± 0.05</td><td>-0.01 ± 0.03</td><td>-1.02 (-1.09 to -0.95)</td><td></td></tr><tr><td>Yes</td><td>6.87 ± 0.06</td><td>-1.05 ± 0.03</td><td>6.86 ± 0.06</td><td>-0.11 ± 0.03</td><td>-0.94 (-1.03 to -0.85)</td><td></td></tr><tr><td>Baseline use of loop diuretics</td><td></td><td></td><td></td><td></td><td></td><td>0.9432</td></tr><tr><td>No</td><td>5.94 ± 0.05</td><td>-0.98 ± 0.04</td><td>5.93 ± 0.05</td><td>0.01 ± 0.04</td><td>-0.99 (-1.09 to -0.89)</td><td></td></tr><tr><td>Yes</td><td>6.95 ± 0.05</td><td>-1.07 ± 0.02</td><td>6.99 ± 0.05</td><td>-0.08 ± 0.02</td><td>-0.99 (-1.05 to -0.92)</td><td></td></tr></tbody></table>

Values are mean ± SE, except as noted. <sup>a</sup>Models of adjusted mean change (SE) include age, baseline eGFR, and baseline LVEF as linear covariates, and region, diabetes status, sex, week reachable, visit by treatment by subgroup interaction (trend test), and baseline uric acid by visit interaction as fixed effects. Age, baseline eGFR, diabetes status, and sex were omitted as a factor if considered as a subgroup.

<sup>b</sup>Treatment comparison all P < 0.0001. <sup>c</sup>Trend test.

Abbreviations as in Table 1.

functional class and NT-proBNP levels, and with higher risk of HHF; 3) in contrast to patients with HF with reduced ejection fraction,<sup>2,10</sup> elevated SUA levels were not associated with increased mortality; 4) treatment with empagliflozin induced an early and sustained decrease in SUA and resulted in the additional clinical benefit of reduced hyperuricemic events; 5) the beneficial effect of empagliflozin to

reduce the risk of HF hospitalization was seen across the entire spectrum of SUA levels; and 6) the SUA-lowering effect of empagliflozin might not be fully explained by a glycosuric or uricosuric effect of the drug.

SUA levels decreased rapidly after initiating therapy with empagliflozin (ie, at 4 weeks) and remained low throughout the treatment period. This durable
<figure><img src="image_7.png" /><figcaption>FIGURE 3 Cumulative Incidence of Clinically Relevant Hyperuricemic Events for Patients Treated With Empagliflozin vs Placebo</figcaption></figure>

Clinically relevant hyperuricemia is defined as the composite episodes of acute gout, gouty arthritis, or the initiation of treatment with serum uric acid-lowering therapy (xanthine oxidase inhibitors, uricosuric agents, or colchicine).

effect to reduce SUA is consistent with previous studies.¹⁰,¹⁶ This SUA-lowering effect was seen across prespecified subgroups, including patients with severely impaired kidney function, although somewhat attenuated with advanced impairment of kidney function. Similar effects to reduce SUA and the need of SUA-lowering treatments have been observed with other SGLT2 inhibitors, which further supports the conclusion for a class effect of this drug class with a clinically meaningful treatment benefit to reduce SUA and to alleviate clinical gout.¹⁷⁻²⁰

Interestingly, we further observed an interaction effect between SUA lowering and presence of DM, where a stronger SUA-lowering effect was observed in patients without DM. This is an interesting observation as one mechanism to explain the SUA lowering by SGLT2 inhibitors has been assumed to be an increased uricosuric effect secondary to the induced glucosuria and a decrease in renal urate reabsorption in the proximal convoluted tubule via glucose

transporter 9b (GLUT9b).²¹,²² As the glycosuric effect of empagliflozin is inevitably smaller in nondiabetic than in diabetic individuals,²³ a smaller effect on SUA reduction may be expected in nondiabetic patients. By contrast, a stronger reduction of SUA in nondiabetic patients compared with diabetic patients was observed in this study. Furthermore, empagliflozin lowered SUA as well in patients with markedly impaired renal function, in whom a meaningful uricosuric effect is not typically seen. These findings confirm similar observations from previous studies¹⁰ and provide further evidence that the uric acid-lowering effect of empagliflozin is not primarily driven by enhanced renal uric acid excretion. This supports the concept that the SUA-lowering effect with empagliflozin treatment may result from attenuated SUA generation.⁶,⁷

