# Finerenone according to insulin resistance in heart failure: Insights from the FINEARTS - HF trial

John W Ostrominski, Brian L Claggett, Akshay S Desai, Pardeep S Jhund, Carolyn S.P. Lam, Michele Senni, Sanjiv J Shah, Adriaan A Voors, Faiez Zannad, Bertram Pitt, et al.

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John W Ostrominski, Brian L Claggett, Akshay S Desai, Pardeep S Jhund, Carolyn S.P. Lam, et al.. Finerenone according to insulin resistance in heart failure: Insights from the FINEARTS - HF trial. European Journal of Heart Failure, 2025, 10.1002/ejhf.70034 . hal-05247281

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# Finerenone according to insulin resistance in heart failure: Insights from the FINEARTS-HF trial

John W. Ostrominski<fnref n="1" />●, Brian L. Claggett<fnref n="1" />, Akshay S. Desai<fnref n="1" />, Pardeep S. Jhund², Carolyn S.P. Lam³, Michele Senni⁴, Sanjiv J. Shah⁵, Adriaan A. Voors⁶, Faiez Zannad⁷, Bertram Pitt⁸, Katja Rohwedder⁹, Meike Brinker¹⁰, Patrick Schloemer¹¹, John J.V. McMurray², Scott D. Solomon<fnref n="1" />, and Muthiah Vaduganathan<fnref n="1" />*

Received 29 July 2025; revised 19 August 2025; accepted 21 August 2025

## Aims

The estimated glucose disposal rate (eGDR) is a simple, non-invasive measure of insulin resistance. In this exploratory analysis of FINEARTS-HF, we evaluated whether lower eGDR, reflecting greater insulin resistance, is associated with adverse outcomes in heart failure (HF).

## Methods and results

The eGDR was calculated at baseline using waist circumference, glycated haemoglobin, and hypertension status. Clinical outcomes and treatment effects of finerenone according to baseline eGDR (<median or ≥median) were evaluated. Among 5851 (98%) participants with a calculable eGDR (median [interquartile range] 5.1 [3.9–6.3] mg/kg/min), lower eGDR was associated with greater albuminuria and worse HF-related health status at baseline. Compared with participants with eGDR ≥5.1 mg/kg/min, those with eGDR <5.1 mg/kg/min experienced a 63% higher rate of cardiovascular death and total HF events (adjusted rate ratio [aRR] 1.63; 95% confidence interval [CI] 1.41–1.87; *p* < 0.001). Similar findings were observed in participants with diabetes (aRR 1.72; 95% CI 1.40–2.12) and without diabetes (aRR 1.34; 95% CI 1.07–1.68; *p*<sub>interaction</sub> = 0.06). Lower baseline eGDR was additionally associated with a higher rate of vascular events, kidney outcomes, new-onset diabetes, and all-cause death. Treatment benefits of finerenone on cardiovascular death and total HF events (*p*<sub>interaction</sub> = 0.64) and new-onset diabetes (*p*<sub>interaction</sub> = 0.36) appeared consistent irrespective of baseline eGDR category. Baseline eGDR category did not modify the safety profile of finerenone.

## Conclusions

The eGDR, a validated measure of insulin resistance, was associated with a wide range of cardiovascular, kidney, and metabolic outcomes in patients with HF, including among those without diabetes. Finerenone reduced risk of cardiovascular outcomes and new-onset diabetes, irrespective of baseline insulin resistance.
Clinical Trial Registration: [ClinicalTrials.gov](https://ClinicalTrials.gov) NCT04435626.

<footnote n="1">¹Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; ²British Heart Foundation Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK; ³National Heart Centre Singapore and Duke-National University of Singapore, Singapore; ⁴University of Milano-Bicocca and ASST Papa Giovanni XXIII Hospital, Bergamo, Italy; ⁵Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; ⁶University Medical Center Groningen, Groningen, The Netherlands; ⁷Université de Lorraine, Inserm Clinical Investigation Centre, CHU, Nancy, France; ⁸Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA; ⁹Bayer AG, Global Medical Affairs, Berlin, Germany; ¹⁰Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany; and ¹¹Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany</footnote>

<footnote>*Corresponding author. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA, Email: mvaduganathan@bwh.harvard.edu</footnote>
## Graphical Abstract

Finerenone According to Insulin Resistance in Heart Failure: Insights from the FINEARTS-HF Trial

eGDR and Clinical Outcomes

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

Effect of Finerenone, by Baseline eGDR

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

eGDR, a validated measure of insulin resistance, was associated with a wide range of cardiovascular, kidney, metabolic, and mortality outcomes in HFmrEF/HFpEF, and did not modify the efficacy or safety of finerenone.

Insulin resistance in heart failure with mildly reduced or preserved ejection fraction: insights from FINEARTS-HF. CI, confidence interval; CV, cardiovascular; eGDR, estimated glucose disposal rate; HF, heart failure.

## Keywords

Heart failure • Heart failure with preserved ejection fraction • Insulin resistance •

Cardiometabolic • Kidney disease • Mineralocorticoid receptor antagonists

## Introduction

Insulin resistance is a multifactorial and heterogeneous systemic disorder characterized by impaired insulin-mediated control of glucose metabolism,¹,² and is increasingly recognized as a core pathobiological mechanism linking cardiovascular, kidney, and metabolic diseases.³,⁴ While the association between insulin resistance and diabetes is well-established,² insulin resistance is additionally associated with increased risks of incident heart failure (HF),⁵ atherosclerotic cardiovascular disease,⁶,⁷ and mortality.⁸⁻¹⁰ Greater insulin resistance has also been shown to adversely impact several domains of kidney structure and function,⁷,¹¹ including intrarenal haemodynamics, podocyte viability, and tubular function.³ As such, measures of insulin resistance may capture a broad range of multiorgan risk, with implications for integrative risk stratification and personalized treatment efforts.

The estimated glucose disposal rate (eGDR) is a simple, non-invasive, three-variable measure of insulin resistance, incorporating waist circumference, glycated haemoglobin (HbA₁c), and hypertension status. Since its initial development and validation in persons with type 1 diabetes,¹² lower eGDR – reflecting greater insulin resistance – has been associated

with adverse cardiovascular and kidney outcomes in persons with diabetes.⁹,¹³⁻¹⁵ However, whether eGDR is associated with a similar spectrum of risk in persons with HF, with and without diabetes, remains uncertain.

