Effect of Dapagliflozin on Metabolomics and Cardiac Mechanics in Chronic Kidney Disease

Summary

The goal of this study is to better understand the effects of a sodium-glucose transport protein 2 inhibitor, dapagliflozin, added on to standard of care on heart and lung function and circulating metabolites (substances created when our bodies break down food, drugs, or its own tissues) in patients with chronic kidney disease.

Timeline

Start

2024-01-16

Primary completion

2026-09-30

Completion

2026-09-30

Publications

• Background Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-e492. doi: 10.1161/CIR.0000000000000558. Epub 2018 Jan 31. No abstract available.
• Background Saran R, Robinson B, Abbott KC, Agodoa LYC, Bhave N, Bragg-Gresham J, Balkrishnan R, Dietrich X, Eckard A, Eggers PW, Gaipov A, Gillen D, Gipson D, Hailpern SM, Hall YN, Han Y, He K, Herman W, Heung M, Hirth RA, Hutton D, Jacobsen SJ, Jin Y, Kalantar-Zadeh K, Kapke A, Kovesdy CP, Lavallee D, Leslie J, McCullough K, Modi Z, Molnar MZ, Montez-Rath M, Moradi H, Morgenstern H, Mukhopadhyay P, Nallamothu B, Nguyen DV, Norris KC, O'Hare AM, Obi Y, Park C, Pearson J, Pisoni R, Potukuchi PK, Rao P, Repeck K, Rhee CM, Schrager J, Schaubel DE, Selewski DT, Shaw SF, Shi JM, Shieu M, Sim JJ, Soohoo M, Steffick D, Streja E, Sumida K, Tamura MK, Tilea A, Tong L, Wang D, Wang M, Woodside KJ, Xin X, Yin M, You AS, Zhou H, Shahinian V. US Renal Data System 2017 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2018 Mar;71(3 Suppl 1):A7. doi: 10.1053/j.ajkd.2018.01.002. No abstract available.
• Background Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G, Orenstein D, Wilson PW, Woo YJ; American Heart Association Advocacy Coordinating Committee; Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council on Arteriosclerosis; Thrombosis and Vascular Biology; Council on Cardiopulmonary; Critical Care; Perioperative and Resuscitation; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease; Council on Cardiovascular Surgery and Anesthesia, and Interdisciplinary Council on Quality of Care and Outcomes Research. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011 Mar 1;123(8):933-44. doi: 10.1161/CIR.0b013e31820a55f5. Epub 2011 Jan 24.
• Background Ahmed A, Campbell RC. Epidemiology of chronic kidney disease in heart failure. Heart Fail Clin. 2008 Oct;4(4):387-99. doi: 10.1016/j.hfc.2008.03.008.
• Background House AA. Management of Heart Failure in Advancing CKD: Core Curriculum 2018. Am J Kidney Dis. 2018 Aug;72(2):284-295. doi: 10.1053/j.ajkd.2017.12.006. Epub 2018 Feb 23.
• Background Ueda T, Kawakami R, Sugawara Y, Okada S, Nishida T, Onoue K, Soeda T, Okayama S, Takeda Y, Watanabe M, Kawata H, Uemura S, Saito Y. Worsening of renal function during 1 year after hospital discharge is a strong and independent predictor of all-cause mortality in acute decompensated heart failure. J Am Heart Assoc. 2014 Nov 4;3(6):e001174. doi: 10.1161/JAHA.114.001174.
• Background Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000 Mar 1;35(3):681-9. doi: 10.1016/s0735-1097(99)00608-7.
• Background Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, Granger CB, Michelson EL, Ostergren J, Cornel JH, de Zeeuw D, Pocock S, van Veldhuisen DJ; Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Investigators. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006 Feb 7;113(5):671-8. doi: 10.1161/CIRCULATIONAHA.105.580506.
• Background Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Nov 23;377(21):2099. doi: 10.1056/NEJMc1712572. No abstract available.
