Abstract
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/m2 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/m2 (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 pinteraction>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.
| Original language | English |
|---|---|
| Pages (from-to) | 773-786 |
| Number of pages | 14 |
| Journal | The Lancet |
| Volume | 404 |
| Issue number | 10454 |
| DOIs | |
| Publication status | Published - 24 Aug 2024 |
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In: The Lancet, Vol. 404, No. 10454, 24.08.2024, p. 773-786.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure
T2 - a prespecified analysis of the SELECT trial
AU - SELECT Trial Investigators
AU - Deanfield, John
AU - Verma, Subodh
AU - Scirica, Benjamin M.
AU - Plutzky, Jorge
AU - Emerson, Scott S.
AU - Ryan, Donna
AU - Lingvay, Ildiko
AU - Colhoun, Helen M.
AU - Kosiborod, Mikhail N.
AU - Hovingh, G. Kees
AU - Hardt-Lindberg, Søren
AU - Frenkel, Ofir
AU - Weeke, Peter E.
AU - Rasmussen, Søren
AU - Goudev, Assen
AU - Lang, Chim C.
AU - Urina-Triana, Miguel
AU - Pietilä, Mikko
AU - Abe, Mitsunori
AU - Abhaichand, Rajpal K.
AU - Abhayaratna, Walter P.
AU - Abhyankar, Atul
AU - Abidin, Imran B.Zainal
AU - Abou Assi, Hiba
AU - Accini Mendoza, Jose L.
AU - Adas, Mine
AU - Agaiby, John M.
AU - Agarwal, Devendra K.
AU - Agha, Maher
AU - Ahmed, Azazuddin
AU - Ahtiainen, Petteri
AU - Aigner, Elmar
AU - Ajay, Naik
AU - Ali, Norsiah
AU - Al-Karadsheh, Amer
AU - Allison, Roy
AU - Allison, Dale C.
AU - Alpenidze, Diana
AU - Altuntas, Yuksel
AU - Al-Zoebi, Ayham
AU - Ambuj, Roy
AU - Amerena, John
AU - Anderson, Robert J.
AU - Ando, Toshiaki
AU - Andrews, Robert
AU - Antonova, Elizaveta
AU - Appel, Karl Friedrich
AU - Arantes, Flávia B.
AU - Araz, Mustafa
AU - Arbel, Yaron
AU - Arenas León, José L.
AU - Argyrakopoulou, Georgia
AU - Ariani, Mehrdad
AU - Arias Mendoza, Maria A.
AU - Arif, Ahmed A.
AU - Arneja, Jaspal
AU - Aroda, Vanita R.
AU - Aronne, Louis J.
AU - Arstall, Margaret
AU - Asamoah, Njaimeh
AU - Asanin, Milika
AU - Audish, Hanid
AU - Avram, Rodica
AU - Badat, Aysha
AU - Badiu, Corin V.
AU - Bakdash, Wa'el
AU - Bakiner, Okan S.
AU - Bandezi, Vuyokazi N.
AU - Bang, Liew H.
AU - Bansal, Sandeep
AU - Baranyai, Marietta
AU - Barbarash, Olga
AU - Barber, Mark
AU - Barnum, Otis
AU - Barone Rochette, Gilles
AU - Bashkin, Amir
AU - Baum, Seth
AU - Bays, Harold E.
AU - Bazzoni Ruiz, Alberto E.
AU - Beckowski, Maciej
AU - Beerachee, Yaswin
AU - Bellary, Srikanth
AU - Belousova, Lidia
AU - Berk, Martin
AU - Bernstein, Marc
AU - Berra, Cesare
AU - Beshay, Isaac
AU - Bhagwat, Ajit
AU - Bhan, Arti
AU - Biggs, William C.
AU - Billings, Liana
AU - Bitar, Fahed
AU - Block, Bradley
AU - Bo, Simona
AU - Bogdanski, Pawel
AU - Bolshakova, Olga O.
AU - Boshchenko, Alla A.
AU - Bosworth, Hayden
AU - Botero Lopez, Rodrigo
AU - Bôttcher, Morten
AU - Bourgeois, Ronald
AU - Brautigam, Donald
AU - Breton, Cristian F.
AU - Broadley, Andrew
AU - Brockmyre, Andrew P.
AU - Brodie, Steven K.
AU - Bucci, Marco
AU - Budincevic, Hrvoje
AU - Budoff, Matthew J.
AU - Buffman, Barry
AU - Buljubasic, Nediljka
AU - Buranapin, Supawan
AU - Burgess, Lesley
AU - Burguera, Bartolomé
AU - Buriakovska, Olena
AU - Buscemi, Silvio
AU - Busch, Robert
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AU - Harris, Barry
AU - Hartleib, Michael
AU - Hartman, Aaron N.