Moreover, aldosterone signalling and insulin resistance appear to have an important bidirectional relationship. First, excess/dysfunctional adiposity and hyperglycaemia – key features of insulin resistance – have been shown to increase mineralocorticoid receptor (MR) signalling through increased aldosterone production and ligand-independent MR activation,¹⁶,¹⁷ respectively. Second, higher levels of circulating aldosterone have been associated with impairments in insulin signalling and insulin resistance,¹⁸,¹⁹ and inhibitors of the angiotensin and aldosterone systems – including the non-steroidal MR antagonist finerenone – have been shown to reduce new-onset diabetes.²⁰,²¹ However, whether the benefits of finerenone on clinical outcomes and health status in HF are modified by insulin resistance status has not been evaluated.

In this analysis of the FINEARTS-HF trial, we evaluated the association between baseline eGDR and a range of cardiovascular, kidney, metabolic, and mortality outcomes in persons with HF and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF),
with or without diabetes. We additionally assessed whether the efficacy and safety of finerenone were modified by eGDR.

# Methods

## The FINEARTS-HF trial: design and patient population

The design,²² baseline characteristics,²³ and principal results of the FINEARTS-HF trial have been previously published.²⁴ Briefly, FINEARTS-HF was a prospective, double-blind, randomized comparison of finerenone (target dose 20 or 40 mg based on baseline estimated glomerular filtration rate [eGFR] ≤60 or >60 ml/min/1.73 m²) versus placebo in addition to usual therapy in persons with chronic HFmrEF/HFpEF, with or without diabetes. Key eligibility criteria included age ≥40 years, New York Heart Association functional class II–IV, left ventricular ejection fraction (LVEF) ≥40%, elevated natriuretic peptides, and evidence of structural heart disease (left atrial enlargement or left ventricular hypertrophy) within 12 months of screening. Eligible persons could be enrolled either during hospitalization or in ambulatory care.

Key exclusion criteria included serum potassium >5.0 mmol/L, eGFR <25 ml/min/1.73 m², any MR antagonist use within 30 days prior to randomization, symptomatic hypotension (mean systolic blood pressure <90 mmHg at screening or at randomization), and uncontrolled systolic blood pressure (≥160 mmHg if not on treatment with ≥3 blood pressure-lowering medications or ≥180 mmHg irrespective of treatment, on two consecutive measurements obtained ≥2 min apart, at screening or at randomization). The study protocol was approved by ethics committees or institutional review boards at each participating site, and all participants provided written informed consent.

## Assessment of estimated glucose disposal rate and subgroup definitions

Using an established algorithm (online supplementary Table S1),¹²,¹³ eGDR (a measure of systemic insulin resistance) was calculated using baseline waist circumference (assessed according to site-level standards in FINEARTS-HF), HbA₁c values, and hypertension status (defined as either a history of hypertension or baseline blood pressure ≥140/90 mmHg). To align with invasive assessment of insulin resistance (e.g. hyperinsulinaemic-euglycaemic clamp), eGDR is typically expressed in milligrams of glucose disposed (i.e. into tissues from circulation) per kilogram of body weight per minute. Consistent with a prior analysis,¹³ eGDR subgroups were defined *a priori* as < median (greater insulin resistance) or ≥ median (greater insulin sensitivity). As precise eGDR thresholds are not well-established in persons with HF, eGDR was additionally evaluated as an ordinal (per 1.0 mg/kg/min decrease) and continuous variable.

## Study efficacy and safety outcomes

The primary study outcome was a composite of cardiovascular death and total (first and recurrent) HF events (HF hospitalizations and urgent HF visits). Key secondary endpoints in this analysis included the individual components of the primary composite outcome, non-fatal myocardial infarction, non-fatal stroke, new-onset atrial fibrillation, all-cause death, and a composite kidney endpoint (sustained ≥50% decline in eGFR, sustained decline in eGFR to <15 ml/min/1.73 m², or

initiation of chronic dialysis or renal transplant). Moreover, the association between eGDR-determined insulin resistance and new-onset diabetes was explored, using two definitions of new-onset diabetes: (1) ≥2 HbA₁c values ≥6.5%; and (2) ≥2 HbA₁c values ≥6.5% or new initiation of a glucose-lowering medication other than a sodium-glucose co-transporter 2 inhibitor (SGLT2i).²⁰ All primary events and instances of initiation of chronic dialysis, kidney transplantation, and new-onset atrial fibrillation were adjudicated by an independent, centralized clinical event committee blinded to study drug assignment. Other study outcomes were investigator-reported. All efficacy analyses were performed in the intention-to-treat population.

Safety analyses were performed among those who received at least one dose of study drug and considered events that occurred during treatment or up to 3 days after permanent drug discontinuation. Effects of finerenone versus placebo were examined on the incidence of at least one adverse event, at least one serious adverse event, hyperkalaemia, elevations in serum creatinine, and systolic blood pressure <100 mmHg, according to baseline eGDR category.

## Statistical analysis

Participants without sufficient data to calculate baseline eGDR were excluded from the analysis. Baseline characteristics were cross-tabulated according to eGDR category and described as number (%), mean ± standard deviation, or median (interquartile range [IQR]).

The association between eGDR category and clinical outcomes was evaluated using the semiparametric proportional hazard rates method of Lin-Wei-Yang-Ying²⁵ (LWYY; for recurrent events endpoints) and Cox proportional hazards regression models (for time to first endpoints). Rate ratios (RR) with 95% confidence intervals (CI) were estimated for recurrent event endpoints and hazard ratios (HR) with 95% CI were estimated for time-to-first endpoints. The proportional hazards assumption was evaluated using Schoenfeld residuals, without evidence of violation. Analyses were adjusted for the following covariates selected on the basis of medical knowledge and prior research⁵,²⁶: age, sex, self-reported race, New York Heart Association functional class, smoking status (current, former, or never), LVEF, atrial fibrillation (history of or present on baseline electrocardiogram), history of stroke, history of myocardial infarction, serum creatinine, baseline systolic blood pressure, baseline diastolic blood pressure, log-transformed N-terminal pro-B-type natriuretic peptide (NT-proBNP), baseline use of a SGLT2i, and randomized treatment. To explore potentially non-linear associations between baseline eGDR and clinical outcomes, Poisson regression was used to estimate incidence rates (per 100 person-years) and 95% CI across the continuous range of eGDR, with output displayed as restricted cubic splines; the number of knots was selected to minimize the Akaike information criterion.