• Background Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016 Mar 17;374(11):1094. doi: 10.1056/NEJMc1600827. No abstract available.
• Background Herrington WG, Savarese G, Haynes R, Marx N, Mellbin L, Lund LH, Dendale P, Seferovic P, Rosano G, Staplin N, Baigent C, Cosentino F. Cardiac, renal, and metabolic effects of sodium-glucose co-transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc task force on sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail. 2021 Aug;23(8):1260-1275. doi: 10.1002/ejhf.2286. Epub 2021 Jul 20.
• Background Verma S, Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, Dyck JE, Uddin GM, Oudit GY, Mayoux E, Lehrke M, Marx N, Lopaschuk GD. Empagliflozin Increases Cardiac Energy Production in Diabetes: Novel Translational Insights Into the Heart Failure Benefits of SGLT2 Inhibitors. JACC Basic Transl Sci. 2018 Aug 26;3(5):575-587. doi: 10.1016/j.jacbts.2018.07.006. eCollection 2018 Oct.
• Background 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 Jul;39(7):1115-22. doi: 10.2337/dc16-0542.
• Background Kumar N, Garg A, Bhatt DL, Sabongui S, Gupta N, Chaudhry S, Arena R, Verma S. Empagliflozin improves cardiorespiratory fitness in type 2 diabetes: translational implications. Can J Physiol Pharmacol. 2018 Nov;96(11):1184-1187. doi: 10.1139/cjpp-2018-0359.
• Background Verma S, Garg A, Yan AT, Gupta AK, Al-Omran M, Sabongui A, Teoh H, Mazer CD, Connelly KA. Effect of Empagliflozin on Left Ventricular Mass and Diastolic Function in Individuals With Diabetes: An Important Clue to the EMPA-REG OUTCOME Trial? Diabetes Care. 2016 Dec;39(12):e212-e213. doi: 10.2337/dc16-1312. Epub 2016 Sep 27. No abstract available.
• Background Bagby SP. Obesity-initiated metabolic syndrome and the kidney: a recipe for chronic kidney disease? J Am Soc Nephrol. 2004 Nov;15(11):2775-91. doi: 10.1097/01.ASN.0000141965.28037.EE. No abstract available.
• Background Smogorzewski M, Piskorska G, Borum PR, Massry SG. Chronic renal failure, parathyroid hormone and fatty acids oxidation in skeletal muscle. Kidney Int. 1988 Feb;33(2):555-60. doi: 10.1038/ki.1988.33.
• Background Rhee EP. Metabolomics and renal disease. Curr Opin Nephrol Hypertens. 2015 Jul;24(4):371-9. doi: 10.1097/MNH.0000000000000136.
• Background Hocher B, Adamski J. Metabolomics for clinical use and research in chronic kidney disease. Nat Rev Nephrol. 2017 May;13(5):269-284. doi: 10.1038/nrneph.2017.30. Epub 2017 Mar 6.
• Background Grams ME, Shafi T, Rhee EP. Metabolomics Research in Chronic Kidney Disease. J Am Soc Nephrol. 2018 Jun;29(6):1588-1590. doi: 10.1681/ASN.2018030256. Epub 2018 May 3. No abstract available.
• Background Kalim S, Rhee EP. An overview of renal metabolomics. Kidney Int. 2017 Jan;91(1):61-69. doi: 10.1016/j.kint.2016.08.021. Epub 2016 Sep 28.
• Background Chen DQ, Cao G, Chen H, Argyopoulos CP, Yu H, Su W, Chen L, Samuels DC, Zhuang S, Bayliss GP, Zhao S, Yu XY, Vaziri ND, Wang M, Liu D, Mao JR, Ma SX, Zhao J, Zhang Y, Shang YQ, Kang H, Ye F, Cheng XH, Li XR, Zhang L, Meng MX, Guo Y, Zhao YY. Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan. Nat Commun. 2019 Apr 1;10(1):1476. doi: 10.1038/s41467-019-09329-0.
• Background Wang F, Sun L, Sun Q, Liang L, Gao X, Li R, Pan A, Li H, Deng Y, Hu FB, Wu J, Zeng R, Lin X. Associations of Plasma Amino Acid and Acylcarnitine Profiles with Incident Reduced Glomerular Filtration Rate. Clin J Am Soc Nephrol. 2018 Apr 6;13(4):560-568. doi: 10.2215/CJN.07650717. Epub 2018 Mar 8.
