Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease
2017; Lippincott Williams & Wilkins; Volume: 136; Issue: 10 Linguagem: Inglês
10.1161/circulationaha.117.029166
ISSN1524-4539
AutoresBen A. Kappel, Michael Lehrke, Katharina Schütt, Anna Artati, Jerzy Adamski, Corinna Lebherz, Nikolaus Marx,
Tópico(s)Pancreatic function and diabetes
ResumoHomeCirculationVol. 136, No. 10Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEffect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease Ben A. Kappel, MD, PhD, Michael Lehrke, MD, Katharina Schütt, MD, Anna Artati, PhD, Jerzy Adamski, PhD, Corinna Lebherz, MD and Nikolaus Marx, MD Ben A. KappelBen A. Kappel From Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (B.A.K., M.L., K.S., C.L., N.M.); Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.A., J.A.); Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany (J.A.); and German Center for Diabetes Research, Neuherberg, Germany (J.A.). , Michael LehrkeMichael Lehrke From Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (B.A.K., M.L., K.S., C.L., N.M.); Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.A., J.A.); Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany (J.A.); and German Center for Diabetes Research, Neuherberg, Germany (J.A.). , Katharina SchüttKatharina Schütt From Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (B.A.K., M.L., K.S., C.L., N.M.); Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.A., J.A.); Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany (J.A.); and German Center for Diabetes Research, Neuherberg, Germany (J.A.). , Anna ArtatiAnna Artati From Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (B.A.K., M.L., K.S., C.L., N.M.); Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.A., J.A.); Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany (J.A.); and German Center for Diabetes Research, Neuherberg, Germany (J.A.). , Jerzy AdamskiJerzy Adamski From Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (B.A.K., M.L., K.S., C.L., N.M.); Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.A., J.A.); Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany (J.A.); and German Center for Diabetes Research, Neuherberg, Germany (J.A.). , Corinna LebherzCorinna Lebherz From Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (B.A.K., M.L., K.S., C.L., N.M.); Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.A., J.A.); Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany (J.A.); and German Center for Diabetes Research, Neuherberg, Germany (J.A.). and Nikolaus MarxNikolaus Marx From Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (B.A.K., M.L., K.S., C.L., N.M.); Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (A.A., J.A.); Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany (J.A.); and German Center for Diabetes Research, Neuherberg, Germany (J.A.). Originally published5 Sep 2017https://doi.org/10.1161/CIRCULATIONAHA.117.029166Circulation. 2017;136:969–972In the recent EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), treatment with empagliflozin, a member of the group of antidiabetic sodium-glucose cotransporter 2 inhibitors, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes mellitus and cardiovascular disease.1 In heart failure and type 2 diabetes mellitus, cardiac metabolic flexibility is impaired, and alteration in glucose or fatty acid (FA) metabolism and changes in the use of ketone bodies and branched chain amino acids (BCAAs) occur.2 Because sodium-glucose cotransporter 2 inhibitors lead to a mild increase in ketones, it has been hypothesized that empagliflozin may exhibit some of its beneficial effects through a shift in myocardial metabolism toward an energy-efficient use of ketone bodies, which may improve myocardial work efficiency and function.3,4 