Treatment effects of finerenone versus placebo according to baseline eGDR category were evaluated for the primary and each of the specified secondary endpoints using the LWYY method (for recurrent events endpoints) and Cox proportional hazards regression models (for time to first endpoints), with stratification for LVEF (<60% or ≥60%) and geographic region. Heterogeneity in treatment response to finerenone on each of the primary and secondary endpoints was assessed through interaction testing. For selected outcomes, the impact of competing risk of all-cause death on treatment effect estimates was considered through the Fine-Gray method. Treatment effects of finerenone versus placebo on changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) scores between baseline and 12 months, according to baseline eGDR category, were additionally
assessed through linear regression with adjustment for baseline values, LVEF category (<60% or ≥60%), and geographic region. Treatment effects of finerenone versus placebo across the continuous range of eGDR were additionally explored using Poisson regression with restricted cubic splines. All statistical analyses were performed using Stata, version 18.5 (StataCorp, LLC; College Station, TX, USA); *p*-values <0.05 were considered statistically significant.

# Results

## Patient population

Among 5851 of 6001 (98%) FINEARTS-HF participants with calculable eGDR at baseline, the median [IQR] eGDR was 5.1 [3.9–6.3] mg/kg/min. While baseline eGDR tended to be lower among participants with diabetes compared to those without diabetes, the baseline eGDR distributions between these groups were highly overlapping (online supplementary Figure S1).

Compared with participants with higher baseline eGDR (greater insulin sensitivity), those with lower eGDR (greater insulin resistance) were more likely to have younger age and male sex, but less likely to have self-reported Asian race (Table 1). Participants with lower baseline eGDR were additionally more likely to have higher body mass index (BMI) and albuminuria, greater symptoms and functional limitations, a history of diabetes, and be treated with β-blockers, renin–angiotensin system or angiotensin receptor–neprilysin inhibitors, SGLT2i, glucagon-like peptide-1 receptor agonists, and statins (Table 1). Prior myocardial infarction, prior stroke, and baseline LVEF were similar between the eGDR subgroups. Baseline characteristics were similar between treatment arms, within each eGDR subgroup (online supplementary Table S2).

## Clinical outcomes according to baseline estimated glucose disposal rate

Baseline eGDR was significantly and non-linearly associated with the primary composite outcome of cardiovascular death and total HF events (Figure 1). Namely, participants with baseline eGDR values between 6 and 10 mg/kg/min experienced similar event rates, with risk increasing steeply with eGDR <6 mg/kg/min. After accounting for clinically relevant covariates, participants with eGDR <5.1 mg/kg/min experienced a 63% higher rate of cardiovascular death and total HF events compared with those with eGDR ≥5.1 mg/kg/min (adjusted RR [aRR] 1.63; 95% CI 1.41–1.87; *p* < 0.001) (Table 2). Lower eGDR category was similarly associated with a higher rate of cardiovascular death and total HF events irrespective of age category (*p*<sub>interaction</sub> = 0.33), sex (*p*<sub>interaction</sub> = 0.78), race (*p*<sub>interaction</sub> = 0.55), BMI category (*p*<sub>interaction</sub> = 0.24), diabetes status (*p*<sub>interaction</sub> = 0.06), eGFR category (*p*<sub>interaction</sub> = 0.27), and LVEF category (*p*<sub>interaction</sub> = 0.38) (online supplementary Table S3). However, baseline NT-proBNP appeared to modify the association between eGDR and the primary composite outcome (*p*<sub>interaction</sub> = 0.045), with a steeper association observed for participants with baseline NT-proBNP concentrations below (aRR 1.92; 95% CI 1.45–2.54) versus above (aRR 1.39; 95% CI 1.18–1.63) the trial median.

Generally similar findings were observed when eGDR was modeled as a continuous variable (online supplementary Figures S2 and S3). However, when compared with White participants, FINEARTS-HF participants with Asian, Black, and other race appeared to exhibit steeper associations between lower eGDR and the primary composite outcome (*p*<sub>interaction</sub> = 0.012) (online supplementary Figure S2).

Lower baseline eGDR was associated with a significantly higher rate of other cardiovascular and mortality outcomes, including total HF events (aRR 1.74; 95% CI 1.49–2.05; *p* < 0.001), cardiovascular death (adjusted HR [aHR], 1.29; 95% CI 1.06–1.57; *p* = 0.012) (Table 2 and online supplementary Figure S4), non-fatal myocardial infarction (aHR 1.54; 95% CI 1.04–2.30; *p* = 0.033), and all-cause death (aHR 1.30; 95% CI 1.13–1.49; *p* < 0.001) (Figure 1), but not non-fatal stroke or new-onset atrial fibrillation (online supplementary Table S4 and Figure S5).

Lower baseline eGDR was additionally associated with a higher rate of kidney and metabolic outcomes. Compared with participants with eGDR ≥5.1 mg/kg/min, those with eGDR <5.1 mg/kg/min experienced a 28% and 36% higher rate of new-onset microalbuminuria (aHR 1.28; 95% CI 1.15–1.43; *p* < 0.001) and macroalbuminuria (aHR 1.36; 95% CI 1.14–1.61; *p* < 0.001), respectively (Table 2 and Figure 1). While lower eGDR was not associated with a significantly higher rate of the kidney composite outcome when dichotomized (Table 2), continuous eGDR was significantly and non-linearly associated with the kidney composite outcome (*p* = 0.036) (Figure 1), with higher rates of kidney events with eGDR <6.0 mg/kg/min. Lower eGDR was also associated with a higher rate of new-onset diabetes (Figure 1 and online supplementary Figure S5), with eGDR ≤5.1 mg/kg/min associated with a 61% higher rate of ≥2 HbA1c levels ≥6.5% (aHR 1.61; 95% CI 1.15–2.27; *p* = 0.006) and an 81% higher rate of ≥2 HbA1c levels ≥6.5% or new initiation of a non-SGLT2i glucose-lowering medication (aHR 1.81; 95% CI 1.37–2.40; *p* < 0.001) (Table 2). Findings for all outcomes were similar when eGDR was evaluated ordinally per 1.0 mg/kg/min decrease (online supplementary Table S5).

