Hypokalemia is common in heart failure (HF) and may contribute to glucose intolerance via impairment of insulin release and action (1,2). Individuals with HF exhibit a high risk of incident diabetes (3), but the influence of hypokalemia on this risk in this population is unclear. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has been shown to improve cardiovascular outcomes and reduce new-onset diabetes in individuals with HF with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) (3,4). However, whether the effects of finerenone on serum potassium, including the prevention of hypokalemia events (4), explain its benefits in new-onset diabetes remains uncertain. In this FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With HF) analysis (4), we explored the association between hypokalemia and new-onset diabetes and whether the benefits of finerenone in new-onset diabetes are mediated through changes in potassium levels.
The design and findings of FINEARTS-HF have been reported previously (4). Briefly, FINEARTS-HF was a randomized, placebo-controlled trial that evaluated finerenone in patients with chronic HFmrEF/HFpEF with or without diabetes. The study protocol was approved by the institutional review board or ethics committee at each site, and all participants provided informed consent. 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 described at http://vivli.org/ourmember/Bayer/.
First, the association between time-updated serum potassium and new-onset diabetes, defined as two or more glycated hemoglobin (HbA1c) measurements ≥6.5% or new initiation of a glucose-lowering medication (excluding sodium–glucose cotransporter 2 inhibitors) (3), was examined using multivariable-adjusted Cox proportional hazards and Poisson regression models. To mitigate potential biases related to differential measurement, only potassium and HbA1c levels obtained during scheduled trial visits (Supplementary Table 1) were considered. Second, hypokalemia (serum potassium <3.5 mmol/L) was modeled as a time-varying exposure in multivariable-adjusted Cox proportional hazards regression models restricted to participants who received study medication and had available postbaseline potassium measurements. The rate of new-onset diabetes during person-time accrued after incident hypokalemia was compared with the rate during person-time accumulated before hypokalemia, including participants who never experienced hypokalemia. Exploratory analyses considered a higher potassium threshold (<4.0 mmol/L). Third, causal mediation analyses estimated the proportion of the total effect of finerenone on new-onset diabetes mediated by changes in time-updated serum potassium and hypokalemia events (laboratory defined and investigator reported), using Cox proportional hazards regression models adjusted for baseline HbA1c and stratified by left ventricular ejection fraction category and geographic region. Statistical analyses were conducted using Stata, version 19.5 (StataCorp LLC). Missing HbA1c data were well balanced between the treatment arms (Supplementary Table 1) and were not imputed (3).
Of 6,001 participants, 3,224 (54%) did not have diabetes at baseline and were included (mean ± SD age 72 ± 10 years; 47% female; mean ± SD HbA1c 5.7% ± 0.4%; mean ± SD serum potassium 4.4 ± 0.5 mmol/L). Over a median follow-up of 2.7 (interquartile range 2.0, 3.1) years, lower time-updated serum potassium levels were incrementally associated with a higher rate of new-onset diabetes (adjusted hazard ratio [aHR] per 0.5 mmol/L lower time-updated serum potassium 1.19; 95% CI 1.04–1.36) (Fig. 1A). Similar findings were observed when considering HbA1c values alone (Supplementary Fig. 1). Associations between time-updated serum potassium and new-onset diabetes did not seem to be modified by randomized treatment (Pinteraction = 0.29). The rate of new-onset diabetes increased after laboratory-defined hypokalemia events (aHR 2.07; 95% CI 1.33–3.22) (Fig. 1B). Similar findings were observed after incident serum potassium <4.0 mmol/L (aHR 1.37; 95% CI 1.05–1.80) (Fig. 1C). Treatment effects of finerenone on new-onset diabetes seemed to be slightly mediated by 1) time-updated serum potassium levels (estimated percentage mediation 20%) and 2) the combination of time-updated serum potassium levels and hypokalemia events (estimated percentage mediation 31%) (Fig. 1D).
Figure 1.
Interplay between serum potassium, new-onset diabetes, and finerenone in FINEARTS-HF. A: Association between time-updated serum potassium and the incidence rate (95% CI; dashed lines) of new-onset diabetes, estimated through Poisson regression adjusted for baseline HbA1c, randomized treatment, age, sex, baseline BMI, geographic region, left ventricular ejection fraction (LVEF), smoking history, baseline estimated glomerular filtration rate, log-transformed N-terminal pro–B-type natriuretic peptide, log-transformed urine albumin-to-creatinine ratio, loop diuretic use, thiazide diuretic use, statin use, β-blocker use, and use of renin–angiotensin inhibitor or angiotensin receptor–neprilysin inhibitor. B and C: Cumulative incidence of new-onset diabetes after incident hypokalemia (serum potassium <3.5 mmol/L) (B) and incident serum potassium <4.0 mmol/L (C), compared with before incident hypokalemia or among participants without incident hypokalemia, estimated through Cox proportional hazards models adjusted for the same covariates as in panel A. Incidence rate (95% CI) is given per 100 person-years. D: Forest plot of treatment effects of finerenone on new-onset diabetes, estimated through Cox proportional hazards regression models adjusted for baseline HbA1c (and stratified by LVEF category and geographic region), with and without accounting for time-updated potassium levels and hypokalemia safety events.