Taken together, these observations support the concept that although renal excretion has a contributing role for SUA levels in general, in
<table><caption>FIGURE 4 The Effect of Empagliflozin vs Placebo on Major Outcomes by Tertile SUA Levels at Baseline</caption><thead><tr><th rowspan="2">Endpoint</th><th colspan="2">n with event/N analyzed</th><th rowspan="2">HR (95% CI)</th><th rowspan="2">p-value<br>for trend</th></tr><tr><th>Empagliflozin<br>10 mg</th><th>Placebo</th></tr></thead><tbody><tr><td><strong>First HHF or CV death</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>415/2997</td><td>511/2991</td><td>0.79 [0.69, 0.90]</td><td rowspan="3">0.237</td></tr><tr><td>SUA tertile 1</td><td>96/963</td><td>147/975</td><td>0.65 [0.50, 0.84]</td></tr><tr><td>SUA tertile 2</td><td>130/1032</td><td>132/966</td><td>0.92 [0.72, 1.17]</td></tr><tr><td>SUA tertile 3</td><td>184/970</td><td>226/1018</td><td>0.81 [0.67, 0.98]</td><td></td></tr><tr><td><strong>First HHF</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>259/2997</td><td>352/2991</td><td>0.71 [0.60, 0.83]</td><td rowspan="3">0.549</td></tr><tr><td>SUA tertile 1</td><td>59/963</td><td>89/975</td><td>0.65 [0.47, 0.90]</td></tr><tr><td>SUA tertile 2</td><td>68/1032</td><td>84/966</td><td>0.75 [0.54, 1.03]</td></tr><tr><td>SUA tertile 3</td><td>129/970</td><td>174/1018</td><td>0.74 [0.59, 0.93]</td><td></td></tr><tr><td><strong>Total HHF*</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>407</td><td>541</td><td>0.73 [0.61, 0.88]</td><td rowspan="3">0.619</td></tr><tr><td>SUA tertile 1</td><td>92</td><td>131</td><td>0.67 [0.47, 0.95]</td></tr><tr><td>SUA tertile 2</td><td>99</td><td>124</td><td>0.82 [0.58, 1.16]</td></tr><tr><td>SUA tertile 3</td><td>213</td><td>281</td><td>0.75 [0.56, 0.99]</td><td></td></tr><tr><td><strong>CV death</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>219/2997</td><td>244/2991</td><td>0.91 [0.76, 1.09]</td><td rowspan="3">0.574</td></tr><tr><td>SUA tertile 1</td><td>54/963</td><td>76/975</td><td>0.74 [0.52, 1.05]</td></tr><tr><td>SUA tertile 2</td><td>78/1032</td><td>66/966</td><td>1.13 [0.82, 1.57]</td></tr><tr><td>SUA tertile 3</td><td>85/970</td><td>100/1018</td><td>0.88 [0.66, 1.17]</td><td></td></tr><tr><td><strong>All-cause mortality</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>422/2997</td><td>427/2991</td><td>1.00 [0.87, 1.15]</td><td rowspan="3">0.841</td></tr><tr><td>SUA tertile 1</td><td>117/963</td><td>132/975</td><td>0.94 [0.73, 1.21]</td></tr><tr><td>SUA tertile 2</td><td>132/1032</td><td>114/966</td><td>1.11 [0.86, 1.43]</td></tr><tr><td>SUA tertile 3</td><td>169/970</td><td>176/1018</td><td>0.98 [0.80, 1.22]</td><td></td></tr><tr><td><strong>Incidence of clinically relevant hyperuricemia</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>150/2482</td><td>232/2484</td><td>0.62 [0.51, 0.76]</td><td rowspan="3">0.712</td></tr><tr><td>SUA tertile 1</td><td>8/738</td><td>14/774</td><td>0.61 [0.26, 1.45]</td></tr><tr><td>SUA tertile 2</td><td>29/855</td><td>40/805</td><td>0.69 [0.43, 1.12]</td></tr><tr><td>SUA tertile 3</td><td>112/859</td><td>176/879</td><td>0.59 [0.47, 0.75]</td><td></td></tr></tbody></table>

