Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

著者: John Deanfield, Subodh Verma, Benjamin M. Scirica, Steven E. Kahn, Scott S. Emerson, Donna H. Ryan, Ildiko Lingvay, Helen M. Colhoun, Jorge Plutzky, Mikhail Kosiborod, G Kees Hovingh, Søren Hardt‐Lindberg, Ofir Frenkel, Peter Weeke, Søren Rasmussen, Assen Goudev, Chim C. Lang, Miguel Urina‐Triana, Mikko Pietilä, A. Michael Lincoff, A Michael Lincoff, Mitsunori Abe, Rajpal K Abhaichand, Walter P Abhayaratna, Atul Abhyankar, Imran B Zainal Abidin, Hiba Abou Assi, Jose L Accini Mendoza, Mine Adas, John M Agaiby, Devendra K Agarwal, Maher Agha, Azazuddin Ahmed, Petteri Ahtiainen, Elmar Aigner, Naik Ajay, Norsiah Ali, Amer Al-Karadsheh, Roy Allison, Dale C Allison, Diana Alpenidze, Yuksel Altuntas, Ayham Al-Zoebi, Roy Ambuj, John Amerena, Robert J Anderson, Toshiaki Ando, Robert Andrews, Elizaveta Antonova, Karl-Friedrich Appel, Flávia B Arantes, Mustafa Araz, Yaron Arbel, José L Arenas León, Georgia Argyrakopoulou, Mehrdad Ariani, Maria A Arias Mendoza, Ahmed A Arif, Jaspal Arneja, Vanita R Aroda, Louis J Aronne, Margaret Arstall, Njaimeh Asamoah, Milika Asanin, Hanid Audish, Rodica Avram, Aysha Badat, Corin V Badiu, Wa'el Bakdash, Okan S Bakiner, Vuyokazi N Bandezi, Liew H Bang, Sandeep Bansal, Marietta Baranyai, Olga Barbarash, Mark Barber, Otis Barnum, Gilles Barone Rochette, Amir Bashkin, Seth Baum, Harold E Bays, Alberto E Bazzoni Ruiz, Maciej Beckowski, Yaswin Beerachee, Srikanth Bellary, Lidia Belousova, Martin Berk, Marc Bernstein, Cesare Berra, Isaac Beshay, Ajit Bhagwat, Arti Bhan, William C Biggs, Liana Billings, Fahed Bitar, Bradley Block, Simona Bo, Pawel Bogdanski, Olga O Bolshakova, Alla A Boshchenko, Hayden Bosworth, Rodrigo Botero Lopez, Morten Bôttcher, Ronald Bourgeois, Donald Brautigam, Cristian F Breton, Andrew Broadley, Andrew P Brockmyre, Steven K Brodie, Marco Bucci, Hrvoje Budincevic, Matthew J Budoff, Barry Buffman, Nediljka Buljubasic, Supawan Buranapin, Lesley Burgess, Bartolomé Burguera, Olena Buriakovska, Silvio Buscemi, Robert Busch, John B Buse, Robert Buynak, Maria Byrne, Elena Caceaune, Alberto J Cadena Bonfanti, Cornell V Calinescu, Robert S Call, Silvija Canecki Varzic, Kevin Cannon, Matt Capehorn, Bertrand Cariou, Jeffrey Carr, Rodolfo Carrillo-Jimenez, Marcelo Casas, Almudena Castro, Ahmet Celik, Cintia Cercato, Ondrej Cermak, James Y Cha, Carolina Chacon, Tira Chaicha-Brom, Sandeep Chandra, Mohamed Chettibi, Julia Chevts, Johann Christopher, Witold Chrustowski, Adriana Cif, Rebecca Clark, Wayne Clark, Piers Clifford, Kathleen Coetzee, Giulia Cogni, Anna Maria Colao, David M Colquhoun, Mauricio Concha, Jonathan Condit, Christian Constance, Ciprian Constantin, Silviana Constantinescu, Clive Corbett, George M Cornett, Marcelo Correia, Fiorenzo Cortinovis, Dana Cosma, Steven Creely, David Cross, Brian Curtis, Wojciech Czochra, Nizar Y Daboul, Selcuk Dagdelen, Ronald D'agostino, Cuong Dang, Sudip Datta, Ashwini K Davuluri, Saleem Y Dawood, Douwe M De Jong, Carmen De La Cuesta, Manuel O De Los Rios Ibarra, Carmen De Pablo, Michel De