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AU - Herman, Lee
AU - Herzog, William
AU - Hewitt, Eric
AU - Heymer, Peter
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AU - Høgalmen, Rasmus Geir
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AU - Holmer, Helene
AU - Horoshko, Olha
AU - Houser, Patricia M.
AU - Hove, Jens D.
AU - Hsieh, I. Chang
AU - Hulot, Jean Sébastien
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AU - Ilashchuk, Tetiana
AU - Ilveskoski, Erkki
AU - Ipatko, Irina
AU - Iranmanesh, Ali
AU - Isawa, Tsuyoshi
AU - Issa, Moises
AU - Iteld, Bruce
AU - Iwasawa, Takamasa
AU - Jabbar, Danish
AU - Jackson, Richard A.
AU - Jackson-Voyzey, Ewart
AU - Jacob, Stephan
AU - Jaffrani, Naseem A.
AU - Jardula, Michael F.
AU - Jastreboff, Ania
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AU - Jerkins, Terri
AU - Jimenez-Ramos, Silvia A.
AU - Jitendra Pal Singh, Sawhney
AU - Johnson, Wallace
AU - Joyce, John M.
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AU - Jurowiecki, Jaroslaw
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AU - Kempe, Hans Peter
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AU - Krishnasamy, Sathya S.
AU - Krivosheeva, Inga
AU - Kruljac, Ivan
AU - Kubicki, Ted
AU - Kuchar, Ladislav
AU - Kujawiak, Monika
AU - Kunishige, Hideyuki
AU - Kurtinecz, Melinda
AU - Kurtz Lisboa, Hugo R.
AU - Kushnir, Mykola
AU - Kyyak, Yulian
AU - Lace, Arija
AU - Lakka, Timo
AU - Lalic, Nebojsa
AU - Lalic, Katarina
AU - Lambadiari, Vaia
AU - Lanaras, Leonidas
AU - Langlois, Marie France
AU - Lash, Joseph
AU - Latkovskis, Gustavs
AU - Lau, David
AU - Lazcano Soto, José Roberto
AU - Le Roux, Carel
AU - Ledesma, Gilbert N.
AU - Lee, Li Yuan
AU - Lee, Thung Lip
AU - Lee, Kelvin
AU - Lehrke, Michael
AU - Leite, Silmara O.
AU - Leksycka, Agata
AU - Lenzmeier, Thomas
AU - Leonetti, Frida
AU - Leonidova, Viktoriia
AU - Lepor, Norman
AU - Leung, Melissa
AU - Levchenko, Olena
AU - Levins, Peter
AU - Levy, Louis J.
AU - Lewis, Matthew
AU - Liberopoulos, Evangelos
AU - Liberty, Idit
AU - Lindholm, Carl Johan
AU - Linhart, Ales
AU - Liu, Ming En
AU - Liu, Jenny
AU - Lofton, Holly
AU - Logemann, Timothy
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AU - Lorraine, Richard
AU - Lovell, Charles F.
AU - Ludvik, Bernhard
AU - Lukaszewicz, Monika
AU - Lupkovics, Géza
AU - Lupovitch, Steven
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AU - Lynch, Mary
AU - Lysak, Zoreslava
AU - Lysenko, Tatyana A.
AU - Maeda, Hajime
AU - Maeda, Itaru
AU - Mæng, Michael
AU - Mahajan, Ajay U.
AU - Maher, Vincent
AU - Maia, Lilia N.
AU - Makotoko, Ellen M.
AU - Malavazos, Alexis
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AU - Manita, Mamoru
AU - Mannucci, Edoardo
AU - Mareev, Viacheslav
AU - Marin, Liliana
AU - Markova, Tatiana
AU - Marso, Steven P.
AU - Martens as National Lead cardiologists on behalf of the SELECT Trial Investigators, FMAC
AU - Martinez, Cuper
AU - Martinez Cano, Carlos A.
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AU - Masmiquel Comas, Luis
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N1 - Publisher Copyright: © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2024/8/24
Y1 - 2024/8/24
N2 - 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/m2 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/m2 (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 pinteraction>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.
AB - 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/m2 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/m2 (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 pinteraction>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.
UR - https://www.scopus.com/pages/publications/85201638599
U2 - 10.1016/S0140-6736(24)01498-3
DO - 10.1016/S0140-6736(24)01498-3
M3 - Article
C2 - 39181597
AN - SCOPUS:85201638599
SN - 0140-6736
VL - 404
SP - 773
EP - 786
JO - The Lancet
JF - The Lancet
IS - 10454
ER -