## Treatment effects of finerenone according to baseline estimated glucose disposal rate

Over a median follow-up of 2.7 [1.9–3.0] years, finerenone consistently reduced cardiovascular death and total HF events in FINEARTS-HF participants with eGDR <5.1 mg/kg/min (RR 0.85; 95% CI 0.71–1.02) and ≥5.1 mg/kg/min (RR 0.80; 95% CI 0.67–0.96; *p*<sub>interaction</sub> = 0.64). Absolute rate differences appeared similar in both eGDR subgroups (−3.0 per 100 person-years for eGDR <5.1 mg/kg/min and −3.0 per 100 person-years for eGDR ≥5.1 mg/kg/min). Similar findings were observed when eGDR was evaluated as a continuous variable (*p*<sub>interaction</sub> = 0.41) (Figure 2). Baseline eGDR additionally did not appear to modify the effect of finerenone on the individual components of the primary outcome (online supplementary Figure S6) and the kidney composite outcome (Figure 2 and online supplementary Table S6).
<table><caption>**Table 1** Baseline characteristics of FINEARTS-HF participants, by baseline estimated glucose disposal rate category</caption><thead><tr><th rowspan="2">Characteristic</th><th colspan="2">Baseline eGDR category</th></tr><tr><th>Greater insulin resistance<br/>&lt;5.1 mg/kg/min (n = 2912)</th><th>Greater insulin sensitivity<br/>≥5.1 mg/kg/min (n = 2939)</th></tr></thead><tbody><tr><td>Age, years</td><td>71 ± 9</td><td>73 ± 10</td></tr><tr><td>Female sex</td><td>1218 (41.8)</td><td>1456 (49.5)</td></tr><tr><td>Race</td><td></td><td></td></tr><tr><td>Asian</td><td>192 (6.6)</td><td>789 (26.8)</td></tr><tr><td>Black</td><td>46 (1.6)</td><td>36 (1.2)</td></tr><tr><td>White</td><td>2588 (88.9)</td><td>2020 (68.7)</td></tr><tr><td>Other</td><td>86 (3.0)</td><td>94 (3.2)</td></tr><tr><td>Geographic region</td><td></td><td></td></tr><tr><td>Asia</td><td>189 (6.5)</td><td>781 (26.6)</td></tr><tr><td>Eastern Europe</td><td>1451 (49.8)</td><td>1162 (39.5)</td></tr><tr><td>Latin America</td><td>335 (11.5)</td><td>290 (9.9)</td></tr><tr><td>North America</td><td>283 (9.7)</td><td>167 (5.7)</td></tr><tr><td>Western Europe, Oceania and others</td><td>654 (22.5)</td><td>539 (18.3)</td></tr><tr><td>Any previous HF hospitalization</td><td>1741 (59.8)</td><td>1787 (60.8)</td></tr><tr><td>Time since HF event at randomization</td><td></td><td></td></tr><tr><td>≤7 days</td><td>611 (21.0)</td><td>573 (19.5)</td></tr><tr><td>>7 days to ≤3 months</td><td>931 (32.0)</td><td>1053 (35.8)</td></tr><tr><td>>3 months or no index event</td><td>1370 (47.0)</td><td>1313 (44.7)</td></tr><tr><td>Systolic blood pressure, mmHg</td><td>132 ± 15</td><td>127 ± 16</td></tr><tr><td>Body mass index, kg/m<sup>2</sup></td><td>33.6 ± 5.5</td><td>26.3 ± 4.4</td></tr><tr><td>Body mass index category</td><td></td><td></td></tr><tr><td>&lt;30 kg/m<sup>2</sup></td><td>799 (27.4)</td><td>2418 (82.3)</td></tr><tr><td>≥30 kg/m<sup>2</sup></td><td>2113 (72.6)</td><td>521 (17.7)</td></tr><tr><td>Waist circumference, cm</td><td>115.6 ± 12.0</td><td>92.4 ± 10.6</td></tr><tr><td>Elevated waist circumference<sup>a</sup></td><td>2773 (95.2)</td><td>833 (28.4)</td></tr><tr><td>Serum creatinine, mg/dl</td><td>1.2 ± 0.4</td><td>1.1 ± 0.3</td></tr><tr><td>eGFR, ml/min/1.73 m<sup>2</sup></td><td>62 ± 20</td><td>63 ± 20</td></tr><tr><td>Urine albumin-to-creatinine ratio, mg/g</td><td>21 [7–92]</td><td>16 [6–52]</td></tr><tr><td>Serum potassium, mmol/L</td><td>4.4 ± 0.5</td><td>4.4 ± 0.5</td></tr><tr><td>Left ventricular ejection fraction, %</td><td>53 ± 8</td><td>53 ± 8</td></tr><tr><td>NT-proBNP, pg/ml</td><td>930 [409–1765]</td><td>1163 [501–2205]</td></tr><tr><td>HbA<sub>1c</sub>, %</td><td>6.8 ± 1.4</td><td>6.0 ± 0.7</td></tr><tr><td>Baseline KCCQ total symptom score</td><td>63 ± 24</td><td>71 ± 23</td></tr><tr><td>New York Heart Association functional class</td><td></td><td></td></tr><tr><td>II</td><td>1863 (64.0)</td><td>2188 (74.4)</td></tr><tr><td>III/IV</td><td>1048 (36.0)</td><td>751 (25.6)</td></tr><tr><td>Smoking status</td><td></td><td></td></tr><tr><td>Current</td><td>243 (8.3)</td><td>254 (8.6)</td></tr><tr><td>Former</td><td>940 (32.3)</td><td>806 (27.4)</td></tr><tr><td>Never</td><td>1729 (59.4)</td><td>1879 (63.9)</td></tr><tr><td>Medical history</td><td></td><td></td></tr><tr><td>Hypertension</td><td>2863 (98.3)</td><td>2336 (79.5)</td></tr><tr><td>Diabetes</td><td>1621 (55.7)</td><td>762 (25.9)</td></tr><tr><td>Atrial fibrillation<sup>b</sup></td><td>1573 (54.0)</td><td>1629 (55.4)</td></tr><tr><td>Stroke</td><td>317 (10.9)</td><td>373 (12.7)</td></tr><tr><td>Myocardial infarction</td><td>780 (26.8)</td><td>732 (24.9)</td></tr><tr><td>Medications</td><td></td><td></td></tr><tr><td>β-blocker</td><td>2523 (86.6)</td><td>2451 (83.4)</td></tr><tr><td>ACEi, ARB, or ARNI</td><td>2402 (82.5)</td><td>2242 (76.3)</td></tr><tr><td>Calcium channel blocker</td><td>1094 (37.6)</td><td>829 (28.2)</td></tr><tr><td>Sodium-glucose co-transporter 2 inhibitor</td><td>464 (15.9)</td><td>327 (11.1)</td></tr><tr><td>Loop diuretic</td><td>2553 (87.7)</td><td>2553 (86.9)</td></tr><tr><td>Glucagon-like peptide-1 receptor agonist</td><td>133 (4.6)</td><td>30 (1.0)</td></tr><tr><td>Potassium-lowering medication</td><td>6 (0.2)</td><td>7 (0.2)</td></tr><tr><td>Aspirin</td><td>994 (34.1)</td><td>911 (31.0)</td></tr><tr><td>Statin</td><td>2066 (70.9)</td><td>1895 (64.5)</td></tr></tbody></table>

