# Interplay Between Heart Failure Events, New-Onset Diabetes, and Finerenone in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

John W Ostrominski, Henri Lu, Brian L Claggett, Akshay S Desai, Pardeep S Jhund, Alasdair D Henderson, Carolyn S.P. Lam, Michele Senni, Sanjiv Shah, Adriaan A Voors, et al.

► To cite this version:

John W Ostrominski, Henri Lu, Brian L Claggett, Akshay S Desai, Pardeep S Jhund, et al. Interplay Between Heart Failure Events, New-Onset Diabetes, and Finerenone in Heart Failure With Mildly Reduced or Preserved Ejection Fraction. Diabetes Care, 2025, Online ahead of print. 10.2337/dc25-2540. [hal-05444715](https://hal-univ-lorraine.fr/hal-05444715v1)

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# Interplay Between Heart Failure Events, New-Onset Diabetes, and Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

*Running Title: HF Events and New-Onset Diabetes in FINEARTS-HF*

John W. Ostrominski, MD¹*; Henri Lu, MD¹,²*; Brian L. Claggett, PhD¹; Akshay S. Desai, MD MPH¹; Pardeep S. Jhund, MBChB MSc PhD³; Alasdair D. Henderson, PhD³; Carolyn S.P. Lam, MBBS PhD⁴; Michele Senni, MD⁵; Sanjiv J. Shah, MD⁶; Adriaan A. Voors, MD PhD⁷; Faiez Zannad, MD PhD⁸; Bertram Pitt, MD⁹; Meike Brinker, MD¹⁰; Patrick Schloemer, PhD¹¹; Katja Rohwedder, MD¹²; John J.V. McMurray, MD³; Scott D. Solomon, MD¹; Muthiah Vaduganathan, MD MPH¹

¹: Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

²: Division of Cardiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

³: British Heart Foundation Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK

⁴: National Heart Centre Singapore and Duke-National University of Singapore, Singapore

⁵: University of Milano-Bicocca ASST Papa Giovanni XXIII Hospital, Bergamo, Italy

⁶: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

⁷: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

⁸: Université de Lorraine, Inserm Clinical Investigation Centre, CHU, Nancy, France

⁹: Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA

¹⁰: Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany

¹¹: Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany

¹²: Bayer AG, Global Medical Affairs, Berlin, Germany

*: Contributed equally and share first authorship

## Address for Correspondence

Muthiah Vaduganathan, MD MPH
Cardiovascular Division
Brigham and Women's Hospital
Harvard Medical School
75 Francis St
Boston MA 02115

Email: mvaduganathan@bwh.harvard.edu

Phone: (857) 407-4561

X/Twitter: @mvaduganathan

Word Count: 750

Figures: 1

Key Words: Heart failure; diabetes; trials; treatment; prevention
Heart failure (HF) and diabetes frequently co-exist. While this intersectionality may principally reflect the well-established contribution of diabetes to HF pathogenesis,¹ whether HF impacts the risk of diabetes has not been rigorously examined. Acute health events, including HF hospitalization, are associated with neurohormonal activation, muscle catabolism, and other metabolic and inflammatory responses that may enhance insulin resistance and dysglycemia.² As such, worsening HF may represent a high-risk but overlooked period for diabetes emergence. In this analysis of the FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with HF) trial, we explored the association between HF events and new-onset diabetes, and whether the benefits of finerenone on new-onset diabetes³ are mediated through reductions in HF events.

The design and findings of FINEARTS-HF have been reported.⁴ Briefly, FINEARTS-HF was a randomized, placebo-controlled trial that evaluated finerenone in chronic HF with mildly reduced or preserved ejection fraction, with or without diabetes. The study protocol was approved by institutional review boards or ethics committees at each site; all participants provided informed consent.

First, relative timing of investigator-reported diabetes and HF diagnoses was assessed. Second, temporal trajectories of glycated hemoglobin (HbA1c) were evaluated among participants who did and did not experience a HF event post-randomization, using repeated-measures linear regression and restricted cubic splines. Analyses included participants with ≥1 HbA1c measurement within 24 months of the HF event or end of follow-up. Third, multivariable-adjusted Cox proportional hazards regression was used to examine the rate of new-onset diabetes
after (versus before) HF events. Fourth, we assessed whether reductions in HF events with finerenone mediated its benefits on new-onset diabetes, defined as ≥2 HbA1c measurements ≥6.5% or new initiation of a glucose-lowering medication other than a sodium-glucose co-transporter 2 inhibitor.³ Statistical analyses were conducted using Stata, version 19.0 (StataCorp, LLC; College Station, TX).