Tertiles: male: tertile 1 <5.9 mg/dL, tertile 2 ≥5.9 and <7.5 mg/dL, tertile 3 ≥7.5 mg/dL; female: tertile 1 <5.4 mg/dL, tertile 2 ≥5.4 and <6.9 mg/dL, tertile 3 ≥6.9 mg/dL. Cox regression models included age, left ventricular ejection fraction, estimated glomerular filtration rate (eGFR) (CKD-EPI), sex, geographical region, and diabetes status (overall), and uric acid subgroup and uric acid subgroup × treatment interaction (subgroup analyses). *Number of events. Abbreviations as in Figure 1.

patients with HF, other mechanisms than modifying renal excretion may be determining factors of urate metabolism²⁴,²⁵ and a more direct metabolic effect of empagliflozin may account for the SUA reduction.²⁶ These findings are in accord with the notion of SUA being a biomarker of increased catabolism, inflammation, and oxidative stress.⁶,²⁷,²⁸ Moreover, given the potential association of SUA lowering and the clinical outcome benefit of empagliflozin, we provide further evidence to the emerging concept of an effect of SGLT2 inhibitors

treatment to exert protective anticatabolic and cytoprotective effects.²⁹

Notably, the uric acid-generating enzyme xanthine oxidase is activated in HF as a characteristic pathophysiologic feature indicating catabolic, hypoxic, or inflammatory conditions.⁷ Xanthine oxidase, in turn, is a potent source of reactive oxygen species,⁵ and elevated levels of SUA in HF have been recognized as a marker of catabolism, increased oxidative stress, and impaired myocardial metabolic and contractile function.⁶ It may therefore be intriguing to
CENTRAL ILLUSTRATION Clinical Effect of Empagliflozin to Reduce Serum Uric Acid and Relation to
Outcome in Patients With Heart Failure With Preserved Ejection Fraction

<figure><img src="image_8.png" /></figure>

Treatment Effect on Major Outcomes by Tertile SUA at Baseline

<figure><img src="image_9.png" /></figure>

Doehner W, et al. JACC Heart Fail. 2024;■(■):■-■.

<footnote>*Composite of cardiovascular death or hospitalization for HF. †Clinically relevant hyperuricaemia is defined as the composite episodes of acute gout, gouty arthritis or the initiation of treatment with SUA lowering therapy (xanthine oxidase inhibitors, uricosuric agents or colchicine. ‡Number of events.
CV = cardiovascular; EMPEROR-Preserved = EMPagliflozin outcome Tial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction;
HF = heart failure; HHF = hospitalization for heart failure; SUA = serum uric acid.</footnote>
investigate whether the early rapid SUA-lowering effect of empagliflozin might be a useful biomarker of the efficacy of SGLT2 inhibitors.

**STUDY LIMITATIONS.** Our study is a post hoc analysis of a large clinical trial database, and the inevitable limitations of such analyses apply. Despite multivariate adjustments for available covariables, we could not adjust for baseline differences for unmeasured variables. The clinical hyperuricemic events were not centrally adjudicated but were investigator-reported events. Analyses on changes of SUA and interaction with DM or kidney function are subgroup analyses and, despite some biological plausibility, may be viewed with caution until confirmation in subsequent studies.

Some previous studies in patients with HF³⁰ or DM¹² have observed a higher prevalence of high SUA levels in men. Notably, these earlier studies reported on SUA subgroups combining male and female patients, and did not account for the physiologically lower SUA levels in women than in men. In our study, we identified tertile cutpoints separately for men and women based on sex-dependent distribution of SUA. Using this approach, the prevalence of hyperuricemia was not dependent on sex, a finding in accord with other studies using a similar approach.¹⁰

## CONCLUSIONS

The study showed that hyperuricemia is a common comorbidity in patients with HFpEF and is related to increased cardiovascular comorbidity, advanced severity of HF, and increased risk of hospitalization (Central Illustration). Treatment with empagliflozin resulted in a rapid and sustained reduction of SUA and a decreased incidence of clinical hyperuricemic events. The SUA-lowering effect of SGLT2 inhibitors in HF is not explained by uricosuric effects alone and supports the concept of additional favorable effects of empagliflozin on cellular metabolism and oxidative stress. Further studies are warranted to establish whether the SUA-lowering effect of SGLT2 inhibitors may act as a potential biomarker of reduced oxidative stress in patients with HFpEF.