Values expressed as mean ± standard deviation, n (%), or median [interquartile range].

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; eGDR, estimated glucose disposal rate; eGFR, estimated glomerular filtration rate; HbA<sub>1c</sub>, glycated haemoglobin; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

<sup>a</sup>Defined as waist circumference >88/102 cm in female/male participants if not Asian race, and ≥80/90 cm in female/male participants if Asian race.

<sup>b</sup>Defined as atrial fibrillation on baseline electrocardiogram or history of atrial fibrillation.
A: CV Death and Total HF Events

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

B: Kidney Composite Outcome

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

C: New-Onset Microalbuminuria

<figure><img src="image_6.png" /></figure>

D: New-Onset Macroalbuminuria

<figure><img src="image_7.png" /></figure>

E: New-Onset Diabetes

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

F: All-Cause Death

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

**Figure 1** Association between baseline estimated glucose disposal rate (eGDR) and selected cardiovascular (CV), kidney, metabolic, and mortality outcomes in FINEARTS-HF. Microalbuminuria refers to urine albumin-to-creatinine ratio ≥30 mg/g; macroalbuminuria refers to urine albumin-to-creatinine ratio ≥300 mg/g. Endpoint definition is two consecutive glycated haemoglobin measurements ≥6.5%. Figures represent the continuous flexible association between baseline eGDR and incidence rate (per 100 person-years) with 95% confidence interval of each outcome, estimated through Poisson regression using restricted cubic splines. The number of knots was selected to minimize the Akaike information criterion; 3 knots used in all figures other than E. Model in E reflects a linear model. All models adjusted for age, sex, race, left ventricular ejection fraction, New York Heart Association functional class, smoking status, atrial fibrillation status (history of or present on baseline electrocardiogram), history of stroke, history of myocardial infarction, baseline systolic blood pressure, baseline diastolic blood pressure, log-transformed N-terminal pro-B-type natriuretic peptide, serum creatinine level, baseline use of a sodium-glucose co-transporter 2 inhibitor, and randomized treatment. HF, heart failure; py, person-years.

Moreover, finerenone appeared to consistently reduce new-onset microalbuminuria ($p_{interaction} = 0.34$), new-onset macroalbuminuria ($p_{interaction} = 0.66$), and both new-onset diabetes endpoints irrespective of baseline eGDR (Figure 2 and online supplementary Table S6). Findings for kidney outcomes and new-onset diabetes were similar after accounting for competing risk of all-cause death (online supplementary Table S6). Further, reductions in all-cause death with finerenone versus placebo appeared greater among participants with eGDR ≥5.1 mg/kg/min versus <5.1 mg/kg/min ($p_{interaction} = 0.045$) (online supplementary Table S6), but this was not observed when eGDR was assessed as a continuous variable ($p_{interaction} = 0.33$) (Figure 2).

Benefits of finerenone on KCCQ total summary score between baseline and 12 months were additionally consistent among participants with eGDR <5.1 mg/kg/min (mean difference, 1.9; 95%

CI 0.4–3.4) and eGDR ≥5.1 mg/kg/min (mean difference, 1.5; 95% CI 0.3–2.8; $p_{interaction} = 0.70$) (online supplementary Table S7). Further, between baseline and 12 months, $HbA_{1c}$ declined to a similar extent with finerenone versus placebo among participants with lower eGDR at baseline ($p_{interaction} = 0.89$) (online supplementary Figure S7).

