Effect of Empagliflozin on Multiple Biomarkers in Heart Failure: Insights From the Empire Heart Failure Trial.

Abstract

HomeCirculation: Heart FailureVol. 15, No. 8Effect of Empagliflozin on Multiple Biomarkers in Heart Failure: Insights From the Empire Heart Failure Trial Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEffect of Empagliflozin on Multiple Biomarkers in Heart Failure: Insights From the Empire Heart Failure Trial Jesper Jensen, MD, PhD, Massar Omar, MD, PhD, Caroline Kistorp, MD, PhD, Christian Tuxen, MD, PhD, Mikael Kjær Poulsen, MD, PhD, Jens Faber, MD, DmSc, Lars Køber, MD, DmSc, Finn Gustafsson, MD, DmSc, Jacob Eifer Møller, MD, DmSc and Morten Schou, MD, PhD Jesper JensenJesper Jensen Correspondence to: Jesper Jensen, MD‚ Department of Cardiology, Herlev and Gentofte University Hospital, Herlev, Denmark. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2821-9947 Department of Cardiology (J.J., M.S.), Herlev and Gentofte University Hospital, Denmark. Search for more papers by this author , Massar OmarMassar Omar https://orcid.org/0000-0002-9634-3889 Department of Cardiology, Odense University Hospital, Denmark (M.O., M.K.P., J.E.M.). Steno Diabetes Center Odense, Denmark (M.O.). Faculty of Health Sciences, University of Southern Denmark, Odense (M.O., J.E.M.). Search for more papers by this author , Caroline KistorpCaroline Kistorp https://orcid.org/0000-0002-3019-6775 Department of Endocrinology (C.K.), Rigshospitalet, Copenhagen, Denmark. Department of Clinical Medicine, University of Copenhagen, Denmark (C.K., J.F., L.K., F.G., M.S.). Search for more papers by this author , Christian TuxenChristian Tuxen Department of Cardiology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark (C.T.). Search for more papers by this author , Mikael Kjær PoulsenMikael Kjær Poulsen Department of Cardiology, Odense University Hospital, Denmark (M.O., M.K.P., J.E.M.). Search for more papers by this author , Jens FaberJens Faber Department of Internal Medicine, Center of Endocrinology and Metabolism (J.F.), Herlev and Gentofte University Hospital, Denmark. Department of Clinical Medicine, University of Copenhagen, Denmark (C.K., J.F., L.K., F.G., M.S.). Search for more papers by this author , Lars KøberLars Køber https://orcid.org/0000-0002-6635-1466 Department of Cardiology (L.K., F.G., J.E.M.), Rigshospitalet, Copenhagen, Denmark. Department of Clinical Medicine, University of Copenhagen, Denmark (C.K., J.F., L.K., F.G., M.S.). Search for more papers by this author , Finn GustafssonFinn Gustafsson https://orcid.org/0000-0003-2144-341X Department of Cardiology (L.K., F.G., J.E.M.), Rigshospitalet, Copenhagen, Denmark. Department of Clinical Medicine, University of Copenhagen, Denmark (C.K., J.F., L.K., F.G., M.S.). Search for more papers by this author , Jacob Eifer MøllerJacob Eifer Møller Department of Cardiology, Odense University Hospital, Denmark (M.O., M.K.P., J.E.M.). Department of Cardiology (L.K., F.G., J.E.M.), Rigshospitalet, Copenhagen, Denmark. Faculty of Health Sciences, University of Southern Denmark, Odense (M.O., J.E.M.). Search for more papers by this author and Morten SchouMorten Schou https://orcid.org/0000-0002-4271-2466 Department of Cardiology (J.J., M.S.), Herlev and Gentofte University Hospital, Denmark. Department of Clinical Medicine, University of Copenhagen, Denmark (C.K., J.F., L.K., F.G., M.S.). Search for more papers by this author Originally published21 Apr 2022https://doi.org/10.1161/CIRCHEARTFAILURE.121.009333Circulation: Heart Failure. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 21, 2022: Ahead of Print The SGLT2i (sodium-glucose cotransporter-2 inhibitors) empagliflozin or dapagliflozin have demonstrated clinically meaningful reductions in hospitalizations for heart failure (HF) when added to contemporary guideline-directed medical therapy in patients with HF and reduced ejection fraction (HFrEF).1 Currently, available data also suggest reduced progression of kidney disease and mortality with SGLT2i.1 The reduction in hospitalizations occur after few weeks of initiating treatment and is most likely caused by multiple mechanisms.2 The effect of SGLT2i on important biomarkers in HF is lacking and such analyses could contribute