Effects of Semaglutide With or Without Concomitant Mineralocorticoid Receptor Antagonist Use in Participants With Type 2 Diabetes and Chronic Kidney Disease: A FLOW Trial Prespecified Secondary Analysis
Peter Rossing, George L. Bakris, Vlado Perkovic, Richard E. Pratley, Katherine R. Tuttle, Kenneth W. Mahaffey, Thomas Idorn, Nicolas Belmar, Heidrun Bosch‐Traberg, Søren Rasmussen, Robert S. Busch, Roland E. Schmieder, Pieter Gillard, Johannes F. E. Mann, FLOW Investigator Group, Andrea Da Porto, A. Oviedo, Alicia Elbert, Elizabeth Gelersztein, Alejandro Chertkoff, A. Wassermann, Miguel Ángel Quevedo, R. J. MacIsaac, S Roger, Richard Phoon, Kerr Pg, Andrew E. Ajani, Shaobo Tan, David Colquhoun, Amanda Mather, P. Gillard, Christophe De Block, Corinne Debroye, Francis Duyck, J.M. Krzesinski, Bruno Lapauw, V. Preumont, C. Vercammen, Zdravko Kamenov, Roza Bobeva, G. Levterov, S. Gerilovska, N. Yabrudi, Bilyana Stoyanovska-Elencheva, Z. Nikitov, Daniel Franco, Gustavo Akerman Augusto, Jean‐Pierre Salles, Luís Henrique Santos Canani, Márcio Krakauer, Maria Cerqueira, Miguel C. Riella, Hitasha Bajaj, Rolf Schlößer, Buki Ajala, Neeru P Aggarwal, R Dumas, Daniel J. O’Keefe, Sean Peterson, George Tsoukas, Chetna Tailor, Richard Tytus, Ronald Akhras, Hasnain Khandwala, Oren Steen, Diane Carbonneau, Jihoon Cha, Ann Steele, G. HOWARD BAILEY, Joseph Berlingieri, Peter Dzongowski, David Z.I. Cherney, Thomas G. Elliott, C. J. Kovacs, Pavel Hamet, BRUCE PERKINS, Karthik Tennankore, Anil Kumar Gupta, Linong Ji, Yan Li, Gongsheng Yuan, Xinzhong Dong, B. Cariou, S. Clavel, Loı̈c Le Marchand, Yves Reznik, Philippe Moulin, E. Legrand, I. Benoit Tricaud, Pierre Gourdy, Philippe Zaoui, Anne Monier, Isabelle Kazes, Dominik Dahl, Melissa M. Esser, Thilo Krüger, Ludger Rose, R. Schmieder, Alexander Segner, Young Hee Lee-Barkey
Abstract
OBJECTIVE: In the Evaluate Renal Function With Semaglutide Once Weekly (FLOW) trial, semaglutide reduced the risk of major kidney and cardiovascular (CV) outcomes and all-cause mortality in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). This prespecified analysis assessed the effects of semaglutide on kidney, CV, and mortality outcomes by baseline mineralocorticoid receptor antagonist (MRA) use. RESEARCH DESIGN AND METHODS: Participants were randomized to once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary kidney outcome was a composite of time to first persistent ≥50% eGFR reduction from baseline, kidney failure, or death from kidney/CV causes. Baseline MRA was predominantly spironolactone; finerenone was only available after recruitment ended. RESULTS: Effects were analyzed by baseline MRA use (n = 257 [136 in the semaglutide group and 121 in the placebo group]) and nonuse (n = 3,276 [1,631 in the semaglutide group and 1,645 in the placebo group]). Semaglutide reduced the risk of the primary kidney outcome by 49% (59 events; hazard ratio [HR] 0.51 [95% CI 0.30, 0.86]) and 21% (682 events; HR 0.79 [95% CI 0.68, 0.92]; P-interaction = 0.12) versus placebo in MRA and non-MRA subgroups, respectively. There was no heterogeneity, favoring the effects of semaglutide on major adverse CV events (MACE) and all-cause mortality in both MRA subgroups (P-interaction > 0.7). Albuminuria at 104 weeks was reduced from baseline with semaglutide by 15% (95% CI -41, 31) in MRA users and 33% (26, 39) in nonusers versus placebo (P-interaction = 0.22). Estimated glomerular filtration rate decline was similarly reduced with semaglutide (P-interaction = 0.71). The safety profile of semaglutide was comparable between subgroups. CONCLUSIONS: In participants with T2D and CKD, consistent benefits of semaglutide on major kidney outcomes, MACE, and all-cause mortality were observed regardless of baseline MRA use.