## Safety of finerenone according to baseline estimated glucose disposal rate category

Irrespective of treatment assignment, incidences of serious adverse events (40.8% vs. 38.1%) and adverse events leading to drug discontinuation (2.8% vs. 3.0%) were similar among participants with eGDR <5.1 mg/kg/min versus ≥5.1 mg/kg/min (online
<table><caption>**Table 2** Selected cardiovascular, kidney, metabolic, and mortality outcomes in FINEARTS-HF, according to baseline estimated glucose disposal rate category</caption><thead><tr><th rowspan="2">Outcome</th><th colspan="2">Baseline eGDR category</th><th rowspan="2">p-value</th></tr><tr><th>&lt;5.1 mg/kg/min<br>(n = 2912)</th><th>≥5.1 mg/kg/min<br>(n = 2939)</th></tr></thead><tbody><tr><td colspan="4"><strong>Primary composite outcome and components</strong></td></tr><tr><td>CV death and total HF events</td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>1318</td><td>978</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>18.7</td><td>13.6</td><td></td></tr><tr><td>Unadjusted RR (95% CI)</td><td>1.38 (1.21–1.57)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>Adjusted RR (95% CI)<sup>a</sup></td><td>1.63 (1.41–1.87)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>Total HF events</td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>1060</td><td>750</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>15.1</td><td>10.5</td><td></td></tr><tr><td>Unadjusted RR (95% CI)</td><td>1.44 (1.24–1.67)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>Adjusted RR (95% CI)<sup>a</sup></td><td>1.74 (1.49–2.05)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>CV death</td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>260</td><td>228</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>3.7</td><td>3.2</td><td></td></tr><tr><td>Unadjusted HR (95% CI)</td><td>1.16 (0.97–1.39)</td><td>Ref.</td><td>0.09</td></tr><tr><td>Adjusted HR (95% CI)<sup>a</sup></td><td>1.29 (1.06–1.57)</td><td>Ref.</td><td>0.012</td></tr><tr><td colspan="4"><strong>Selected secondary outcomes</strong></td></tr><tr><td>All-cause death</td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>521</td><td>454</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>7.4</td><td>6.3</td><td></td></tr><tr><td>Unadjusted HR (95% CI)</td><td>1.17 (1.03–1.33)</td><td>Ref.</td><td>0.014</td></tr><tr><td>Adjusted HR (95% CI)<sup>a</sup></td><td>1.30 (1.13–1.49)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>Kidney composite outcome</td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>38</td><td>33</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>0.6</td><td>0.5</td><td></td></tr><tr><td>Unadjusted HR (95% CI)</td><td>1.17 (0.73–1.87)</td><td>Ref.</td><td>0.51</td></tr><tr><td>Adjusted HR (95% CI)<sup>a</sup></td><td>1.11 (0.67–1.84)</td><td>Ref.</td><td>0.68</td></tr><tr><td>New-onset microalbuminuria (UACR ≥30 mg/g)</td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>789</td><td>804</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>30.5</td><td>24.7</td><td></td></tr><tr><td>Unadjusted HR (95% CI)</td><td>1.21 (1.10–1.33)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>Adjusted HR (95% CI)<sup>a</sup></td><td>1.28 (1.15–1.43)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>New-onset macroalbuminuria (UACR ≥300 mg/g)</td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>335</td><td>282</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>6.1</td><td>4.6</td><td></td></tr><tr><td>Unadjusted HR (95% CI)</td><td>1.30 (1.11–1.53)</td><td>Ref.</td><td>0.001</td></tr><tr><td>Adjusted HR (95% CI)<sup>a</sup></td><td>1.36 (1.14–1.61)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>New-onset diabetes (HbA<sub>1c</sub> criteria alone)<sup>b</sup></td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>78</td><td>93</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>3.0</td><td>1.9</td><td></td></tr><tr><td>Unadjusted HR (95% CI)</td><td>1.55 (1.15–2.10)</td><td>Ref.</td><td>0.004</td></tr><tr><td>Adjusted HR (95% CI)<sup>a</sup></td><td>1.61 (1.15–2.27)</td><td>Ref.</td><td>0.006</td></tr><tr><td>New-onset diabetes (HbA<sub>1c</sub> criteria + new initiation of glucose-lowering medications)<sup>c</sup></td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>117</td><td>139</td><td></td></tr><tr><td>Event rate, per 100 py</td><td>4.6</td><td>2.9</td><td></td></tr><tr><td>Unadjusted HR (95% CI)</td><td>1.57 (1.23–2.00)</td><td>Ref.</td><td>&lt;0.001</td></tr><tr><td>Adjusted HR (95% CI)<sup>a</sup></td><td>1.81 (1.37–2.40)</td><td>Ref.</td><td>&lt;0.001</td></tr></tbody></table>

CI, confidence interval; CV, cardiovascular; eGDR, estimated glucose disposal rate; HbA1c, glycated haemoglobin; HF, heart failure; HR, hazard ratio; py, person-years; RR, rate ratio; UACR, urine albumin-to-creatinine ratio.

<sup>a</sup>Models adjusted for age, sex, race, left ventricular ejection fraction, New York Heart Association functional class, smoking status, atrial fibrillation status (history of or present on baseline electrocardiogram), history of stroke, history of myocardial infarction, baseline systolic blood pressure, baseline diastolic blood pressure, log-transformed N-terminal pro-B-type natriuretic peptide, serum creatinine level, baseline use of a sodium-glucose co-transporter 2 inhibitor, and randomized treatment.

<sup>b</sup>Restricted to participants without diabetes at baseline. New-onset diabetes defined as ≥2 consecutive HbA1c levels ≥6.5%.

<sup>c</sup>Restricted to participants without diabetes at baseline. New-onset diabetes defined as ≥2 consecutive HbA1c levels ≥6.5% or new initiation of a non-sodium-glucose co-transporter 2 inhibitor glucose-lowering medication.
<figure><img src="image_10.png" /><figcaption>B: Kidney Composite Outcome</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>C: New-Onset Microalbuminuria</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>D: New-Onset Macroalbuminuria</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>E: New-Onset Diabetes</figcaption></figure>

<figure><img src="image_14.png" /><figcaption>F: All-Cause Death</figcaption></figure>

<figure><img src="image_15.png" /></figure>

**Figure 2** Treatment effects of finerenone versus placebo on selected cardiovascular (CV), kidney, metabolic, and mortality outcomes, according to baseline estimated glucose disposal rate (eGDR). Microalbuminuria refers to urine albumin-to-creatinine ratio ≥30 mg/g; macroalbuminuria refers to urine albumin-to-creatinine ratio ≥300 mg/g. Defined as ≥2 consecutive glycated haemoglobin levels ≥6.5%. Figures show the continuous association between baseline eGDR and treatment effects (95% confidence interval [CI]) of finerenone versus placebo on clinical outcomes, estimated using Poisson regression with restricted cubic splines. The number of knots was selected to minimize the Akaike information criterion, with 3 knots in all figures other than E. Model in E is a linear model. HF, heart failure.

supplementary Table S8). Risk of serious adverse events or adverse events leading to drug discontinuation with finerenone versus placebo did not appear to be increased with lower eGDR.

