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Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial

Authors
Wanner, ChristophHeerspink, Hiddo J. L.Zinman, BernardInzucchi, Silvio E.Koitka-Weber, AudreyMattheus, MichaelaHantel, StefanWoerle, Hans-JuergenBroedl, Uli C.von Eynatten, MaximilianGroop, Per-HenrikEMPA-REG OUTCOME InvestigatorsAizenberg, D.Ulla, M.Waitman, J.De Loredo, L.Farias, J.Fideleff, H.Lagrutta, M.Maldonado, N.Colombo, H.Ferre Pacora, F.Wasserman, A.Maffei, L.Lehman, R.Selvanayagam, J.d'Emden, M.Fasching, P.Paulweber, B.Toplak, H.Luger, A.Drexel, H.Prager, R.Schnack, C.Schernthaner, G.Fliesser-Goerzer, E.Kaser, S.Scheen, A.Van Gaal, L.Hollanders, G.Kockaerts, Y.Capiau, L.Chachati, A.Persu, A.Hermans, M.Vantroyen, D.Vercammen, C.Van de Borne, P.Mathieu, C.Benhalima, K.Lienart, F.Mortelmans, J.Strivay, M.Vereecken, G.Keymeulen, B.Lamkanfi, F.Chacra, A.Eliaschewitz, F.Zanella, M.Faludi, A.Bertolami, M.Hayashida, C.Nunes Salles, J.Monte, O.Dinato, M.Manenti, E.Rassi, N.Halpern, A.Lima Filho, M.Ayoub, J.Felicio, J.Borges, J.Gross, J.Sgarbi, J.Betti, R.Tiburcio, A.Purisch, S.Schmid, H.Takahashi, M.Castro, M.Rea, R.Hissa, M.Geloneze Neto, B.Saraiva, J.Henein, S.Lochnan, H.Imran, S. A.Clayton, D.Bayly, K.Berlingieri, J.Boucher, P.Chan, Y.Gupta, M.Chehayeb, R.Ouellett, A.Ur, E.Woo, V.Zinman, B.St Amour, E.Terront Lozano, M.Yupanqui Lozno, H.Urina, M.Lopez Jaramillo, P.Jaramillo, N.Sanchez, G.Perez, G.Tusek, S.Mirosevic, G.Goldoni, V.Jurisic-Erzen, D.Balasko, A.Balic, S.Drvodelic-Sunic, E.Varzic, S. CaneckiMachkova, M.Weiner, P.Lastuvka, J.Olsovsky, J.Krarup, T.Ridderstrale, M.Tarnow, L.Boesgaard, T. WellovLihn, A. SaetreChristensen, P.Juhl, H.Urhammer, S.Lund, P.Adojaan, B.Jakovlev, U.Lanno, R.Lubi, M.Marandi, T.Gouet, D.Courreges, J.Zaoui, P.Choukroun, G.Petit, C.Formagne, L.Estour, B.Mabire, P.Daugenet, C.Lemarie, B.Clavel, S.Aure, P.Remaud, P.Halimi, J.Hadjadj, S.Couffinhal, T.Glonti, S.Metreveli, D.Lominadze, Z.Giorgadze, E.Burtchuladze, T.Javashvili, L.Kurashvili, G.Kurashvili, R.Virsaladze, D.Nadareishvili, L.Khomasuridze, A.Cahill, T.Green, F.MacRury, S.Waldron, M.Middleton, A.McKnight, J.Pearson, E.Butler, M.Choksi, M.Caldwell, I.Farmer, I.Wyatt, N.Patrick, J.O'Brien, I.Devers, M.Bousboulas, S.Pappas, S.Piaditis, G.Vryonidou, A.Tentolouris, N.Karamitsos, K.Manes, C.Benroubi, M.Avramidis, I.Ozaki, R.Tan, K.Siu, S.Tsang, C.Dudas, M.Nagy, K.Salamon, C.Ip, T.Geroo, L.Patkay, J.Tabak, A.Juhasz, F.Szentpeteri, I.Tamas, G.Ghaisas, N.Bantwal, G.Mohan, V.Gupta, J.Sadhu, N.Kulkarni, A.Garg, N.Reddy, S.Deshpande, N.Gutlapalli, K.Pillai, M.Premchand, R.Badgandi, M.Jain, S.Aravind, S.Shamanna, P.Pandey, A.Gupta, S.Pramono, B.Saksono, H. DanteAgung, P.Wahono, S. DjokoSuastika, K.Tanggo, Y.Juwana, Y.Siswanto, B.Adawi, F.Efrati, S.Mazen, E.Bashkin, A.Herskovits, T.Jaffe, A.Schiff, E.Wainstein, J.Taddei, S.Aiello, A.Arca, M.Calabro, P.Cignarelli, M.Fioretto, P.Reggiani, G. MarchesiniGnasso, A.Marchionni, N.Marsilii, A.Bucci, M.Mezzetti, A.Pozzilli, P.Colivicchi, F.Santini, M.Moro, E.Toscano, V.Fucili, A.Semplicini, A.Monno, S.Furui, K.Higashiue, S.Hiramatsu, N.Kawamitsu, K.Takenaka, T.Takahashi, H.Hojo, F.Onishi, Y.Izumino, K.Okubo, M.Wakida, Y.Kondo, Y.Hieshima, K.Jinnouchi, H.Suzuki, A.Ito, M.Park, S.Kim, Y.Hong, T.Park, H.Gwon, H.Kim, H.Kang, K.Jeong, M.Seung, K.Lim, D.Rha, S.Tahk, S.Yang, J.Yoon, J.Shin, M.Kim, D.Jeong, J.Ahmad, N. NikMustafa, N.Mohamed, W. WanFung, Y.Ghani, R. AbdulChandramouli, A.Chee, K.Kadir, K. AbdulLing, K.Abu