Still, these hypotheses are not proven yet, and data are lacking on the metabolic signature of sodium-glucose cotransporter 2 inhibitor-treated patients. Therefore, we performed an untargeted metabolomics approach in a group of empagliflozin-treated patients with type 2 diabetes mellitus and cardiovascular disease.In a prospective study (http://www.clinicaltrials.org; unique identifier: NCT03131232; ethics committee approved, and all patients gave informed consent), we enrolled 25 patients with type 2 diabetes mellitus and cardiovascular disease with a clinical indication for intensification of their glucose-lowering therapy and treated them with empagliflozin 10 mg/day. Serum was taken at baseline and after 1 month.Untargeted metabolomics were performed at the Genome Analysis Center Munich using the DiscoveryHD4 platform, which consists of 4 different methods: 2 separate reverse phase/ultraperformance liquid chromatography-tandem mass spectrometry with positive ion mode electrospray ionization, reverse phase/ultraperformance liquid chromatography-tandem mass spectrometry with negative electrospray ionization, and hydrophilic interaction chromatography/ultraperformance liquid chromatography-tandem mass spectrometry with negative electrospray ionization. Raw data were extracted, peak-identified, and quality control processed using hardware and software of Metabolon Inc. Data were analyzed by patient-matched Wilcoxon signed-rank test using MetaboAnalyst 3.0. Metabolites with P<0.05 and q<0.1were considered statistically significant.Patients characteristics were as follows (mean±SD): age 64.1±9.9 years; body mass index 31.6±5.0 kg/m2; duration of diabetes mellitus 11.5±5.8 years; hemoglobin A1c 8.5±1.3%; left ventricular function: ejection fraction 48.7±13.0%; and therapy: antihypertensive 96%, lipid lowering 92%, and antiplatelet/anticoagulation 96%. Thus, the patient population was comparable to the population in EMPA-REG OUTCOME. Empagliflozin treatment for 1 month significantly decreased hemoglobin A1c levels from 8.5±1.3% to 8.0±1.3% (P=0.001) and increased glucagon levels from 138±57pg/mL to 172±81pg/mL (P=0.026), whereas insulin levels were not altered. We measured 1269 metabolites (863 identified metabolites, 406 unknown metabolites), and among them 162 metabolites were altered by empagliflozin. As expected, empaglifozin reduced glucose and other sugars in the serum (Figure, A and B). Pathway enrichment analyses revealed an activation of tricarboxylic acid cycle as shown by increased levels of aconitate and fumarate (Figure, A and B). Because levels of pyruvate and lactate were not altered by empagliflozin, enhanced glycolysis is unlikely to be responsible for this finding. However, empagliflozin significantly increased levels of acetyl- and propionylcarnitine (known to reflect levels of acetyl- and propionyl-CoA), suggesting that degradation of FAs, amino acids and ketone bodies fuel the tricarboxylic acid cycle. Still, the lack of an increase in long-chain acyl carnitines (Figure, A), together with unchanged free FAs (data not shown), make it unlikely that enhanced triglyceride breakdown is responsible for tricarboxylic acid cycle activation. In contrast, empagliflozin particularly increased short-chain acylcarnitines derived from the degradation of BCAAs (valine, isoleucine, and leucine) (Figure, A and B). In addition to leucine and isoleucine, empagliflozin increased the degradation of lysine, the third ketogenic amino acid. Finally, empagliflozin enhanced β-hydroxybutyrylcarnitine levels, suggesting expanded utilization of ketone bodies. It is important to note that empagliflozin enhanced intermediate metabolites of the urea cycle, suggesting its activation and thus confirming increased amino acid utilization (Figure, A and