• Background Hiltunen TP, Rimpela JM, Mohney RP, Stirdivant SM, Kontula KK. Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension. PLoS One. 2017 Nov 9;12(11):e0187729. doi: 10.1371/journal.pone.0187729. eCollection 2017.
• Background Cozzolino M, Mangano M, Stucchi A, Ciceri P, Conte F, Galassi A. Cardiovascular disease in dialysis patients. Nephrol Dial Transplant. 2018 Oct 1;33(suppl_3):iii28-iii34. doi: 10.1093/ndt/gfy174.
• Background Zewinger S, Kleber ME, Rohrer L, Lehmann M, Triem S, Jennings RT, Petrakis I, Dressel A, Lepper PM, Scharnagl H, Ritsch A, Thorand B, Heier M, Meisinger C, de Las Heras Gala T, Koenig W, Wagenpfeil S, Schwedhelm E, Boger RH, Laufs U, von Eckardstein A, Landmesser U, Luscher TF, Fliser D, Marz W, Meinitzer A, Speer T. Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. Eur Heart J. 2017 May 21;38(20):1597-1607. doi: 10.1093/eurheartj/ehx118.
• Background Potocnjak I, Radulovic B, Degoricija V, Trbusic M, Pregartner G, Berghold A, Meinitzer A, Frank S. Serum concentrations of asymmetric and symmetric dimethylarginine are associated with mortality in acute heart failure patients. Int J Cardiol. 2018 Jun 15;261:109-113. doi: 10.1016/j.ijcard.2018.03.037. Epub 2018 Mar 11.
• Background Schepers E, Barreto DV, Liabeuf S, Glorieux G, Eloot S, Barreto FC, Massy Z, Vanholder R; European Uremic Toxin Work Group (EUTox). Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. Clin J Am Soc Nephrol. 2011 Oct;6(10):2374-83. doi: 10.2215/CJN.01720211. Epub 2011 Aug 4.
• Background Memon L, Spasojevic-Kalimanovska V, Stanojevic NB, Kotur-Stevuljevic J, Simic-Ogrizovic S, Giga V, Dopsaj V, Jelic-Ivanovic Z, Spasic S. Are levels of NT-proBNP and SDMA useful to determine diastolic dysfunction in chronic kidney disease and renal transplant patients? J Clin Lab Anal. 2013 Nov;27(6):461-70. doi: 10.1002/jcla.21628.
• Background Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, DeFronzo RA, Norton L, Abdul-Ghani M. Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes. Diabetes Care. 2016 Nov;39(11):2036-2041. doi: 10.2337/dc15-2688. Epub 2016 Aug 25.
• Background Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, Pieber TR, Muscelli E. Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. 2016 May;65(5):1190-5. doi: 10.2337/db15-1356. Epub 2016 Feb 9.
• Background Mulder S, Hammarstedt A, Nagaraj SB, Nair V, Ju W, Hedberg J, Greasley PJ, Eriksson JW, Oscarsson J, Heerspink HJL. 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 Obes Metab. 2020 Jul;22(7):1157-1166. doi: 10.1111/dom.14018. Epub 2020 Mar 25.
• Background Kappel BA, Lehrke M, Schutt K, Artati A, Adamski J, Lebherz C, Marx N. Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease. Circulation. 2017 Sep 5;136(10):969-972. doi: 10.1161/CIRCULATIONAHA.117.029166. No abstract available.
• Background Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, Fulcher G, Barrett TD, Shaw W, Desai M, Matthews DR, Neal B. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program. Circulation. 2018 Jul 31;138(5):458-468. doi: 10.1161/CIRCULATIONAHA.118.034222.
• Background Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018 Jan 23;137(4):323-334. doi: 10.1161/CIRCULATIONAHA.117.032038. Epub 2017 Nov 13.
• Background Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):371-80; discussion 380. doi: 10.1161/CIRCULATIONAHA.114.012957. Epub 2014 Dec 22.
• Background Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, Wishart DS, Xia J. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res. 2018 Jul 2;46(W1):W486-W494. doi: 10.1093/nar/gky310.

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Indications