Hassan, M.Foo, S.Lee, S.Garcia Hernandez, P.Aguilar-Salinas, C.Vidrio Velazquez, M.Flores, F.Alpizar Salazar, M.Micher Escalante, D.Garcia Soria, M.Cardona Munoz, E.Storms, G.Schaper, N.Kooy, A.Krekels, M.van Bemmel, T.Verhoeven, R.Mulder, H.Oldenburg-Ligtenberg, P.Gonkel, F.de Jong, A.van Soest, J.Viergever, P.Mevissen, H.Lochorn, G.Zwiers, G.Hoogslag, P.Ronner, E.Nierop, P.Al-Windy, N.Kragten, J.Dekelver, P.Benatar, J.Krebs, J.Scott, R.Heggen, E.Berz, A.Fossum, C.Hurtig, U.Langslet, G.Baranowski, M.Sparby, J.Karlsson, T.Karlsson, ThomasDelgado Torres, C.Rodriguez Escudero, A.Lisson, R.Allemant Maldonado, A.Gallardo Rojas, W.Gonzales Bravo, L.Lema Osores, J.Farfan, J.Zapata, L.Godoy Junchaya, J.Roldan Concha, Y.Urquiaga Calderon, J.Sy, R.Tan, G.Aquitania, G.De Los Santos, G.Panelo, A.Roderos, O.Rosales, R.Toledo, R.Liwag, A.Ramoncito, H.Skokowska, E.Krzyzagorska, E.Ogorek, M.Wojnowski, L.Spyra, J.Konieczny, M.Piesiewicz, W.Kus, W.Ocicka-Kozakiewicz, A.Orlowska-Kunikowska, E.Zmuda, W.Duarte, S.Leitao, A.Monteiro, P.Rita, H.Salgado, V.Pinto, L.Queiros, J.Teixeira, J.Rogado, C.Duarte, R.Sobral do Rosario, F.Silva, A.Andrade, L.Velez, M.Brazao, M.Istratoaie, O.Lichiardopol, R.Catrinoiu, D.Militaru, C.Zetu, C.Barbonta, D.Cosma, D.Crisan, C.Pop, L.Esip, V.Khetagurova, F.Petrov, A.Arutyunov, G.Boyarkin, M.Agafyina, A.Vorokhobina, N.Petunina, N.Libov, I.Zalevskaya, A.Nikolaev, K.Barbarash, O.Potemkin, V.Bystrova, A.Krasilnikova, E.Barbarich, V.Chumakova, G.Tarasov, N.Meleshkevich, T.Zateyshchikov, D.Lantseva, O.Belenkiy, D.Obrezan, A.Rossolko, L.Fillipova, E.Yakhontova, P.Khokhlov, A.Tan, R.Sum, C.Chang, H.Distiller, L.Pretorius, M.Nortje, H.Mitha, E.Burgess, L.Blignaut, S.Venter, T.Moodley, R.Lombaard, J.Govind, U.Naidoo, V.Mookadam, M.Engelbrecht, J.Omar, M.Jurgens, J.Podgorski, G.Vawda, H.Naidoo, D.Emanuel, S.Roodt, A.Amod, A.Van Zyl, L.Segura, J.Brito, M.Fernandez-Cruz, A.Artola, S.Iglesias, R.Toural, E.Garcia-Ortiz, L.Saban, J.Mesa, J.Vidal, J.Linares, J.del Canizo, F.Rigla, M.Suarez, C.Llorente, I.Moreno, B.Antoli, A.Gomez Peralta, F.Iglesias, M.Pereg, V.de Teresa, L.Camafort, M.Trescoli, C.Satarasinghe, R.Somasundaram, N.Siyambalapitiya, S.Antonypillai, C.Bulugahapitiya, D.Medagama, U.Huang, C.Lu, Y.Hwang, J.Chiang, C.Wen, M.Chen, J.Lai, W.Chang, K.Wang, J.Yeh, H.Kriangsak, P.Deerochanawong, C.Suwanwalaikorn, S.Mangklabruks, A.Kaewsuwanna, P.Piyayotai, D.Iabluchanskyi, M.Samoylov, O.Godlevska, O.Kovalyova, O.Voloshyna, O.Tseluyko, V.Zotov, S.Vykhovanyuk, I.Dulgeroff, A.Mayfield, R.Zaniewski-Singh, M.Ullal, J.Aloi, J.De La