C). The increase in glucagon levels on empagliflozin treatment could explain some of the metabolic changes observed here by facilitating amino acid catabolism.In the normal heart, carbohydrate and FA oxidation contribute to ≈90% of adenosine triphosphate production; in diabetes mellitus and heart failure with dysregulated cardiac FA oxidation and impaired glucose oxidation/uptake, other circulating substrates such as ketones or BCAAs may become an alternative source of energy. As such, in an elegant study, Bedi et al5 recently demonstrated increased ketone utilization in the severely failing human heart. The role of BCAA is less clear; however, because BCAA catabolism is diminished in heart failure,2 empagliflozin could potentially restore these defects, and together with the increase in ketone bodies derived from isoleucine, leucine and lysine provide an optimal energy source for the heart. In addition, ketones and BCAAs can directly influence cardiac signaling processes,2 thus potentially exhibiting additional beneficial effects in the heart.Our study has its limitations. Our data provide a systematic snapshot of the effect of empagliflozin on highly relevant metabolic pathways of the whole organism but do not yield definitive mechanisms on substrate flux in the myocardium. In addition, the data warrant verification in other cohorts. Still, our unbiased metabolomics approach generates novel hypotheses by showing an effect of empagliflozin on expanded ketone body utilization and BCAA catabolism. Thus, the study sets the basis for further experimental work to explore whether the metabolic signature described here in sodium-glucose cotransporter 2 inhibitor-treated patients corresponds to substrate flux and molecular pathways in the heart.Download figureDownload PowerPointFigure. Untargeted serum metabolomics reveal a unique metabolic signature of empagliflozin treatment.A, Modified pathways of untargeted serum metabolomics before and after 1 month of empagliflozin treatment (n=25, patients matching inclusion criteria of EMPA-REG OUTCOME trial [Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients]). Metabolites with P<0.05 and q<0.1 by patient-matched Wilcoxon signed-rank test were considered statistically significant. Fold change indicates empagliflozin over baseline values. Significant increase is highlighted in red, significant decrease in green. As expected, empagliflozin reduces several sugars in the serum. However, tricarboxylic acid (TCA) cycle is activated by empagliflozin treatment. Short-chain but not long- or very long-chain acylcarnitines are increased by empagliflozin treatment, indicating that factors other than triglyceride breakdown contribute augmented energy harvest. B, Pathway visualization: breakdown of ketogenic and branched-chain amino acids (BCAAs) (lysine, leucine, isoleucine, and valine) but not glycolysis contributes ketogenesis and TCA cycle activation. Acyl-CoA is degraded rapidly and not detected in the analysis. Acyl-CoA levels strongly correlate with their corresponding acylcarnitine, which are used for estimation in this study. C, Pathway visualization: empagliflozin enhances intermediate metabolites of the urea cycle and orotate-containing pyrimidines, thus implying nitrogen removal of increased amino acid (AA) catabolism.Ben A. Kappel, MD, PhDMichael Lehrke, MDKatharina Schütt, MDAnna Artati, PhDJerzy Adamski, PhDCorinna Lebherz, MDNikolaus Marx, MDSources of FundingThis work was supported by a CORONA Foundation grant to Drs Marx, Lehrke, and Schütt.DisclosuresDr Marx has received support for clinical trial leadership from Boehringer Ingelheim, served as a consultant to Boehringer Ingelheim, Merck, NovoNordisk, received grant support from Boehringer Ingelheim, and served as a speaker for Boehringer