to the mechanistic understanding of this drug class. We performed the Empire HF trial, an investigator-initiated, double-blinded, randomized, placebo-controlled trial to investigate the effect of empagliflozin on clinical and biochemical end points in patients with HFrEF. The study was approved by the Danish National Committee on Health Research Ethics and the data that support the findings of this study are available from the corresponding author upon reasonable request. In total, 190 patients with HFrEF were randomized (1:1) to receive empagliflozin 10 mg once daily or matching placebo for 12 weeks. Patients had New York Heart Association class I–III symptoms (78% in class II), a left ventricular ejection fraction of 40% or below (mean, 29% [SD 7.8%]) and were on stable guideline-directed medical therapy (96% on renin-angiotensin-aldosterone system inhibitor, 95% on β-blocker, and 66% on mineralocorticoid receptor antagonist).3 Thirteen percent had a history of type 2 diabetes and 12% had an estimated glomerular filtration rate below 60 mL/min per 1.73 m2. Baseline characteristics were similar between the allocated groups,3 including for the presented end points (data not shown). The neutral result on the prespecified primary end point, NT-proBNP (N-terminal pro-B-type natriuretic peptide) has previously been published.3 The present analyses include prespecified secondary end points (uric acid, hs-cTnI [high-sensitivity cardiac troponin I], and MR-proADM [mid-regional proadrenomedullin]) and exploratory end points (hematocrit, hemoglobin, ferritin, copeptin, endothelin-1, MR-proANP [mid-regional proatrial natriuretic peptide], and LDL [low-density lipoprotein]). Analyses were performed in patients with complete data in ANCOVA models. Biomarker measurements were log-transformed before the analyses. The end point was the change from baseline to 12 weeks for each biomarker. Covariates included the baseline value of the biomarker, age, sex, site of randomization, history of type 2 diabetes, and the allocated group. Across end points, at least 96% of patients in the empagliflozin group and 92% of patients allocated to placebo had complete data. Missing data were missing at random. The results are depicted in the Figure.Download figureDownload PowerPointFigure. Empagliflozin effects on multiple biomarkers. Adj indicates adjusted; E, empagliflozin; Geom, geometric; hs-cTnI, high-sensitivity cardiac troponin I; IQR, interquartile range; LDL, low-density lipoprotein; MR-proADM, mid-regional proadrenomedullin; MR-proANP, mid-regional proatrial natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; and P, placebo.Empagliflozin treatment resulted in increases in copeptin, hematocrit, and hemoglobin, while decreases were observed for ferritin and uric acid when compared with placebo. As for NT-proBNP, no significant treatment effects were observed for MR-proANP, hs-cTnI, MR-proADM, endothelin-1, or LDL. This is the first documented effect of SGLT2i on copeptin in patients with HFrEF primarily without type 2 diabetes.4 Copeptin is a measure of vasopressin activation and the increase may represent a compensatory response to the early increase in diuresis and the resulting increase in plasma osmolarity observed with SGLT2i. The initial copeptin increase might explain the decreased diuretic effect observed during long-term treatment.2 The observed increases in hematocrit and hemoglobin could be markers of decreased plasma volume, supporting the diuretic hypothesis. However, the marked decrease in ferritin indicates a direct effect on the depletion of iron stores due to increased erythropoiesis which would also result in increased hematocrit and hemoglobin. An increase in erythropoietin has previously been observed with SGLT2i treatment in patients with type 2 diabetes,2 but this needs further investigations in HFrEF populations without diabetes. The decrease in ferritin could also be a measure of the anti-inflammatory effect of SGLT2i,2 however, the unchanged concentration of the proinflammatory marker MR-proADM argues against this interpretation. The observed decrease in uric acid supports previous evidence and is likely a direct consequence of the SGLT2 inhibition in the proximal convoluted