Pauw, Alexander Dela Llana, Maja Delibasic, Diana Delic-Brkljacic, Thibaud Demicheli, Ralf J Denger, Devang Desai, Piyush Desai, Cyrus V Desouza, Dror Dicker, Nemanja Djenic, Simon Dobson, Masayuki Doi, Jesse A Doran, Reinhart Dorman, Francesco Dotta, Carl E Dukes, Ernesto Duronto, Ronen Durst, Irina V Dvoryashina, Iftikhar O Ebrahim, Holger Eggebrecht, Kenneth Egstrup, Elif I Ekinci, Björn Eliasson, Ken Eliasson, Georgiana Enache, Dan Enculescu, Patrick English, Polina Ermakova, Olga Ershova, Hirotaka Ezaki, Marat Ezhov, Eduardo Farias, Javier M Farias, Pedro S Farsky, Daniel Ferreira, Pierre Filteau, Matthew P Finneran, Eric M Folkens, Alberto G Fonseca, Luisa Fonseca, Steven Fordan, Nyda Fourie, Sara França, Denise R Franco, Edward Franek, Keith Friedman, Lucia Frittitta, Michael Froer, Krunoslav Fuckar, Kenshi Fujii, Ryoko Fujita, Yasushi Fukushima, Mohamed Fulat, Mahesh Fulwani, Grzegorz Gajos, Albert Galyavich, Michael L Gambill, Dheeraj Gandotra, Gandy Winston, Pedro A Garcia Hernandez, Raymundo García Reza, Naveen Garg, Sandeep Garg, William T Garvey, Juan C Garza, Blandine Gatta-Cherifi, Valeri Gelev, Steven A Geller, Jeffrey G Geohas, Borislav Georgiev, Adline Ghazi, Matthew P Gilbert, Olga Gilinskaya, Gunnar Gislason, Dilek Gogas Yavuz, Olga González Albarrán, Ivan G Gordeev, Sidney C Gorton, Assen Goudev, Tone Gretland Valderhaug, Bjorn Groenemeijer, Ibrahim Gul, Lars Gullestad, Irina Gurieva, Galina N Guseva, Andreas Hagenow, Martin Haluzik, Sigrun Halvorsen, Naima Hammoudi, Keiichi Hanaoka, Nicolae Hancu, Ursula Hanusch, Kathleen Harris, Barry Harris, Michael Hartleib, Aaron N Hartman, Yoshiki Hata, Brian Heimer, Lee Herman, William Herzog, Eric Hewitt, Peter Heymer, Shirish Hiremath, Joeran Hjelmesaeth, Rasmus Geir Høgalmen, Hans Olav Høivik, Helene Holmer, Olha Horoshko, Patricia M Houser, Jens D Hove, I-Chang Hsieh, Jean-Sébastien Hulot, Zanariah Hussein, Tetiana Ilashchuk, Erkki Ilveskoski, Irina Ipatko, Ali Iranmanesh, Tsuyoshi Isawa, Moises Issa, Bruce Iteld, Takamasa Iwasawa, Danish Jabbar, Richard A Jackson, Ewart Jackson-Voyzey, Stephan Jacob, Naseem A Jaffrani, Michael F Jardula, Ania Jastreboff, Svend E Jensen, Terri Jerkins, Silvia A Jimenez-Ramos, Sawhney Jitendra Pal Singh, Wallace Johnson, John M Joyce, Malgorzata Jozefowska, Prakash Jugnundan, Wolfgang Jungmair, Jaroslaw Jurowiecki, Toshiaki Kadokami, Dhiman Kahali, Gerd Kahrmann, Sergio E Kaiser, Piotr Kalmucki, Mehmet Kanadasi, David Kandath, Grzegorz Kania, J Kannan, Cornelia Kapp, Agnieszka Karczmarczyk, Athanasios Kartalis, Susanne Kaser, Sazzli Shahlan Kasim, Richard Kastelic, Toshiaki Kato, Tzvetana Katova, Upendra Kaul, Alexandra Kautzky-Willer, Masahiro Kawanishi, Meral Kayikcioglu, Elena E Kazakova, Philip Keeling, Hans-Peter Kempe, Dean J Kereiakes, Mathieu Kerneis, Tiina Keski-Opas, Suhail Khadra, Larisa Khaisheva, Marina Kharakhulakh, Tatiana Khlevchuk, Jeffrey Khoo, Songsak Kiatchoosakun, Noriyuki Kinoshita, Masaharu Kinoshita, Ryoji Kitamura, Arihiro Kiyosue, Irina Klavina, Eric J Klein, Zdenek Klimsa, David Klonoff, Eric Klug, Zhanna