Ingelheim, Merck, NovoNordisk, Lilly, and Astra Zeneca. Drs Lehrke and Schütt have served as speakers for Boehringer Ingelheim.FootnotesCirculation is available at http://circ.ahajournals.org.Correspondence to: Nikolaus Marx, MD, Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany. E-mail [email protected]References1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373:2117–2128. doi: 10.1056/NEJMoa1504720.CrossrefMedlineGoogle Scholar2. Lopaschuk GD, Ussher JR. Evolving concepts of myocardial energy metabolism: more than just fats and carbohydrates.Circ Res. 2016; 119:1173–1176. doi: 10.1161/CIRCRESAHA.116.310078.LinkGoogle Scholar3. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME trial: a "thrifty substrate" hypothesis.Diabetes Care. 2016; 39:1108–1114. doi: 10.2337/dc16-0330.CrossrefMedlineGoogle Scholar4. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis.Diabetes Care. 2016; 39:1115–1122. doi: 10.2337/dc16-0542.CrossrefMedlineGoogle Scholar5. Bedi KC, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, Wang LL, Javaheri A, Blair IA, Margulies KB, Rame JE. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure.Circulation. 2016; 133:706–716. doi: 10.1161/CIRCULATIONAHA.115.017545.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Gessner A, Gemeinhardt A, Bosch A, Kannenkeril D, Staerk C, Mayr A, Fromm M, Schmieder R and Maas R (2022) Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers, Cardiovascular Diabetology, 10.1186/s12933-021-01436-x, 21:1, Online publication date: 1-Dec-2022. Santos-Gallego C, Mayr M and Badimon J (2022) SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism, Circulation, 146:11, (819-821), Online publication date: 13-Sep-2022.Selvaraj S, Fu Z, Jones P, Kwee L, Windsor S, Ilkayeva O, Newgard C, Margulies K, Husain M, Inzucchi S, McGuire D, Pitt B, Scirica B, Lanfear D, Nassif M, Javaheri A, Mentz R, Kosiborod M and Shah S (2022) Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF, Circulation, 146:11, (808-818), Online publication date: 13-Sep-2022. Gong Q, Zhang R, Wei F, Fang J, Zhang J, Sun J, Sun Q and Wang H (2022) SGLT2 inhibitor-empagliflozin treatment ameliorates diabetic retinopathy manifestations and exerts protective effects associated with augmenting branched chain amino acids catabolism and transportation in db/db mice, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2022.113222, 152, (113222), Online publication date: 1-Aug-2022. Zainal A and Merkhan M (2022) IMPACT OF ANTIDIABETIC DRUGS ON RISK AND OUTCOME OF COVID-19 INFECTION: A REVIEW, Military Medical Science Letters, 10.31482/mmsl.2022.004, 91:2, (140-160), Online publication date: 3-Jun-2022. Wang X, Ni J, Guo R, Li L, Su J, He F and Fan G (2021) SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism, Heart Failure Reviews, 10.1007/s10741-021-10096-8, 27:3, (961-980), Online publication date: 1-May-2022. Dimou A, Tsimihodimos V and Bairaktari E (2022) The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology, International Journal of Molecular Sciences, 10.3390/ijms23074022, 23:7, (4022) Horibe K, Morino K, Miyazawa I, Tanaka-Mizuno S, Kondo K, Sato D, Ohashi N, Ida S, Yanagimachi T, Yoshimura M, Itoh R, Murata K, Miura K, Arima H, Fujita Y, Ugi S and Maegawa H (2022) Metabolic changes induced by dapagliflozin, an SGLT2 inhibitor, in Japanese patients with type 2 diabetes treated by oral anti-diabetic agents: A randomized, clinical trial, Diabetes Research and Clinical Practice, 10.1016/j.diabres.2022.109781, 186, (109781), Online publication date: 1-Apr-2022. Salvatore T, Galiero R, Caturano A, Rinaldi L, Di Martino A, Albanese G, Di Salvo J, Epifani R, Marfella R, Docimo G, Lettieri M, Sardu C and Sasso F (2022) An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors, International Journal of