Metabolic Effects of Empagliflozin in Heart Failure: A Randomized, Double-Blind, and Placebo-Controlled Trial (Empire HF Metabolic)
2021; Lippincott Williams & Wilkins; Volume: 143; Issue: 22 Linguagem: Inglês
10.1161/circulationaha.120.053463
ISSN1524-4539
AutoresJ. Steen Jensen, Massar Omar, Caroline Kistorp, Christian Tuxen, Finn Gustafsson, Lars Køber, Finn Gustafsson, Jens Faber, Julie Lyng Forman, Jacob Eifer Møller, Morten Schou,
Tópico(s)Metabolism, Diabetes, and Cancer
ResumoHomeCirculationVol. 143, No. 22Metabolic Effects of Empagliflozin in Heart Failure: A Randomized, Double-Blind, and Placebo-Controlled Trial (Empire HF Metabolic) Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessLetterPDF/EPUBMetabolic Effects of Empagliflozin in Heart Failure: A Randomized, Double-Blind, and Placebo-Controlled Trial (Empire HF Metabolic) Jesper Jensen, MD Massar Omar, MD Caroline Kistorp, MD, PhD Christian Tuxen, MD, PhD Ida Gustafsson, MD, PhD Lars Køber, MD, DmSc Finn Gustafsson, MD, DmSc Jens Faber, MD, DmSc Julie L. Forman, MSc, PhD Jacob E. Møller, MD, DmSc Morten SchouMD, PhD Jesper JensenJesper Jensen https://orcid.org/0000-0003-2821-9947 Department of Cardiology (J.J., M.S.), Herlev and Gentofte University Hospital, Denmark. Department of Clinical Medicine (J.J., C.K., L.K., F.G., J.F., M.S.), University of Copenhagen, Denmark. , Massar OmarMassar Omar https://orcid.org/0000-0002-9634-3889 Department of Cardiology, Odense University Hospital, Denmark (M.O., J.E.M.). Steno Diabetes Center Odense, Denmark (M.O.). , Caroline KistorpCaroline Kistorp https://orcid.org/0000-0002-3019-6775 Department of Endocrinology (C.K.), Rigshospitalet, Copenhagen, Denmark. Department of Clinical Medicine (J.J., C.K., L.K., F.G., J.F., M.S.), University of Copenhagen, Denmark. , Christian TuxenChristian Tuxen Department of Cardiology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark (C.T., I.G.). , Ida GustafssonIda Gustafsson Department of Cardiology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark (C.T., I.G.). , 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 (J.J., C.K., L.K., F.G., J.F., M.S.), University of Copenhagen, Denmark. , 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 (J.J., C.K., L.K., F.G., J.F., M.S.), University of Copenhagen, Denmark. , Jens FaberJens Faber Department of Internal Medicine, Center of Endocrinology and Metabolism (J.F.), Herlev and Gentofte University Hospital, Denmark. Department of Clinical Medicine (J.J., C.K., L.K., F.G., J.F., M.S.), University of Copenhagen, Denmark. , Julie L. FormanJulie L. Forman https://orcid.org/0000-0001-7368-0869 Section of Biostatistics (J.L.F.), University of Copenhagen, Denmark. , Jacob E. MøllerJacob E. Møller Department of Cardiology, Odense University Hospital, Denmark (M.O., 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, Denmark (M.O., J.E.M.). , Morten SchouMorten Schou Correspondence to: Morten Schou, MD, PhD, Department of Cardiology, Herlev and Gentofte University Hospital, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4271-2466 Department of Cardiology (J.J., M.S.), Herlev and Gentofte University Hospital, Denmark. Department of Clinical Medicine (J.J., C.K., L.K., F.G., J.F., M.S.), University of Copenhagen, Denmark. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark (M.O., J.E.M.). Originally published1 Jun 2021https://doi.org/10.1161/CIRCULATIONAHA.120.053463Circulation. 2021;143:2208–2210The general notion has been that the mechanisms behind the clinical benefits of sodium-glucose cotransporter 2 inhibitors in patients with heart failure and reduced ejection fraction (HFrEF) are related to effects beyond improved glycemic control.1 However, insulin resistance is a common metabolic characteristic of heart failure, and improved insulin resistance may better the long-term prognosis,2 for example, by preventing type 2 diabetes (T2D) or by reverse cardiac remodeling. In HFrEF, dapagliflozin prevents T2D,3 but whether sodium-glucose cotransporter 2 inhibitors improve insulin resistance is unknown. Therefore, we investigated the effect of empagliflozin on insulin resistance in patients with HFrEF.The data that support the findings of this study are available from the corresponding author on reasonable request. This was a prespecified substudy in the subgroup of patients consecutively enrolled at Herlev and Gentofte University Hospital (Denmark) as part of the Empire HF trial (Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction).4 