TY - JOUR
T1 - Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus
T2 - Systematic review and meta-analysis of cardiovascular outcomes trials
AU - Zelniker, Thomas A.
AU - Wiviott, Stephen D.
AU - Raz, Itamar
AU - Im, Kyungah
AU - Goodrich, Erica L.
AU - Furtado, Remo H.M.
AU - Bonaca, Marc P.
AU - Mosenzon, Ofri
AU - Kato, Eri T.
AU - Cahn, Avivit
AU - Bhatt, Deepak L.
AU - Leiter, Lawrence A.
AU - McGuire, Darren K.
AU - Wilding, John P.H.
AU - Sabatine, Marc S.
N1 - Funding Information:
This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft Grant ZE 1109/1-1 to Dr Zelniker) and by a Lemann Foundation Cardiovascular Research Postdoctoral Fellowship from Harvard University/Brigham and Women’s Hospital (to Dr Furtado). The funding sources had no role in data collection, analysis, writing of the manuscript, or the decision to submit for publication. All authors had full access to all the data. All statistical analyses were performed at the TIMI Study Group (Thrombolysis in Myocardial Infarction).
Funding Information:
Dr Zelniker reports grants to his institution from AstraZeneca and grants from Bristol-Myers Squibb during the conduct of the study. Dr Wiviott reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Arena, Daiichi San-kyo, Eisai, Eli Lilly, and Janssen during the conduct of the study; grants from AMGEN and Sanofi Aventis; grants, personal fees, and other fees from Merck; and personal fees from Aegerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, St Jude Medical, and Xoma outside the submitted work. Dr Raz reports personal fees from AstraZen-eca and Bristol-Myers Squibb during the conduct of the study and personal fees from Boehringer Ingelheim, Concenter BioPharma/Silkim Ltd, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FuturRx, Insuline Medical, Medial EarlySign, CameraEyes, Exsco-pia, Dermal Biomics, Johnson & Johnson, Novartis Pharma AG, Teva, Glucome, and DarioHealth outside the submitted work. Dr Bonaca reports grants from Amgen, AstraZeneca, Merck, and Pfizer and personal fees from Aralez, Amgen, AstraZeneca, Bayer, Janssen, Pfizer, and Sanofi during the conduct of the study. Dr Mosenzon reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, and Novo Nordisk during the conduct of the study and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Jansen and Jansen, and Novartis outside the submitted work. Dr Kato reports personal fees from AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Bristol-Myers Squibb, and Tanabe-Mitsubishi Pharma and a research grant from Ono Pharmaceutical outside the submitted work. Dr Cahn reports personal fees from Novo Nordisk, Elli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, and Glucome outside the submitted work and grants and personal fees from AstraZeneca. Dr Furtado reports the following: honoraria from Modest and As-traZeneca and research grants from Modest, AstraZeneca, DalCor, Boehinger, Pfizer, Bayer, and Sanofi. Dr Bhatt discloses the following relationships: Advisory Board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; Chair of American Heart Association Quality Oversight Committee; and Data Monitoring Committees of Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial (Portico Re-sheathable Transcatheter Aortic Valve System US IDE Trial), funded by St Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial (Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation), funded by Daiichi Sankyo), and Population Health Research Institute. Dr Bhatt also reports honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, American College of Cardiology Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI [Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention] clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (Continuing Medical Education steering committees); other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry (National Cardiovascular Data Registry) Steering Committee (Chair), Veterans Affairs CART (Cardiovascular Assessment, Reporting, and Tracking system) Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca (including for the DECLARE-TIMI 58 Executive Committee), Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Eli Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr Leiter reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi; personal fees from Servier; and grants from GlaxoSmithKline outside the submitted work. Dr McGuire reports personal fees from AstraZeneca during the conduct of the study and personal fees from Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi US, Merck Sharp & Dohme, Eli Lilly, Novo Nordisk, Glaxo-SmithKline, AstraZeneca, Lexicon, Eisai, Esperion, Metavant, Pfizer, and Applied Therapeutics outside the submitted work. Dr Wilding reports personal fees and other fees from Brigham and Women’s Hospital during the conduct of the study; grants, personal fees, and consultancy fees (paid to his institution) from As-traZeneca and Novo Nordisk; personal fees and consultancy fees (paid to his institution) from Boehringer Ingelheim, Eli Lilly, Janssen, Napp, Mundipharma, Sanofi, and Takeda; and consultancy fees (paid to his institution) from Wilmington Healthcare outside the submitted work. Dr Sabatine reports grants from As-traZeneca during the conduct of the study; grants and personal fees from Am-gen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, Medimmune, Merck, and Novartis; grants from Daiichi-Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Takeda, Abbott Laboratories, Critical Diagnostics, Genzyme, Gilead, and Roche Diagnostics; and personal fees from Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, Alnylam, Ionis, and MyoKardia outside the submitted work. Dr Im and Ms Goodrich report no conflicts.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/4/23
Y1 - 2019/4/23
N2 - Background: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined. Methods: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease. Results: In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001). Conclusions: In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.
AB - Background: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined. Methods: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease. Results: In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001). Conclusions: In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.
KW - diabetes mellitus, type 2
KW - glucagon-like peptide 1 receptor agonists
KW - meta-analysis
KW - sodium-glucose co
KW - transporter-2 inhibitors
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UR - http://www.scopus.com/inward/citedby.url?scp=85065306608&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.118.038868
DO - 10.1161/CIRCULATIONAHA.118.038868
M3 - Article
C2 - 30786725
AN - SCOPUS:85065306608
SN - 0009-7322
VL - 139
SP - 2022
EP - 2031
JO - Circulation
JF - Circulation
IS - 17
ER -