Molecular Sciences, 10.3390/ijms23073651, 23:7, (3651) Izundegui D and Nayor M (2022) Metabolomics of Type 1 and Type 2 Diabetes: Insights into Risk Prediction and Mechanisms, Current Diabetes Reports, 10.1007/s11892-022-01449-0, 22:2, (65-76), Online publication date: 1-Feb-2022. Puetz A, Artati A, Adamski J, Schuett K, Romeo F, Stoehr R, Marx N, Federici M, Lehrke M and Kappel B (2021) Non‐targeted metabolomics identify polyamine metabolite acisoga as novel biomarker for reduced left ventricular function, ESC Heart Failure, 10.1002/ehf2.13713, 9:1, (564-573), Online publication date: 1-Feb-2022. Lunyera J, Diamantidis C, Bosworth H, Patel U, Bain J, Muehlbauer M, Ilkayeva O, Nguyen M, Sharma B, Ma J, Shah S and Scialla J (2021) Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease, Metabolomics, 10.1007/s11306-021-01858-4, 18:1, Online publication date: 1-Jan-2022. Butt J, Adamson C, Docherty K, de Boer R, Petrie M, Inzucchi S, Kosiborod M, Maria Langkilde A, Lindholm D, Martinez F, Bengtsson O, Schou M, O'Meara E, Ponikowski P, Sabatine M, Sjöstrand M, Solomon S, Jhund P, McMurray J and Køber L (2021) Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide: Insights From the DAPA-HF Trial, Circulation: Heart Failure, 14:12, Online publication date: 1-Dec-2021. Thiele K, Rau M, Hartmann N, Möllmann J, Jankowski J, Böhm M, Keszei A, Marx N and Lehrke M (2021) Effects of empagliflozin on erythropoiesis in patients with type 2 diabetes: Data from a randomized, placebo‐controlled study, Diabetes, Obesity and Metabolism, 10.1111/dom.14517, 23:12, (2814-2818), Online publication date: 1-Dec-2021. Nakao M, Shimizu I, Katsuumi G, Yoshida Y, Suda M, Hayashi Y, Ikegami R, Hsiao Y, Okuda S, Soga T and Minamino T (2021) Empagliflozin maintains capillarization and improves cardiac function in a murine model of left ventricular pressure overload, Scientific Reports, 10.1038/s41598-021-97787-2, 11:1, Online publication date: 1-Dec-2021. Kitada K, Kidoguchi S, Nakano D and Nishiyama A (2021) Sodium/glucose cotransporter 2 and renoprotection: From the perspective of energy regulation and water conservation, Journal of Pharmacological Sciences, 10.1016/j.jphs.2021.07.006, 147:3, (245-250), Online publication date: 1-Nov-2021. Pabel S, Hamdani N, Luedde M and Sossalla S (2021) SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?, Current Heart Failure Reports, 10.1007/s11897-021-00529-8, 18:5, (315-328), Online publication date: 1-Oct-2021. Mkrtumyan A, Markova T and Mishchenko N (2021) Cardioprotective mechanisms of sodium-glucose cotransporter 2 inhibitors, Diabetes mellitus, 10.14341/DM12541, 24:3, (291-299) Supruniuk E, Żebrowska E and Chabowski A (2021) Branched chain amino acids—friend or foe in the control of energy substrate turnover and insulin sensitivity?, Critical Reviews in Food Science and Nutrition, 10.1080/10408398.2021.1977910, (1-39) Ning Z, Song Z, Wang C, Peng S, Wan X, Liu Z and Lu A (2021) How Perturbated Metabolites in Diabetes Mellitus Affect the Pathogenesis of Hypertension?, Frontiers in Physiology, 10.3389/fphys.2021.705588, 12 Nayor M, Shah S, Murthy V and Shah R (2021) Molecular Aspects of Lifestyle and Environmental Effects in Patients With Diabetes, Journal of the American College of Cardiology, 10.1016/j.jacc.2021.02.070, 78:5, (481-495), Online publication date: 1-Aug-2021. Rau M, Thiele K, Korbinian Hartmann N, Möllmann J, Wied S, Böhm M, Scharnagl H, März W, Marx N and Lehrke M (2021) Effects of empagliflozin on lipoprotein subfractions in patients with type 2 diabetes: data from a randomized, placebo-controlled study, Atherosclerosis, 10.1016/j.atherosclerosis.2021.06.915, 330, (8-13), Online publication date: 1-Aug-2021. Vrachatis D, Papathanasiou K, Iliodromitis K, Giotaki S, Kossyvakis C, Raisakis K, Kaoukis