Kobalava, Satoshi Kodera, Tokushi Koga, Alexander Kokkinos, Pavel Koleckar, László Könyves, Michael J Koren, Adrian P Kormann, Karam Kostner, Kristin Kreutzmann, Saravanan Krishinan, Sathya S Krishnasamy, Inga Krivosheeva, Ivan Kruljac, Ted Kubicki, Ladislav Kuchar, Monika Kujawiak, Hideyuki Kunishige, Melinda Kurtinecz, Hugo R Kurtz Lisboa, Mykola Kushnir, Yulian Kyyak, Arija Lace, Timo Lakka, Nebojsa Lalic, Katarina Lalic, Vaia Lambadiari, Leonidas Lanaras, Chim Lang, Marie-France Langlois, Joseph Lash, Gustavs Latkovskis, David Lau, José Roberto Lazcano Soto, Carel Le Roux, Gilbert N Ledesma, Li Yuan Lee, Thung-Lip Lee, Kelvin Lee, Michael Lehrke, Silmara O Leite, Agata Leksycka, Thomas Lenzmeier, Frida Leonetti, Viktoriia Leonidova, Norman Lepor, Melissa Leung, Olena Levchenko, Peter Levins, Louis J Levy, Matthew Lewis, Evangelos Liberopoulos, Idit Liberty, Carl-Johan Lindholm, Ildiko Lingvay, Ales Linhart, Ming-En Liu, Jenny Liu, Holly Lofton, Timothy Logemann, Johannes J Lombaard, Landman Lombard, Richard Lorraine, Charles F Lovell, Bernhard Ludvik, Monika Lukaszewicz, Géza Lupkovics, Steven Lupovitch, Sirona Lupu, Mary Lynch, Zoreslava Lysak, Tatyana A Lysenko, Hajime Maeda, Itaru Maeda, Michael Mæng, Ajay U Mahajan, Vincent Maher, Lilia N Maia, Ellen M Makotoko, Alexis Malavazos, Jan Malecha, Emilia Malicherova, Mamoru Manita, Edoardo Mannucci, Viacheslav Mareev, Liliana Marin, Tatiana Markova, Steven P Marso, F.M.A.C. Martens, Cuper Martinez, Carlos A Martinez Cano, Cristina Martins, Luis Masmiquel Comas, Takashi Matsumoto, Kenneth Mcdonald, Barbara Mcgowan, Frank Mcgrew, Barry K Mclean, David D Mcpherson, Juan Francisco Merino Torres, Peter Meyers, Sebastian Meyhöfer, Pedro Mezquita Raya, Maria Milanova, Davor Milicic, Gary Miller, Richard E Mills, Nicoleta M Mîndrescu, Geltrude Mingrone, Dotska A Minkova, Marco Mirani, Alexander Miras, Cristina V Mistodie, Satoru Mitomo, Sanjay Mittal, Taiji Miyake, Naomasa Miyamoto, David Molony, Pedro Monteiro, Thomas Mooe, Naeem Moosa, Cristobal Morales Portillo, Enrique C Morales Villegas, Emily J Morawski, Claire Morbey, Robert P Morin, Kuniaki Morisaki, Magdalena Morosanu, Ofri Mosenzon, Yuriy Mostovoy, Iqbal Munir, Fabrizio Muratori, Ryan Murray, Avinash Murthy, Min Myint, Galyna Myshanych, Valerica Nafornita, Takuya Nagano, Sunil Nair, Samer N Nakhle, Masahiro Natsuaki, Bindu M Nayak, Djamel Eddine Nibouche, Stephen Nicholls, José C Nicolau, Georgiana Nicolescu, Peter Nierop, Leo Niskanen, George Ntaios, Ottar Kjell Nygård, Joshua B Oaks, Andrey Obrezan, Philip O'donnell, Mitsutoshi Oguri, Abdurrahman Oguzhan, Fumiki Oh, Mitsuru Ohsugi, Yoshio Okada, Hideki Okayama, Adriana Onaca, Haruhiko Onaka, Patrick Oneil, Tiong Kiam Ong, Stephen Ong, Yasuhiro Ono, Paul J Opsahl, Lucyna Ostrowska, Alejandra Oviedo, Oner Ozdogan, Ebru Ozpelit, Emmanouil Pagkalos, Uberto Pagotto, Dénes Páll, Amritanshu- Shekhar Pandey, Oleksandr Parkhomenko, Krishna Malakondareddy Parvathareddy, Minesh B Patel, Sotirios Patsilinakos, Neil Paul, Sue Pedersen, Isabel Pereira, Edward Scott Pereira, Paula Perez