Finerenone was associated with higher odds of increased serum creatinine levels, laboratory-defined hyperkalaemia, and systolic blood pressure <100 mmHg compared with placebo, but these risks did not appear to be enhanced in participants with lower eGDR at baseline (online supplementary Table S8). Incidences of hyperkalaemia leading to hospitalization with finerenone versus placebo were low, irrespective of eGDR category (9 [0.6%] vs. 5 [0.3%] among those with eGDR <5.1 mg/kg/min; 6 [0.4%] vs. 1 [0.1%] among those with eGDR ≥5.1 mg/kg/min). Moreover, lower odds of laboratory-defined hypokalaemia with finerenone versus placebo were similar irrespective of eGDR category (online supplementary Table S8).

Discussion

In this exploratory analysis of the FINEARTS-HF trial, greater eGDR-defined insulin resistance at baseline identified significantly

increased risks of a wide spectrum of cardiovascular, kidney, metabolic, and mortality outcomes in HFmrEF/HFpEF (Graphical Abstract). Treatment benefits of finerenone on cardiovascular events and HF-related health status appeared consistent irrespective of eGDR, as were benefits on new-onset diabetes and albuminuria. Moreover, baseline eGDR did not appear to modify the established safety profile of finerenone (Graphical Abstract). These findings underscore the role of insulin resistance as an integrative contributor to adverse cardiovascular-kidney-metabolic health trajectories in persons with HF.

Herein, we identified a broad spectrum of eGDR-defined insulin sensitivity in HFmrEF/HFpEF, and there was considerable overlap in baseline eGDR among FINEARTS-HF participants with and without diabetes. While specific eGDR thresholds for insulin resistance identification have not been rigorously established in HF, this observation is consistent with prior analyses demonstrating a high (~50–60%) prevalence of insulin resistance in HF, even in the absence of diabetes.²⁶⁻²⁸ Similar findings have been observed in chronic HF with reduced ejection fraction.²⁶ Mechanisms of insulin resistance in HF are likely multifactorial,
including excess/dysfunctional adiposity,²⁸ sarcopenia and impaired
skeletal muscle function,²⁹ increased neurohormonal activation,¹
systemic inflammation,³⁰ and oxidative stress.¹

However, whether insulin resistance independently contributes
to disease status in HFpEF remains controversial. In a recent
analysis of Pulmonary Vascular Disease Phenomics Program
(PVDOMICS) study participants, adiposity, but not homeostatic
model assessment of insulin resistance (HOMA-IR)-defined insulin
resistance, was associated with haemodynamic abnormalities,
exercise and functional impairments, and cardiac remodelling
in HFpEF.²⁸ However, other studies have shown associations
between insulin resistance, incident HFpEF,³¹ and adverse myocar-
dial remodelling in HFpEF.²⁷ In addition, the cross-sectional nature
of the PVDOMICS study precluded causal insights, stressing the
need for longitudinal studies examining clinical outcomes. Herein,
eGDR-defined insulin resistance was steeply associated with
cardiovascular death and total HF events, with similar findings
in persons with BMI <30 and ≥30 kg/m², and with and without
diabetes. Taken together, while excess adiposity is central to
HFpEF pathogenesis and a major determinant of insulin resistance,
these findings suggest that further efforts to phenotype metabolic
status in persons with HFpEF may enhance risk stratification and
personalized treatment efforts, regardless of the presence of
diabetes or BMI-defined obesity.

In addition to cardiovascular death and HF progression, greater eGDR-defined insulin resistance in FINEARTS-HF was associated with increased risk of non-fatal myocardial infarction, new-onset diabetes, the composite kidney outcome, new-onset micro- and macroalbuminuria, and all-cause death. These findings support and extend prior analyses,<sup>3,6,8–11,27</sup> and emphasize the multisys- tem impact of insulin resistance in persons with HF. Critically, atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes frequently coexist in persons with HFpEF and addi- tively contribute to adverse outcomes.<sup>32</sup> As such, in addition to mitigating HF progression, prevention or delay of comorbid condi- tions that might adversely modify HF natural history is an impor- tant and patient-centred priority of HF care.<sup>33</sup> However, a single integrative measure of multisystem risk is lacking. This analysis underscores the potential of eGDR to enhance comprehensive risk stratification efforts in persons with HF. However, further research efforts are needed to ascertain the incremental value of eGDR, compared with its individual components, for risk discrimination and calibration in this population. The inclusion of waist circumfer- ence in the eGDR algorithm additionally supports routine collec- tion of anthropometric measures that capture abdominal adiposity to enhance prognostication and care.<sup>34</sup>

Consistent with prior analyses using eGDR,¹³ insulin resistance
appeared more common among men compared with women in this
analysis, and least common among Asian individuals. While these
observations may reflect differences in baseline characteristics
and other biological determinants, they may alternatively highlight
important limitations of the eGDR construct. Namely, the current
eGDR algorithm does not include terms for sex or ethnicity, which
are crucial for waist circumference interpretation.⁴ Metabolic com-
plications of excess adiposity, including diabetes, have been shown
to emerge at substantially smaller waist circumference values in

women (compared with men), and in Asian and Black (compared
with White) individuals.³⁵ Hence, lack of inclusion of sex and race
or ethnicity (or region) in eGDR calculation may lead to systematic
underestimation of the degree of insulin resistance among women
and individuals with Asian or Black race. The steeper associations
between eGDR and cardiovascular outcomes, as well as poten-
tially earlier risk inflection points, among non-White versus White
FINEARTS-HF participants is consistent with prior epidemiologi-
cal analyses and suggests further efforts to tailor eGDR to more
diverse populations may be needed.