Among 6,001 participants, 2,412 (40%) had diabetes at baseline, of whom 1,671 (69%) had a diagnosis of diabetes that preceded HF and 741 (31%) had a diagnosis of diabetes either concurrent (within 6 months) with or after HF (Figure 1A). Participants who experienced a HF event (n=1,034) had higher HbA1c levels compared with those who did not (P<0.001), and HbA1c levels tended to increase within the 6 months prior to HF events (Figure 1B). The incidence of new-onset diabetes increased sharply after a HF event (Figure 1C), with a >2-fold higher rate of new-onset diabetes after (versus before) a worsening HF event (adjusted hazard ratio [HR], 2.61; 95% CI, 1.76-3.85). Findings were similar when new-onset diabetes was defined using HbA1c levels alone (HR, 2.18; 95% CI, 1.25-3.80). However, most (87%) new-onset diabetes events occurred before HF events or among participants without a HF event. Reductions in HF events with finerenone did not meaningfully attenuate its benefits on new-onset diabetes (HR before and after adjustment for HF events: 0.76 [95% CI, 0.59-0.97] and 0.77 [95% CI, 0.60-0.98], respectively) (Figure 1D).

This exploratory FINEARTS-HF analysis provides important insights into the interplay between diabetes and HF. First, most diagnoses of diabetes preceded HF diagnoses among FINEARTS-HF participants, reinforcing the importance of diabetes prevention and optimal treatment to
reduce HF risk. However, nearly 1-in-3 diabetes diagnoses were approximately concurrent with or after HF diagnoses, underscoring the need for screening and prevention efforts once HF is established. Second, increments in HbA1c in the 6 months preceding HF events may reflect worsening insulin resistance. Hyperinsulinemia may contribute to HF events (e.g., through sodium retention), but may also be attributable to worsening HF status, electrolyte derangements, or other factors. Third, the association between higher HbA1c levels and HF progression, together with steeply higher risks of new-onset diabetes after HF events, highlight a bidirectional relationship between HF and diabetes. These findings suggest that interventions that reduce HF events may also prevent or delay incident diabetes in some individuals. However, consistent with the observation that most new-onset diabetes events did not occur after worsening HF, reductions in HF events with finerenone did not fully account for its benefit on new-onset diabetes. Hence, finerenone may exert its glycemic effects through alternative mechanisms, including direct and selective effects on mineralocorticoid receptor signaling⁵ and/or reductions in hypokalemia.⁴

This analysis has some limitations, including possible misclassification of dates of diabetes and HF diagnoses (e.g., due to recall bias), residual confounding, and uncertain generalizability to non-trial settings.

Overall, HF events were associated with a substantially increased risk of new-onset diabetes in FINEARTS-HF, suggesting bidirectional interplay between HF and metabolic function. Benefits of finerenone on new-onset diabetes appeared independent of its effects on HF events.
**Acknowledgements:** Drs. Ostrominski and Vaduganathan are the guarantors of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. J.W.O, H.L., and M.V. conceived the study design. H.L. and B.L.C. conducted the analysis. J.W.O drafted the manuscript. All authors reviewed/edited the manuscript.

**Funding:** FINEARTS-HF was funded by Bayer AG.

**Data Sharing Statement:** Data are made available to qualified scientific and medical researchers through vivli.org. All requests will be reviewed by an independent scientific review panel and data provided according to the conditions reviewed at https://vivli.org/ourmember/Bayer/.