tubule of the kidney nephron.2 The consequently increased glucose more distally in the nephron interacts with the glucose transporter 9, hereby increasing the excretion of uric acid. The modest reductions in NT-proBNP observed with SGLT2 inhibitors in other studies are underpinned by the present study. For the first time in HFrEF, this is supported by a similar finding with another natriuretic peptide, MR-proANP. The simultaneously unchanged concentrations of natriuretic peptides and hs-cTnI in the present study indicate that the initial cardiac effects of SGLT2i are due to volume changes rather than direct effects on the myocardium.5These biomarker analyses indicate that the diuretic effect of short-term empagliflozin in HFrEF is counterbalanced by increased copeptin. Commonly used cardiac biomarkers were not changed with empagliflozin and these may not be appropriate for monitoring the short-term cardiac treatment response with SGLT2i.Article InformationSources of FundingThe Empire HF (Heart Failure) trial was supported by the Danish Heart Foundation, Copenhagen, Denmark (grants 17-R116-A7714-22076 and 18-R124-A8573-22107); the Research Council at Herlev and Gentofte University Hospital, Herlev, Denmark (institutional research grant); the Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Herlev, Denmark (institutional research grant); the A.P. Møller Foundation for the Advancement of Medical Science, Copenhagen, Denmark (grant 17-L-0002); Steno Diabetes Center Odense, Odense, Denmark (institutional research grant); and the Capital Region of Denmark, Copenhagen, Denmark (grant A6058). Thermo Fischer Scientific (Hennigsdorf, Germany) funded the endothelin-1 kits. The manufacturer of empagliflozin had no role in any aspect of the study.Nonstandard Abbreviations and AcronymsHFheart failureHFrEFheart failure and reduced ejection fractionLDLlow-density lipoproteinSGLT2isodium-glucose cotransporter-2 inhibitorDisclosures Dr Jensen reports grants from the Research Council at Herlev and Gentofte University Hospital, Herlev, Denmark, grants from the Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Herlev, Denmark, and grants from the A.P. Møller Foundation for the Advancement of Medical Science, Copenhagen, Denmark, during the conduct of the study; and grants from the Danish Heart Foundation and personal fees from scientific advisory board from AstraZeneca and Boehringer Ingelheim, outside the submitted work. Dr Omar reports grants from the Steno Diabetes Center Odense, Odense, Denmark, during the conduct of the study. Dr Kistorp reports personal fees from scientific advisory panel and speaker fees from Boehringer Ingelheim, Merck, Sharp & Dohme, AstraZeneca, Amgen, Novartis, Novo Nordisk, and Shire, outside the submitted work. Dr Tuxen reports personal fees from scientific advisory board and speaker fees from Bayer and Orion Pharma outside the submitted work. Dr Køber reports and personal fees from speaker honorarium from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim, outside the submitted work. Dr Gustafsson reports personal fees from scientific advisory panel and speaker fees from AstraZeneca, Boehringer Ingelheim, Abbott, Orion Pharma, Pfizer, and Novartis, and acting as an unpaid advisor for Corvia, outside the submitted work. Dr Møller reports grants from Abiomed Inc, and personal fees from speaker honorarium from Novartis and Orion Pharma, outside the submitted work. Dr Schou reports grants from the Danish Heart Foundation, Copenhagen, Denmark, and from the Capital Region of Denmark, Copenhagen, Denmark, during the conduct of the study; personal fees from speaker honorarium and nonfinancial support (as the national lead investigator of the DAPA-HF trial [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]) from AstraZeneca, and personal fees from speaker honorarium from Novo Nordisk and Boehringer Ingelheim, outside the submitted work. The other authors report no conflicts.FootnotesRegistration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03198585.For Sources of Funding and Disclosures, see page 801.Correspondence to: Jesper Jensen, MD‚ Department of Cardiology, Herlev and Gentofte University Hospital, Herlev, Denmark. Email jesper.jensen.[email protected]dk