Patients with New York Heart Association class I to III symptoms, left ventricular ejection fraction ≤40%, with or without T2D, and on stable guideline-directed heart failure and antidiabetic therapy were randomly assigned (1:1) to empagliflozin 10 mg or matching placebo. An institutional review board approved the study, and all patients provided written informed consent.Study procedures were performed at baseline and repeated at 12 weeks, and for the present substudy, procedures included standardized oral glucose tolerance testing to assess glucose metabolism and a whole-body dual energy x-ray absorptiometry scan to assess body composition (Discovery Hologic Inc). Plasma glucose and insulin during the oral glucose tolerance testing were analyzed on the Atellica IM platform (Siemens Healthineers), and 2 measures of insulin sensitivity were obtained: Homeostatic Model Assessment as a measure of hepatic insulin sensitivity and the Matsuda Index as a measure of peripheral insulin sensitivity. Both have been validated against current gold standards and are commonly accepted surrogates in the published literature.5 Analyses were performed by using ANCOVA models with sex, age, the baseline value of the end point, and the treatment group as covariates. A 2-sided P value <0.05 was considered statistically significant.In total, 120 patients were enrolled,4 including 108 (90%) patients without a history of T2D, of whom 19 (18%) had new-onset T2D and 35 (32%) had impaired glucose tolerance based on the oral glucose tolerance testing. Glucose metabolism measures were complete for 51 (85%) in the empagliflozin group and 50 (83%) in the placebo group and, for body composition measures, 60 (100%) in the empagliflozin group and 59 (98%) in the placebo group. Empagliflozin improved hepatic and peripheral insulin sensitivity, with adjusted between-group differences in the change from baseline to 12 weeks of 13% ([95% CI, 4.5–21], P=0.004) and 20% ([95% CI, 11–27], P<0.0001), respectively (Figure [A and B]). Supplemental analyses with multiple imputations of missing data and with further adjustments for baseline N-terminal pro-brain natriuretic peptide and left ventricular ejection fraction, or for changes in lean body mass showed overall similar results (data not shown). Empagliflozin reduced fasting plasma glucose (–5.2% [95% CI, –8.7 to –1.8], P=0.003) and plasma glucose area under the curve (–7.0% [95% CI, –2.5 to –12], P=0.002). No changes were observed for plasma insulin area under the curve (–9.9% [95% CI, –22 to 1.3], P=0.09) or pancreatic β-cell function (Disposition Index, 5.3% [95% CI, –20 to 25], P=0.7). Empagliflozin reduced total body weight and lean mass. No changes were observed in fat mass, fat percentage, or visceral adipose tissue (Figure [C–G]).Download figureDownload PowerPointFigure. Effect of empagliflozin on insulin sensitivity and body composition. For each end point (A–G), boxplots represent unadjusted values at baseline, 12 weeks, and the change from baseline to 12 weeks for the empagliflozin group (red) and the placebo group (blue). The box represents median and interquartile range; whiskers represent 1.5 times the interquartile range. The treatment effect for each end point is the between-group difference in the change from baseline to 12 weeks, in the empagliflozin group vs the placebo group, from ANCOVA models adjusted for sex, age, the baseline value of the end point, and the treatment group. HOMA2 indicates Homeostatic Model Assessment; and pp, percentage point.To our knowledge, this is the first study reporting the effect of sodium-glucose cotransporter 2 inhibitors on insulin resistance in patients who have HFrEF primarily without diabetes. The present findings indicate that a similar improvement in insulin resistance is induced by empagliflozin in patients with HFrEF without diabetes as previously reported in patients with T2D without heart failure. Our findings suggest that empagliflozin primarily modulates glucose metabolism by decreasing plasma glucose. Thereby, the adverse actions of hyperglycemia in several tissues are potentially decreased. Empagliflozin reduced total body weight, but, in contrast with previous findings in T2D, the weight loss consisted mainly of a reduction in lean mass, not fat. It remains unknown to what extent this early loss represents a decrease in muscle mass or water. With the early and sustained effect of sodium-glucose cotransporter-2 inhibitors