**Duality of Interest**

**Dr. Ostrominski** has received grant support from the National Institutes of Health (5T32HL007604-39 and L30HL175757) and served on advisory boards for Corcept Therapeutics. **Dr. Lu** has received research grant support or served on advisory boards for Bayer, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Zoll and Abbott. **Dr. Claggett** 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. Dr. Desai 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. **Dr. Jhund** reports speakers' fees from AstraZeneca, ProAdWise Communications; advisory board fees from AstraZeneca, Novartis; research funding from AstraZeneca, Analog Devices Inc, Roche Diagnostics. PSJ's employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis and Novo Nordisk; and he is Director of GCTP Ltd. **Dr. Lam** has received research grants from the National Medical Research Council of Singapore, Novo Nordisk, and Roche Diagnostic; has received consulting fees from Alnylam Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biomeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Corteria, CPC Clinical Research, Cytokinetics, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Pfizer, Quidel Corporation, Radcliffe Group Ltd., Roche and Us2.ai; has patent PCT/SG2016/050217 pending and patent US Patent No. 10,631,828 B1; US 10,702,247 B2; US 11,301,996 B2; US 11,446,009 B2; US 11,931,207 B2; US 12,001,939; US 12,400,762 B2; and is a co-founder and non-executive director of Us2.ai. **Dr. Senni** has served on Advisory Boards, Consultancy and Honoraria for Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, Boehringer Ingelheim. **Dr. Shah** 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 Ultromics. **Dr.**
**Voors'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. **Dr. Zannad** 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. **Dr. Pitt** is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences*, Sarfez Pharmaceuticals*, SQinnovations*, G3 Pharmaceuticals, Sea Star Medical*, Vifor*, Prointel*, Brainstorm Medical* (*=stock/stock options). US Patent 9931412 -site specific delivery of eplerenone to the myocardium, US Patent pending 63/045,783 Histone modulating agents for the prevention and treatment of organ failure. Drs **Rohwedder, Brinker**, and **Schloemer** are full-time employees of Bayer. **Dr. McMurray** 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: 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. **Dr. Solomon** 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, Respicardia, 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. **Dr. Vaduganathan** 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 on clinical trial committees for studies sponsored by Amgen, AstraZeneca, Boehringer Ingelheim, Galmed, Novartis, Bayer AG, Occlutech, Pharmacosmos, and Impulse Dynamics.
References

1. Pop-Busui R, Januzzi JL, Bruemmer D, et al. Heart Failure: An Underappreciated Complication of Diabetes. A Consensus Report of the American Diabetes Association. Diabetes Care. 2022;45:1670-1690.

2. Larsen J, Goldner W. Approach to the Hospitalized Patient with Severe Insulin Resistance. J Clin Endocrinol Metab. 2011;96:2652-2662.

3. Butt JH, Jhund PS, Henderson AD, et al. Finerenone and New-Onset Diabetes in Heart Failure: A Prespecified Analysis of the FINEARTS-HF Trial. Lancet Diabetes Endocrinol. 2025;13:107-118.

4. Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024;391:1475-1485.

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Figure 1: Interplay Between Glycemia and HF Events in FINEARTS-HF

Pie chart in (A) reflects the relative investigator-reported timing of diabetes and HF diagnoses among FINEARTS-HF participants with diabetes at baseline. Figure in (B) shows the trajectories of mean HbA1c (95% CI) among participants who did (red) and did not (blue) experience a worsening HF event post-randomization. The gray vertical line denotes timing of the event or end of follow-up. The *P* value for interaction compares the shapes (e.g., slopes) of the splines. The figure in (C) shows the cumulative incidence of new-onset diabetes (≥2 HbA1c measurements ≥6.5% or new initiation of a non-SGLT2i glucose-lowering medication) after a worsening HF event (red) and among participants without a worsening HF event or prior to a worsening HF event (blue). Adjusted hazard ratio (and 95% CI) estimated through Cox proportional hazards regression, adjusted for age, sex, left ventricular ejection fraction, estimated glomerular filtration rate, body mass index, systolic blood pressure, geographic region, log-transformed NT-proBNP, NYHA functional class, randomized treatment, and baseline β-blocker, ACEi, ARB, and ARNi use. Forest plot in (D) shows treatment effects of finerenone on new-onset diabetes, before and after adjusting for treatment effects on worsening HF events. Both models otherwise adjusted for baseline HbA1c and stratified by geographic region and left ventricular ejection fraction (<60%, ≥60%).

**Abbreviations:** ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor-neprilysin inhibitor; HF = heart failure; HR = hazard ratio; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; py = person-years; SGLT2i = sodium-glucose co-transporter 2 inhibitor