TY - JOUR
T1 - SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes
T2 - a systematic review and meta-analysis of cardiovascular outcome trials
AU - Zelniker, Thomas A.
AU - Wiviott, Stephen D.
AU - Raz, Itamar
AU - Im, Kyungah
AU - Goodrich, Erica L.
AU - Bonaca, Marc P.
AU - Mosenzon, Ofri
AU - Kato, Eri T.
AU - Cahn, Avivit
AU - Furtado, Remo H.M.
AU - Bhatt, Deepak L.
AU - Leiter, Lawrence A.
AU - McGuire, Darren K
AU - Wilding, John P.H.
AU - Sabatine, Marc S.
N1 - Funding Information:
TAZ reports a research grant from Deutsche Forschungsgemeinschaft (ZE 1109/1–1), and grants to his institution from AstraZeneca, and grants from Bristol-Myers Squibb during the conduct of the study. SDW reports grants and personal fees from AstraZeneca and Bristol Myers Squibb during the conduct of the study. SDW also reports grants from Amgen and Sanofi Aventis, grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen, grants, personal fees, and other from Merck, and personal fees from Aegerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, St Jude Medical, and Xoma outside of the submitted work. IR reports personal fees from AstraZeneca and Bristol-Myers Squibb during the conduct of the study. IR also reports personal fees from Boehringer Ingelheim, Concenter BioPharma—Silkim Ltd, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk Inc, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation Ltd, Panaxia, FuturRx Ltd, Insuline Medical, Medial EarlySign Ltd, CameraEyes, Exscopia, Dermal Biomics Inc, Johnson & Johnson, Novartis Pharma AG, Teva, Glucome Ltd, and DarioHealth outside of the submitted work. MPB 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. OM reports grants and personal fees from AstraZeneca and Bristol-Myers Squibb during the conduct of the study. OM also reports grants and personal fees from NovoNordisk and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Jansen, and Novartis outside of the submitted work. ETK reports personal fees from AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Bristol-Myers Squibb, and Tanabe-Mitsubishi Pharma outside the submitted work. AC reports personal fees from Novo Nordisk, Eli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, and Glucome, and grants and personal fees from AstraZeneca outside of the submitted work. RHMF reports grants to his institution from AstraZeneca, DalCor, Boehringer, Pfizer, Jansen, and Sanofi outside the submitted work. DLB is on the Advisory Board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences, is on the Board of Directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft, is the Chair of the American Heart Association Quality Oversight Committee, is on Data Monitoring Committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO 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, funded by Daiichi Sankyo), and Population Health Research Institute, received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org ; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI 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 operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees). DLB reports other positions at Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair). DLB also reports funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Eli Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company, and royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease). DLB is site co-investigator for Biotronik, Boston Scientific, St Jude Medical (now Abbott), and Svelte, and is a trustee of the American College of Cardiology. DLB also reports unfunded research with FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. LAL reports grants and personal fees from AstraZeneca during the conduct of the study. LAL also reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi, personal fees from Servier, and grants from GlaxoSmithKline outside of the submitted work. DKM reports personal fees from AstraZeneca during the conduct of the study. DKM also reports personal fees from Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi US, Merck Sharp and Dohme, Eli Lilly, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon, Eisai Inc, Esperion, Metavant, and Pfizer outside of the submitted work. JPW reports personal fees and other from Brigham and Women's Hospital during the conduct of the study JPW also reports grants, personal fees, and consultancy fees paid to his institution from AstraZeneca, Novo Nordisk, and Takeda, personal fees and consultancy fees paid to his institution from Boehringer Ingelheim, Lilly, Janssen, Napp, Mundipharma, and Sanofi, and consultancy fees paid to his institution from Wilmington Healthcare outside of the submitted work. MSS reports grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, Medimmune, Merck, and Novartis, grants from Daiichi-Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Takeda, Abbott Laboratories, Bayer, Critical Diagnostics, Genzyme, Gilead, and Roche Diagnostics, and personal fees from Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, Alnylam, Ionis, and MyoKardia outside of the submitted work. KI and ELG report grants to their institution from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research Development, the Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Roche Diagnostics, and Takeda outside of the submitted work.
Funding Information:
TAZ was supported by the Deutsche Forschungsgemeinschaft (ZE 1109/1–1).
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/1/5
Y1 - 2019/1/5
N2 - Background: The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined. Methods: We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function. Findings: We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83–0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80–0·93]) and not in those without (1·00 [0·87–1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71–0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48–0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline. Interpretation: SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. Funding: None.
AB - Background: The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined. Methods: We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function. Findings: We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83–0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80–0·93]) and not in those without (1·00 [0·87–1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71–0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48–0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline. Interpretation: SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. Funding: None.
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U2 - 10.1016/S0140-6736(18)32590-X
DO - 10.1016/S0140-6736(18)32590-X
M3 - Article
C2 - 30424892
AN - SCOPUS:85059501499
SN - 0140-6736
VL - 393
SP - 31
EP - 39
JO - The Lancet
JF - The Lancet
IS - 10166
ER -