A, Lambadiari V, Avramides D, Reimers B, Stefanini G, Cleman M, Giannopoulos G, Lansky A and Deftereos S (2021) Could Sodium/Glucose Co-Transporter-2 Inhibitors Have Antiarrhythmic Potential in Atrial Fibrillation? Literature Review and Future Considerations, Drugs, 10.1007/s40265-021-01565-3, 81:12, (1381-1395), Online publication date: 1-Aug-2021. Hundertmark M, Agbaje O, Coleman R, George J, Grempler R, Holman R, Lamlum H, Lee J, Milton J, Niessen H, Rider O, Rodgers C, Valkovič L, Wicks E, Mahmod M and Neubauer S (2021) Design and rationale of the EMPA‐VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure, ESC Heart Failure, 10.1002/ehf2.13406, 8:4, (2580-2590), Online publication date: 1-Aug-2021. Wang Y, Li M, Yu Y, Shi H and Chen R (2021) Efficacy and Safety of Sodium-Glucose Co-Transporter 2 Inhibitors in Heart Failure Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials, Cardiology Plus, 10.4103/2470-7511.327238, 6:3, (156-165), Online publication date: 1-Jul-2021. Cardoso R, Graffunder F, Ternes C, Fernandes A, Rocha A, Fernandes G and Bhatt D (2021) SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: A systematic review and meta-analysis, EClinicalMedicine, 10.1016/j.eclinm.2021.100933, 36, (100933), Online publication date: 1-Jun-2021. Kappel B, Moellmann J, Thiele K, Rau M, Artati A, Adamski J, Ghesquiere B, Schuett K, Romeo F, Stoehr R, Marx N, Federici M and Lehrke M (2021) Human and mouse non‐targeted metabolomics identify 1,5‐anhydroglucitol as SGLT2‐dependent glycemic marker, Clinical and Translational Medicine, 10.1002/ctm2.470, 11:6, Online publication date: 1-Jun-2021. Butt J, Docherty K, Petrie M, Schou M, Kosiborod M, O'Meara E, Katova T, Ljungman C, Diez M, Ogunniyi M, Langkilde A, Sjöstrand M, Lindholm D, Bengtsson O, Martinez F, Ponikowski P, Sabatine M, Solomon S, Jhund P, McMurray J and Køber L (2021) Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction, JAMA Cardiology, 10.1001/jamacardio.2021.0379, 6:6, (678), Online publication date: 1-Jun-2021. Palmiero G, Cesaro A, Vetrano E, Pafundi P, Galiero R, Caturano A, Moscarella E, Gragnano F, Salvatore T, Rinaldi L, Calabrò P and Sasso F (2021) Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects, International Journal of Molecular Sciences, 10.3390/ijms22115863, 22:11, (5863) Zverev Y and Rykunova A (2021) Proposed mechanisms of systemic cardiovascular action of gliflosins, Reviews on Clinical Pharmacology and Drug Therapy, 10.17816/RCF1915-22, 19:1, (5-22) Stanciu G, Rusu R, Bild V, Filipiuc L, Tamba B and Ababei D (2021) Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer's Disease and Diabetes, Biomedicines, 10.3390/biomedicines9050576, 9:5, (576) Bletsa E, Filippas-Dekouan S, Kostara C, Dafopoulos P, Dimou A, Pappa E, Chasapi S, Spyroulias G, Koutsovasilis A, Bairaktari E, Ferrannini E and Tsimihodimos V (2021) Effect of Dapagliflozin on Urine Metabolome in Patients with Type 2 Diabetes, The Journal of Clinical Endocrinology & Metabolism, 10.1210/clinem/dgab086, 106:5, (1269-1283), Online publication date: 23-Apr-2021. Butt J, Nicolau J, Verma S, Docherty K, Petrie M, Inzucchi S, Schou M, Kosiborod M, Langkilde A, Martinez F, Ponikowski P, Sabatine M, Sjöstrand M, Solomon S, Bengtsson O, Jhund P, McMurray J and Køber L (2021) Efficacy and safety of dapagliflozin according to aetiology in heart failure with reduced ejection fraction: insights from the DAPA‐HF trial , European Journal of Heart Failure, 10.1002/ejhf.2124, 23:4, (601-613), Online publication date: 1-Apr-2021. Cai R, Xu Y, Su Q and Dini F (2021) Dapagliflozin in Patients with Chronic Heart Failure: A Systematic Review and Meta-Analysis, Cardiology Research and Practice, 10.1155/2021/6657380, 2021, (1-12), Online publication date: 30-Mar-2021. Li X, Lu Q, Qiu Y, do Carmo J, Wang