Rosa, R.Mosely, J.Wittmer, B.Aronoff, S.Rosenfeld, J.Seidner, M.Warren, M.Fishman, N.Weiss, R.Arif, A.Sandberg, M.Lewis, D.Ball, E.Graf, R.Breton, C.Tamayo, R.Richards, R.Cefalu, W.Uwaifo, G.Zayour, D.Hoffman, J.Fitz-Patrick, D.Khan, B.Blaze, K.Bressler, P.Halpern, S.Chappell, D.Bergenstal, R.Cuddihy, R.Matfin, G.Freedman, Z.Gonzalez-Campoy, J.Lerman, S.Rendell, M.Sitar, S.Reeves, M.Howard, T.Soufer, J.Miranda-Palma, B.Laliotis, A.Shomali, M.Teltser, M.Hurley, D.Morawski, E.Cherlin, R.Houchin, V.Welch, M.Goytia-Leos, D.Syed, M.Kowaloff, E.Weinrauch, L.Peniston, J.Brockmyre, A.First, B.Feld, L.Huffman, D.Nassim, O.Gottschlich, G.Patel, A.Knopke, C.Hernandez, M.Diaz, J.Giugliano, G.Nicasio, J.Eagerton, D.Huntley, R.Reed, J., IIIMagee, M.Hippert, R.Sofley, C., Jr.Alzohaili, O.Levins, P.Anspach, R.Shah, S.Brusco, O.Naidu, J.Lindenbaum, J.Jacks, R.Hammond, G.Arena, C.Saxman, K.Mach, M.Kerstein, H.Kereiakes, D.Wahlen, J.Wehmeier, K.Chaykin, L.Rothman, J.Fogelfeld, L.Stroger, John H., Jr.Bittar, N.Rosenstock, J.Kayne, D.Navarro, J.Colfer, H.Mokshagundam, S.Shandilya, L.Connery, L.Wysham, C.Dela Llana, A.Jardula, M.MacAdams, M.Flippo, G.Heurich, E.Curtis, C.Sanders, D.Rawls, R.Velazquez, F.Osea, E.Mahood, K.Feldman, G.Eder, F.Riley, E.Fowler, W.Jain, M.Shepard, M.Schear, M.Barker, B.Strout, C.Obiekwe, O.Shanik, M.Green, C.Blakney, E.Roberson, K.Bretton, E.Pish, R.Kaveh, K.Maynard, B.Barager, W.Soldyshev, R.Austin, B.Parmar, P.Simpson, R.Chauhan, A.Kasper, J.Burr, R.Patel, N.Mariano, H.Pluto, T.Bratcher, C.Juarez, M.Levinson, L.Awad, A.Longshaw, K.Hoffman, K.Richwine, R.Molter, D.Boscia, J., IIIKowalyk, S.Lemis, P.Liss, J.Orr, R.Riser, J.Wood, J.Ubani, A.Paine, W.Hassani, F.Miranda, F.Hansen, V.Hansen, Val R.Farris, N.Bowden, R.Ajani, D.Maw, K.Andersen, J.Bergman, B.Dunmyer, S.Brandon, D.Anderson, M.Bononi, P.Prawer, J.Seidman, B.Cruz, H.Wilks, K.DiSanto, L.Buynak, R.Christensen, T.Denker, P.Koppel, W.Stedman, M.Lewy-Alterbaum, L.Karim, S.Shapiro, J.Gardner, T.Oskin, T.Gabra, N.Malano, J.
Issue Date
Nov-2018
Publisher
Lippincott Williams & Wilkins Ltd.
Keywords
chronic kidney disease; diabetes mellitus; randomized controlled trials
Citation
Journal of the American Society of Nephrology : JASN, v.29, no.11, pp 2755 - 2769
Pages
15
Indexed
SCI
SCIE
SCOPUS
Journal Title
Journal of the American Society of Nephrology : JASN
Volume
29
Number
11
Start Page
2755
End Page
2769
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/52258
DOI
10.1681/ASN.2018010103
ISSN
1046-6673
1533-3450
Abstract
Background Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. Methods Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). Results Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (−0.77; 95% confidence interval, −0.83 to −0.71; placebo: 0.01; 95% confidence interval, −0.08 to 0.10; P<0.001). However, annual mean slope (ml/min per 1.73 m2 per year) did not decline with empagliflozin during chronic treatment (empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: −1.46; 95% confidence interval, −1.74 to −1.17; P<0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m2 per week) increased and mean eGFR returned toward baseline level only in the empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo −0.02; 95% confidence interval, −0.12 to 0.08; P<0.001). Results were consistent across patient subgroups at higher CKD risk. Conclusions The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.
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Anam Hospital (Department of Cardiology, Anam Hospital)
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