This exploratory FINEARTS-HF analysis provides novel insights into the interplay between potassium, new-onset diabetes, and finerenone in patients with HFmrEF/HFpEF. First, lower time-updated potassium levels were incrementally associated with a higher rate of new-onset diabetes, and the risk of new-onset diabetes increased after the emergence of hypokalemia. Second, the benefits of finerenone in new-onset diabetes seemed to be slightly to moderately (∼20–30%) mediated by its effects on serum potassium and hypokalemia events. Although the limited precision of the mediation estimates underscores the need for cautious interpretation, these observations suggest that finerenone may exert most of its glycemic effects through alternative mechanisms, including its unique and selective effects on mineralocorticoid receptor signaling. Indeed, although steroidal mineralocorticoid receptor antagonists are also capable of preventing hypokalemia, they have not been observed to reduce the incidence of new-onset diabetes (5). These findings suggest hypokalemia avoidance, including through finerenone treatment, may mitigate incident diabetes in those with HFmrEF/HFpEF.
This analysis has some limitations. First, β-cell function and insulin resistance were not examined in FINEARTS-HF. Second, use of glycemia measures other HbA1c may have improved diabetes ascertainment. Third, despite interrogation of temporal associations and adjustment for multiple indicators of glycemia (HbA1c and glucose-lowering therapies) and HF severity (e.g., natriuretic peptide levels and diuretic therapies), the potential exists for residual confounding and reverse causation. Therefore, these findings should be considered hypothesis generating.
In conclusion, hypokalemia was associated with an increased risk of new-onset diabetes in patients with HFmrEF/HFpEF. The benefits of finerenone in new-onset diabetes were not fully explained by its effects on serum potassium or hypokalemia events.
This article contains supplementary material online at https://doi.org/10.2337/figshare.33187545.
Article Information
Duality of Interest. J.W.O. has served on advisory boards or had speaker engagements with Bayer AG, Corcept Therapeutics, and Viking Therapeutics. H.L. has received research grant support or served on advisory boards for Bayer, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Zoll, and Abbott. B.L.C. has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Lilly, Intellia, and Rocket and has served on a data and safety monitoring board (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 and personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. P.S.J. has received speaker fees from AstraZeneca and ProAdWise Communications; advisory board fees from AstraZeneca and Novartis; and research funding from AstraZeneca, Analog Devices Inc, and Roche Diagnostics; reports remuneration (to University of Glasgow) for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and is director of Global Clinical Trial Partners Ltd. C.S.P.L. has received research grants from Novo Nordisk and Roche Diagnostic and consulting fees from Alnylam Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Corteria, CPC Clinical Research, Cytokinetics, 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 holds patents US 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; and US 12,400,762 B2; and is cofounder and nonexecutive director of Us2.ai. M.S. has served on advisory boards for, acted as a consultant for, or received honoraria from Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. S.J.S. has received research grants from 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. A.A.V. reports consultancy fees and/or research support (to employer) from Adrenomed, Anacardio, AstraZeneca, Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche diagnostics, and SalubrisBio. F.Z. has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno Scientific, Cellprothera, CEVA, Inventiva, KBP Biosciences, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; holds stock options in G3Pharmaceutical and equities in Cereno, Cardiorenal, and Eshmoun Clinical Research; and is founder of Cardiovascular Clinical Trialists. B.P. is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences, Sarfez Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; holds stock options in KBP Biosciences, Sarfez Pharmaceuticals, SQinnovations, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; and holds U.S. patent 9931412 (for site-specific delivery of eplerenone to myocardium) and has U.S. patent 63/045,783 pending (for histone-modulating agents for prevention and treatment of organ failure). M.B., A.S., Y.D.S., and L.H. are full-time employees of Bayer. J.J.V.M. has received payments (through Glasgow University) for work on clinical trials and consulting or received grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, and Novartis; has received personal consultancy fees from Alnylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp., Boehringer Ingelheim, SQ Innovations, and Catalyze Group; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, 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, and The Corpus; has served on a DSMB for WIRB-Copernicus Group Clinical Inc; and is director of Global Clinical Trial Partners Ltd. S.D.S. has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, 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, and Valo. M.V. has received research grant support from, served on advisory boards for, or had speaker engagements with Alnylam Pharmaceuticals, American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Bristol Myers Squibb, 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 serves on clinical trial committees for studies sponsored by Amgen, AstraZeneca, Boehringer Ingelheim, Galmed, Novartis, Bayer AG, Occlutech, Pharmacosmos, and Impulse Dynamics. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. J.W.O. drafted the manuscript. J.W.O., H.L., and B.L.C. conducted the analysis. J.W.O., H.L., and M.V. conceived the study design. All authors reviewed and edited the manuscript. J.W.O. and M.V. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were John B. Buse and Jennifer B. Green.
Funding Statement
FINEARTS-HF was funded by Bayer AG. J.W.O. is supported by National Institutes of Health (NIH) grants 5T32HL007604-39 and L30HL175757. C.S.P.L. is supported by the National Medical Research Council of Singapore. S.J.S. is supported by NIH grants U54 HL160273, X01 HL169712, R01 HL140731, and R01 HL149423 and American Heart Association grant 24SFRNPCN1291224. J.J.V.M. has received support from the British Heart Foundation, NIH National Heart Lung and Blood Institute (NHLBI), Canadian Medical and Surgical Knowledge, Translation Research Group, and Translational Medicine Academy. S.D.S. has received support from the NIH NHLBI.
Footnotes
Clinical trial reg. no. NCT04435626, clinicaltrials.gov
Supporting information
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