Z, da Silva A, Mouton A, Omoto A, Hall M, Li J and Hall J (2021) Direct Cardiac Actions of the Sodium Glucose Co‐Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure‐Overload Heart Failure, Journal of the American Heart Association, 10:6, Online publication date: 16-Mar-2021. Vallon V and Verma S (2021) Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function, Annual Review of Physiology, 10.1146/annurev-physiol-031620-095920, 83:1, (503-528), Online publication date: 10-Feb-2021. Dimova R and Tankova T (2020) Does SGLT2 Inhibition Affect Sympathetic Nerve Activity in Type 2 Diabetes?, Hormone and Metabolic Research, 10.1055/a-1298-4205, 53:02, (75-84), Online publication date: 1-Feb-2021. Mollace V, Rosano G, Anker S, Coats A, Seferovic P, Mollace R, Tavernese A, Gliozzi M, Musolino V, Carresi C, Maiuolo J, Macrì R, Bosco F, Chiocchi M, Romeo F, Metra M and Volterrani M (2021) Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review, Nutrients, 10.3390/nu13010257, 13:1, (257) Marton A, Kaneko T, Kovalik J, Yasui A, Nishiyama A, Kitada K and Titze J (2020) Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation, Nature Reviews Nephrology, 10.1038/s41581-020-00350-x, 17:1, (65-77), Online publication date: 1-Jan-2021. Rajpal A, Rahimi L and Ismail‐Beigi F (2020) Factors leading to high morbidity and mortality of COVID ‐19 in patients with type 2 diabetes , Journal of Diabetes, 10.1111/1753-0407.13085, 12:12, (895-908), Online publication date: 1-Dec-2020. Trum M, Riechel J, Lebek S, Pabel S, Sossalla S, Hirt S, Arzt M, Maier L and Wagner S (2020) Empagliflozin inhibits Na + /H + exchanger activity in human atrial cardiomyocytes , ESC Heart Failure, 10.1002/ehf2.13024, 7:6, (4429-4437), Online publication date: 1-Dec-2020. Koufakis T, Mustafa O, Ajjan R, Garcia‐Moll X, Zebekakis P, Dimitriadis G and Kotsa K (2020) The use of sodium‐glucose co‐transporter 2 inhibitors in the inpatient setting: Is the risk worth taking?, Journal of Clinical Pharmacy and Therapeutics, 10.1111/jcpt.13107, 45:5, (883-891), Online publication date: 1-Oct-2020. Qian N and Wang Y (2019) Ketone body metabolism in diabetic and non-diabetic heart failure, Heart Failure Reviews, 10.1007/s10741-019-09857-3, 25:5, (817-822), Online publication date: 1-Sep-2020. Moellmann J, Klinkhammer B, Droste P, Kappel B, Haj-Yehia E, Maxeiner S, Artati A, Adamski J, Boor P, Schütt K, Lopaschuk G, Verma S, Marx N and Lehrke M (2020) Empagliflozin improves left ventricular diastolic function of db/db mice, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 10.1016/j.bbadis.2020.165807, 1866:8, (165807), Online publication date: 1-Aug-2020. Rahimi L, Malek M, Ismail-Beigi F and Khamseh M (2020) Challenging Issues in the Management of Cardiovascular Risk Factors in Diabetes During the COVID-19 Pandemic: A Review of Current Literature, Advances in Therapy, 10.1007/s12325-020-01417-8, 37:8, (3450-3462), Online publication date: 1-Aug-2020. Mulder S, Hammarstedt A, Nagaraj S, Nair V, Ju W, Hedberg J, Greasley P, Eriksson J, Oscarsson J and Heerspink H (2020) A metabolomics‐based molecular pathway analysis of how the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin may slow kidney function decline in patients with diabetes, Diabetes, Obesity and Metabolism, 10.1111/dom.14018, 22:7, (1157-1166), Online publication date: 1-Jul-2020. Cure E and Cumhur Cure M (2020) Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis, Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 10.1016/j.dsx.2020.04.024, 14:4, (405-406), Online publication date: 1-Jul-2020. Schnell O, Valensi P, Standl E and Ceriello A (2020) Comparison of mechanisms and transferability of outcomes of SGLT2 inhibition between type 1 and type 2 diabetes, Endocrinology, Diabetes & Metabolism, 10.10
Referência(s)