Baseline eGDR did not appear to modify the benefits of
finerenone on cardiovascular death and total HF events in this anal-
ysis. These findings are consistent with evidence from clinical tri-
als, including the FIDELITY (Flnerenone in chronic kiDney diseasE
and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD
Trial programme analYsis) programme¹³ and a meta-analysis of HF
trials, in which the benefits of MR antagonists on cardiovascular
outcomes in HF were not modified by diabetes status or other clin-
ical variables associated with insulin resistance, such as age, BMI,
and blood pressure.³⁶ Because insulin resistance has been associ-
ated with greater circulating aldosterone concentrations and MR
hyperactivation,<sup>16,17</sup> it has been hypothesized that greater insulin
resistance may identify a subpopulation of individuals more suscep-
tible to the benefits of MR antagonism.<sup>37</sup> However, these findings
suggest that finerenone improves clinical outcomes across a broad
spectrum of eGDR-defined insulin resistance in HFmrEF/HFpEF.

Consistent with preclinical and clinical studies implicating insulin
resistance in impaired kidney structure and function,³,⁷ higher risks
of composite kidney outcomes and new-onset albuminuria were
observed with lower eGDR in this analysis. However, in prior
analyses of the FIDELITY programme and the Chronic Renal Insuf-
sufficiency Cohort study, greater insulin resistance was not associ-
ated with higher risk of kidney events in persons with chronic
kidney disease (CKD).<sup>13,38</sup> These differences may be explained, in
part, by differences between the study populations. Uniquely, this
FINEARTS-HF analysis included persons with and without diabetes,
and with and without CKD. Capture of this wider dynamic range
of risk may have unmasked important pathophysiological relation-
ships and suggests insulin resistance may be a greater contributor
to the onset rather than the progression of CKD. In this context,
finerenone-mediated reductions in new-onset albuminuria, includ-
ing among those with lower eGDR, may have important long-term
implications, given its association with cardiovascular, kidney, and
mortality events.<sup>39</sup> Alternatively, these apparent evidentiary differ-
ences may be related to (i) chance, given the fewer numbers of
kidney events compared with FIDELITY; or (ii) HF status, which
may modify the association between insulin resistance and kidney
events. Indeed, lower eGDR was associated with HF progression
(and incident diabetes) in this analysis, which is associated with
worsening kidney function.<sup>40</sup>

Limitations

This analysis has some limitations. First, the FINEARTS-HF trial was
not designed to examine the interplay between insulin resistance,
outcomes, and finerenone in persons with HFmrEF/HFpEF. As
such, insulin resistance was not directly measured, and findings of this analysis should be considered hypothesis-generating. Second, owing to absence of requisite data elements, we were unable to compare the performance of eGDR with other measures of insulin resistance. However, eGDR has been shown to exhibit stronger performance for prediction of cardiovascular events when compared with triglyceride-based and other measures of insulin resistance in persons without HF.¹⁴ Third, because waist circumference was assessed only at baseline in FINEARTS-HF, we were unable to examine (i) temporal trajectories of eGDR; and (ii) the effect of finerenone therapy on eGDR. Fourth, while extensive adjustment for potential confounders was performed in this analysis, there is potential for residual unmeasured (e.g. body composition and lifestyle factors) confounding or bias. Finally, further research efforts are needed to determine whether these findings are generalizable to community settings and to individuals with more diverse racial and ethnic backgrounds.

## Conclusions

Greater eGDR-defined insulin resistance in FINEARTS-HF was associated with a wide range of cardiovascular, kidney, metabolic, and mortality outcomes, and did not appear to modify treatment benefits of finerenone. These findings underscore the role of insulin resistance as an integrative contributor to adverse cardiovascular-kidney-metabolic health trajectories in persons with HF.

## Supplementary Information

Additional supporting information may be found online in the Supporting Information section at the end of the article.

### Funding

The FINEARTS-HF trial was sponsored by Bayer AG.

**Conflict of interest:** J.W.O. has received grant support from the National Institutes of Health (5T32HL007604-39 and L30HL175757). B.L.C. has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, Rocket, and has served on a DSMB for Novo Nordisk. A.S.D. has received institutional research grants (to Brigham and Women's Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, Zydus. P.S.J. reports speakers' fees from AstraZeneca, ProAdWise Communications; advisory board fees from AstraZeneca; research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, Roche Diagnostics. P.S.J.'s employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis and Novo Nordisk. Director GCTP Ltd. C.S.P.L. has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biophysics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk,

Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and is a co-founder & non-executive director of Us2.ai. M.S. has served on advisory boards, and reporta consultancy and honoria for Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, Boehringer Ingelheim. S.J.S. has received research grants from NIH (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), AHA (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultrromics. A.A.V.'s employer received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche diagnostics, SalubrisBio. F.Z. reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, USA2, having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, Eshmoun Clinical research and being the founder of Cardiovascular Clinical Trialists. B.P. is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences*, Sarbez Pharmaceuticals*, Pharmaceuticals*, SQInnovations*, G3 Pharmaceuticals, Sea Star medical*, Vifor*, Prointel®, Brainstorm Medical* (*= stock/stock options); US Patent 9 931 412 -site specific delivery of eplerenone to the myocardium, US Patent pending 63/045783 Histone modulating agents for the prevention and treatment of organ failure. K.R., M.B., and P.S. are full-time employees of Bayer. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK and Novartis; personal consultancy fees from Alnylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp., British Heart Foundation, National Institute for Health - National Heart Lung and Blood Institute (NIH-NHLBI), Boehringer Ingelheim, SQ Innovations, Catalyze Group; personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd., Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd., Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational Medicine Academy. DSMB: WIRB-Copernicus Group Clinical Inc; he is a director of Global Clinical Trial Partners Ltd. S.D.S has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, Novo Nordisk, Respiocardia, Sanofi Pasteur, Theracos, US2.AI and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Valo. M.V. has received research grant support, served on advisory boards, or had speaker engagements with Alnylam Pharmaceuticals, American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Esperion, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon
Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Recordati, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates in clinical trial committees for studies sponsored by Amgen, AstraZeneca, Boehringer Ingelheim, Galmed, Novartis, Bayer AG, Occlutech, Pharmacosmos, and Impulse Dynamics.

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