on clinical outcomes,1 it may be speculated that, to some extent, this represents a loss of water. This has also been demonstrated with other modalities.4 Reduction in body water could also explain the observed improvement in peripheral insulin resistance with empagliflozin, despite the loss in lean mass. The small sample size should be acknowledged when interpreting the results, and no conclusions can be made regarding possible differences in patients with and without T2D.In patients with HFrEF, 12 weeks of treatment with empagliflozin improved both hepatic and peripheral insulin resistance in a cohort mainly consisting of patients without diabetes. Moreover, reductions in total body weight and lean mass, not in fat mass indices, were observed. These findings likely have implications for the long-term treatment and prevention of T2D in patients with HFrEF.Sources of FundingThis research was supported by The Danish Heart Foundation (grant numbers 17-R116-A7714-22076, 18-R124-A8573-22107), The Research Council at Herlev and Gentofte University Hospital, Denmark (institutional research grant), The Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Denmark (institutional research grant), The A.P. Møller Foundation for the Advancement of Medical Science (grant number 17-l-0002), and The Capital Region of Denmark (grant number A6058). The manufacturer of empagliflozin had no role in any aspect of the study.Disclosures 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. 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 Køber reports personal fees from speaker honoraria from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim, outside the submitted work. Dr F. 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, personal fees from speaker honoraria from Novartis and Orion Pharma, outside the submitted work. Dr Schou reports grants from The Danish Heart Foundation and from The Capital Region of Denmark, during the conduct of the study; personal fees from speaker honoraria and nonfinancial support (as the national lead investigator of the DAPA-HF trial [Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure]) from AstraZeneca, personal fees from speaker honorarium from Novo Nordisk and Boehringer Ingelheim, outside the submitted work. The other authors report no conflicts.FootnotesThe podcast and transcript are available as Data Supplements at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.120.053463.Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03198585.For Sources of Funding and Disclosures, see page 2210.https://www.ahajournals.org/journal/circCorrespondence to: Morten Schou, MD, PhD, Department of Cardiology, Herlev and Gentofte University Hospital, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark. Email morten.schou.[email protected]dkReferences1. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, et al.. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.Lancet. 2020; 396:819–829. doi: 10.1016/S0140-6736(20)31824-9CrossrefMedlineGoogle Scholar2. Riehle C, Abel ED. Insulin signaling and heart failure.Circ Res. 2016; 118:1151–1169. doi: 10.1161/CIRCRESAHA.116.306206LinkGoogle Scholar3. Inzucchi SE, Docherty KF, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Solomon SD, Verma S, Bělohlávek J, et al.; DAPA-HF Investigators and Committees. Dapagliflozin and the incidence of type 2 diabetes in patients with heart failure and reduced ejection fraction: an exploratory analysis from DAPA-HF.Diabetes Care. 2021; 44:586–594. doi: 10.2337/dc20-1675CrossrefMedlineGoogle Scholar4. Jensen J, Omar M, Kistorp C, Tuxen C, Gustafsson I, Køber L, Gustafsson F, Faber J, Malik ME, Fosbøl EL, et al.. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial.Lancet Diabetes Endocrinol. 2021; 9:106–116. doi: 10.1016/S2213-8587(20)30382-XCrossrefMedlineGoogle Scholar5. Otten J, Ahrén B, Olsson T. Surrogate measures of insulin sensitivity vs the hyperinsulinaemic-euglycaemic clamp: a meta-analysis.Diabetologia. 2014; 57:1781–1788. doi: 10.1007/s00125-014-3285-xCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails June 1, 2021Vol 143, Issue 22Article InformationMetrics Download: 1,664 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.053463PMID: 34061581 Originally publishedJune 1, 2021 Keywordsheart failurebody compositiondiabetes mellitus, type 2insulin resistancesodium-glucose transporter 2 inhibitorsempagliflozinPDF download SubjectsHeart FailureClinical StudiesMetabolismMechanisms
Referência(s)