## FUNDING SUPPORT AND AUTHOR DISCLOSURES

This study was funded by Boehringer Ingelheim and Eli Lilly and Company Alliance. Graphical assistance was provided by 7.4 Ltd, HCG, and was funded by Boehringer Ingelheim. Dr Doehner has received consulting fees from Boehringer Ingelheim related to work on clinical events committee during the conduct of the study and personal fees from Aimediq, Bayer, Boehringer Ingelheim, Medtronic, Vifor Pharma and research support from EU (Horizon 2020), German ministry of Education and Research, German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. Dr Anker has received grants and personal fees from Vifor Int and Abbott Vascular; and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Medtronic, Novartis, Occlutech, Servier, V-Wave, and Vifor Int. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Filippatos has received lecture fees and/or committee member contributions in clinical trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and Boehringer Ingelheim; and research support from the European Union. Dr Coats has received fees from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards, Eli Lilly, Menarini, Novartis, Servier, Vifor, Abbott, Actimed, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Impulse Dynamics, Respicardia, and Viatris. Dr Ferreira has received research support from Boehringer Ingelheim, Novartis, and AstraZeneca through the University of Porto. Drs Henrichmoeller and Brueckmann are employees of Boehringer Ingelheim International. Ms Schueler is an employee of mainanalytics GmbH contracted by Boehringer Ingelheim. Dr Pocock has received consultancy fees from Boehringer Ingelheim. Dr Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott, Applied Therapeutics, HeartFlow Inc, Innolife, and Roche Diagnostics; has received consulting fees from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Jana Care, Janssen, Novartis, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Pfizer, and Takeda. Dr Packer has received personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra, outside of the submitted work.

**ADDRESS FOR CORRESPONDENCE:** Dr Wolfram Doehner, Berlin Institute of Health Center for Regenerative Therapies, Charité Universitätsmedizin, Augustenburger Platz 1, 13353 Berlin, Germany.
E-mail: wolfram.doehner@charite.de.
PERSPECTIVES

**COMPETENCY IN MEDICAL KNOWLEDGE:** Hyperuricemia is a common clinical characteristic in patients with HFpEF and reflects a facet of metabolic abnormalities that are typical for HFpEF. Hyperuricemia in patients with HFpEF may reflect an increased level of oxidative stress.

COMPETENCY IN PATIENT CARE AND

**PROCEDURAL SKILLS:** Hyperuricemia is a common comorbidity and complication in patients with HF, being associated with advanced severity of HF, increased risk of hospitalization for HF, and increased incidence of clinical

hyperuricemic events. Treatment with empagliflozin has shown to reduce serum uric acid levels and hyperuricemic events. This effect is considered a class effect of SGLT2 inhibitors.

**TRANSLATIONAL OUTLOOK:** The observed SUA-lowering effect suggests a beneficial effect on cellular metabolism and oxidative stress of SGLT2 inhibitors in patients with HF. If confirmed in future studies, the SUA-lowering effect of SGLT2 inhibitors may act as a potential biomarker of reduced oxidative stress in patients with HFpEF.

REFERENCES

1. Vaduganathan M, Greene SJ, Ambrosy AP, et al. Relation of serum uric acid levels and outcomes among patients hospitalized for worsening heart failure with reduced ejection fraction (from the efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan trial). *Am J Cardiol.* 2014;114:1713-1721.

2. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. *Circulation.* 2003;107:1991-1997.

3. Huang H, Huang B, Li Y, et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. *Eur J Heart Fail.* 2014;16:15-24.

4. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthineoxidase and extracellular superoxide dismutase. *Circulation.* 2002;106:3073-3078.

5. Doehner W, Landmesser U. Xanthine oxidase and uric acid in cardiovascular disease: clinical impact and therapeutic options. *Semin Nephrol.* 2011;31:433-440.

6. Packer M. Uric acid is a biomarker of oxidative stress in the failing heart: lessons learned from trials with allopurinol and SGLT2 inhibitors. *J Card Fail.* 2020;26:977-984.

7. Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure. The myocardial and systemic perspective. *J Am Coll Cardiol.* 2014;64:1388-1400.

8. Cicero AF, Rosticci M, Parini A, Baronio C, D'Addato S, Borghi C. Serum uric acid is inversely proportional to estimated stroke volume and cardiac output in a large sample of pharmacologically

untreated subjects: data from the Brisighella Heart Study. *Intern Emerg Med.* 2014;9:655-660.