Terns, Elba A Perez-Vargas, Yulia Pergaeva, Alexander Perkelvald, Andrey B Peskov, Jonathan Peter, Karina Peters, Catherine Petit, Ivo Petrov, Athena Philis-Tsimikas, Mikko Pietilä, Fausto Pinto, Annamária Piros, Dilok Piyayotai, Dmitriy Platonov, Paul Poirier, Lavinia Pop, Bogdan Popa, Rodica Pop-Busui, John Poremba, Alejandro Porto, Arman Postadzhiyan, Ramesh B Pothineni, Ranganatha P Potu, Talessa Powell, Kerkar G Prafulla, Rudolf Prager, Zhulieta R Prakova-Teneva, Richard E Pratley, Hermione Price, Grazyna Pulka, John Pullman, Zelda E Punt, Raman S Purighalla, Peter Purnell, Mansoor Qureshi, Remi Rabasa-Lhoret, Marina A Raikhel, Gita Rancane, Harpal Randeva, Neda Rasouli, Delia V Reurean Pintilei, Ciro R Reyes, Inga Rezgale, Eva Rice, Thaddeus H Riley, Joseph A Risser, Arsen Ristic, Margarita Rivas Fernández, David Robbins, Yves Robitaille, Helena W Rodbard, Jaime A Rodriguez Plazas, T.J. Römer, Glenn Rosen, Dr Azhari Rosman, Paulo Rossi, Leonid Rudenko, Omari Ruffin, Anwar Irawan Ruhani, Nikolay Runev, Dmitriy Ruyatkin, Alen Ruzic, Vyacheslav V Ryabov, Lars Rydén, Suraj Saggar, Tomohiro Sakamoto, Tim Salter, Aditya K Samal, Yulia Samoilova, Hugo D Sanabria, Seda Sancak, Renee Sangrigoli, Nakarin Sansanayudh, Ferruccio Santini, José F Saraiva, Ruslan Sardinov, William Sargeant, Ramazan Sari, Airani Sathananthan, Thozhukat Sathyapalan, Atsushi Sato, Joachim Sauter, Paolo Sbraccia, J. 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Vossenberg, Mathias Vrolix, Marjana Vukicevic, Ivan Vyshnyvetskyy, Shahid Wadvalla, Jan Wagner, John Wakeling, James Wallace, Wan Mohd Izani Wan Mohamed, Gurpreet S Wander, Kathleen Ward, Mark L Warren, Atsuyuki Watanabe, Bruce Weber, Howard Weintraub, John Weisnagel, James Welker, Ulrich Wendisch, Howard S Wenocur, Craig Wierum, John Wilding, Maged William, Pete Wilson, Jonathan P Wilson, Yuk-Ki Wong, Wanwarang Wongcharoen, Iwona Wozniak, Chau-Chung Wu, Nell Wyatt, Alan Wynne, Hiroshi Yamaguchi, Masahiro Yamasaki, Dilek Yazici, Hung-I Yeh, Yoto Yotov, Qingyang Yuan, Jeffrey Zacher, Olga Zagrebelnaya, Cesar J Zaidman, Alsu Zalevskaya, Stuart Zarich, Maria Chiara Zatelli, Helga Zeller, Elena A Zhdanova, Taiba Zornitzki, Konstantin Zrazhevskiy, Mikhail Zykov, A Michael Lincoff, Donna H Ryan, Helen M Colhoun, John E Deanfield, John E Deanfield, Scott S Emerson, Steven E Kahn, Robert F Kushner, Jorge Plutzky, Kirstine Brown-Frandsen, G Kees Hovingh, Søren Hardt‐Lindberg, Christoffer W Tornøe - The Lancet 2024 被引用: 230

Background Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m 2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m 2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60–0·87 for MACE; 0·79, 0·64–0·98 for the heart failure composite endpoint; 0·76, 0·59–0·97 for cardiovascular death; and 0·81, 0·66–1·00 for all-cause death; all p interaction >0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49–0·87 for MACE; 0·79, 0·58–1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51–0·91 for MACE; 0·75, 0·52–1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding Novo Nordisk.