9. Ouchi M, Oba K, Kaku K, et al. Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin. *Diabetes Obes Metab.* 2018;20:1061-1065.

10. Doehner W, Anker SD, Butler J, et al. Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. *Eur Heart J.* 2022;43:3435-3446.

11. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. *Diabetes Care.* 2018;41:356-363.

12. Verma S, Ji Q, Bhatt DL, et al. Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: a subanalysis of EMPA-REG OUTCOME. *Diabetes Obes Metab.* 2020;22:1207-1214.

13. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. *N Engl J Med.* 2021;385:1451-1461.

14. Anker SD, Butler J, Filippatos GS, et al. Evaluation of the effects of sodium-glucose cotransporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. *Eur J Heart Fail.* 2019;21:1279-1287.

15. Vivli A. Global Clinical Research Data Sharing Platform. Accessed September 24, 2024. https://vivli.org

16. Zanchi A, Burnier M, Muller ME, et al. Acute and chronic effects of SGLT2 inhibitor empagliflozin on renal oxygenation and blood pressure

control in nondiabetic normotensive subjects: a randomized, placebo-controlled trial. *J Am Heart Assoc.* 2020;9:e016173. https://doi.org/10.1161/JAHA.119.016173

17. McDowell K, Welsh P, Docherty KF, et al. Dapagliflozin reduces uric acid concentration, an independent predictor of adverse outcomes in DAPA-HF. *Eur J Heart Fail.* 2022;24:1066-1076.

18. Hu X, Yang Y, Hu X, et al. Effects of sodium-glucose cotransporter 2 inhibitors on serum uric acid in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. *Diabetes Obes Metab.* 2022;24:228-238.

19. Butt JH, Docherty KF, Claggett BL, et al. Association of dapagliflozin use with clinical outcomes and the introduction of uric acid-lowering therapy and colchicine in patients with heart failure with and without gout: a patient-level pooled meta-analysis of DAPA-HF and DELIVER. *JAMA Cardiol.* 2023;8:386-393.

20. Banerjee M, Pal R, Maisnam I, Chowdhury S, Mukhopadhyay S. Serum uric acid lowering and effects of sodium-glucose cotransporter-2 inhibitors on gout: a meta-analysis and meta-regression of randomized controlled trials. *Diabetes Obes Metab.* 2023;25(9):2697-2703. https://doi.org/10.1111/dom.15157

21. Chino Y, Samukawa Y, Sakai S, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. *Biopharm Drug Dispos.* 2014;35:391-404.

22. Bailey CJ. Uric acid and the cardio-renal effects of SGLT2 inhibitors. *Diabetes Obes Metab.* 2019;21:1291-1298.

23. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to
sodium-glucose cotransporter 2 inhibition in sub-
jects without diabetes and patients with type 2
diabetes. *Diabetes*. 2016;65:1190-1195.

24. Doehner W, Jankowska EA, Springer J, Lainscak M, Anker SD. Uric acid and xanthine oxidase in heart failure - emerging data and therapeutic implications. *Int J Cardiol*. 2016;213:15-19.

25. Packer M. Hyperuricemia and gout reduction by SGLT2 inhibitors in diabetes and heart failure. *J Am Coll Cardiol*. 2024;83:371-381.

26. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. *Nat Rev Cardiol*. 2020;17:761-772.

27. Díaz-Rodríguez E, Agra RM, Fernández ÁL, et al. Effects of dapagliflozin on human epicardial

adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. *Cardiovasc Res*. 2018;114:336-346.

28. Hasan R, Lasker S, Hasan A, et al. Canagliflozin attenuates isoprenaline-induced cardiac oxidative stress by stimulating multiple antioxidant and anti-inflammatory signaling pathways. *Sci Rep*. 2020;10:14459.

29. Packer M. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism. *Nat Rev Cardiol*. 2023;20(7):443-462.
https://doi.org/10.1038/s41569-022-00824-4

30. Mogensen UM, Køber L, Jhund PS, et al, PARADIGM-HF Investigators and Committees.

Sacubitril/valsartan reduces serum uric acid con-
centration, an independent predictor of adverse
outcomes in PARADIGM-HF. *Eur J Heart Fail.*
2018;20:514-522.

**KEY WORDS** empagliflozin, heart failure with preserved ejection fraction, hospitalization, metabolism, outcome, uric acid

**APPENDIX** For supplemental tables and a figure, please see the online version of this paper.