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Objective: We examined relations between characteristics of the metabolic syndrome, early cardiovascular risk, and effect of early, intensive statin therapy after acute coronary syndrome.Research Design and Methods: A total of 3,038 patients in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial were characterized by the presence or absence of a history of diabetes, a history of hypertension and/or blood pressure > or = 130/> or = 85, BMI >30 kg/m2, HDL cholesterol <40 mg/dl (men) or <50 mg/dl (women), and triglycerides > or = 150 mg/dl. Patients with three or more of these characteristics were categorized as having metabolic syndrome.Results: A total of 38% of patients (n = 1,161) met criteria for metabolic syndrome as defined in this study and had a 19% incidence of a primary end point event (death, nonfatal myocardial infarction, cardiac arrest, or recurrent unstable myocardial ischemia) during the 16-week trial. Patients with two or fewer characteristics (n = 1,877) were classified as not having metabolic syndrome and had a 14% incidence of a primary end point event. In univariate analysis, the individual characteristics that bore a significant relation to risk were diabetes and low HDL cholesterol. In a multivariable model including age, sex, and randomized treatment assignment, presence of metabolic syndrome was associated with a hazard ratio of 1.49 (95% CI 1.24-1.79, P < 0.0001). Relative risk reduction with 80 mg atorvastatin daily compared with placebo was similar in patients with and without metabolic syndrome.Conclusions: Metabolic syndrome, as defined in the context of this clinical trial, is a strong predictor of early recurrent ischemic events after acute coronary syndrome. [ABSTRACT FROM AUTHOR]

Background: High-density lipoprotein (HDL) cholesterol levels are a strong inverse predictor of cardiovascular events. However, it is not clear whether this association is maintained at very low levels of low-density lipoprotein (LDL) cholesterol.Methods: A post hoc analysis of the recently completed Treating to New Targets (TNT) study assessed the predictive value of HDL cholesterol levels in 9770 patients. The primary outcome measure was the time to a first major cardiovascular event, defined as death from coronary heart disease, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. The predictive relationship between HDL cholesterol levels at the third month of treatment with statins and the time to the first major cardiovascular event was assessed in univariate and multivariate analyses and was also assessed for specific LDL cholesterol strata, including subjects with LDL cholesterol levels below 70 mg per deciliter (1.8 mmol per liter).Results: The HDL cholesterol level in patients receiving statins was predictive of major cardiovascular events across the TNT study cohort, both when HDL cholesterol was considered as a continuous variable and when subjects were stratified according to quintiles of HDL cholesterol level. When the analysis was stratified according to LDL cholesterol level in patients receiving statins, the relationship between HDL cholesterol level and major cardiovascular events was of borderline significance (P=0.05). Even among study subjects with LDL cholesterol levels below 70 mg per deciliter, those in the highest quintile of HDL cholesterol level were at less risk for major cardiovascular events than those in the lowest quintile (P=0.03).Conclusions: In this post hoc analysis, HDL cholesterol levels were predictive of major cardiovascular events in patients treated with statins. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter. (ClinicalTrials.gov number, NCT00327691 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

This analysis assessed the safety of atorvastatin in the 10- to 80-mg dose range using pooled data from 44 completed trials comprising 16,495 dyslipidemic patients treated with atorvastatin (n = 9,416), placebo (n = 1,789), and other statins (n = 5,290). A retrospective analysis was conducted and included treatment-associated adverse events, serious adverse events, and musculoskeletal and hepatic adverse events. Only 3% (n = 241) of atorvastatin-treated patients withdrew from studies due to treatment-associated adverse events, compared with 1% of those (n = 16) on placebo and 4% of those (n = 188) receiving other statins; the most frequently reported treatment-associated adverse events were related to the digestive system. Serious adverse events were rare and seldom led to withdrawal. Persistent elevations in hepatic transaminases to >3 times the upper limit of normal (ULN) were experienced by 0.5% (n = 47) of atorvastatin-treated patients. A persistent elevation in creatine phosphokinase (CPK) (>10 x ULN) was observed in only 1 atorvastatin-treated patient and was not associated with myopathy. The incidence of treatment-associated myalgia was low in the atorvastatin (1.9% [n = 181]), placebo (0.8% [n = 14]), and other statin (2.0% [n = 105]) groups, and was not related to the atorvastatin dose. No cases of rhabdomyolysis or myopathy were reported. Thus, the overall incidence of treatment-associated adverse events observed with atorvastatin did not increase in the 10- to 80-mg dose range, and was similar to that observed with placebo and in patients treated with other statins. Specific analysis of musculoskeletal and hepatic adverse events showed that these occurred infrequently and rarely resulted in treatment discontinuation. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown., Objectives: These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status., Methods: SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4., Results: Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (P trend  = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017)., Conclusions: Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934)., Competing Interests: Funding Support and Author Disclosures SOLOIST-WHF was supported by Sanofi and Lexicon Pharmaceuticals, Inc. Dr A.S. Bhatt has received research grant support to his institution from the National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute on Aging, American College of Cardiology Foundation, and the Centers for Disease Control and Prevention; and has received prior consulting fees from Sanofi Pasteur and Novo Nordisk. Dr D.L. Bhatt is the Chair of SOLOIST-WHF with research funding paid by Lexicon to Brigham and Women’s Hospital and the Icahn School of Medicine at Mount Sinai. He discloses the following relationships—Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and U.S. national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither Dr D.L. Bhatt nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker BioMarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; Trustee: American College of Cardiology; and Unfunded Research: FlowCo. Dr Steg has received research grants from Amarin, Bayer, Sanofi, and Servier; has received speaker or consultant fees from Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Kowa, Idorsia, Lexicon, Merck, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier; and is a Senior Associate Editor of Circulation. Dr Szarek has received salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, WraSer, and the Yale Cardiovascular Research Group; has received fees for performing analyses, steering committee fees, and travel support from Sanofi and Regeneron; has received consulting fees from CiVi, Esperion, Amarin, Silence Therapeutics, and New Amsterdam Pharmaceuticals; has received Data Safety and Monitoring Board membership fees from Resverlogix and Janssen; and is a member of the JACC editorial board. Dr Cannon has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Merck, Novo Nordisk, and Pfizer; has received consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi; and has served on the Data and Safety Monitoring Boards for the Veterans Administration, Applied Therapeutics, and Novo Nordisk. Dr Leiter has received research funding from, has provided Continuing Medical Education on behalf of, and/or has acted as an adviser to Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, HLS, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi. Dr McGuire has received personal fees for consulting from Boehringer Ingelheim, Sanofi US, Merck & Co, Merck Sharp and Dohme Corp, Eli Lilly USA, Novo Nordisk, AstraZeneca, Lexicon Pharmaceuticals, Eisai, Pfizer, Metavant, Applied Therapeutics, Afimmune, Bayer, CSL Behring, and Esperion; has received research support for Clinical Trials Leadership from Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, and CSL Behring; and has received honoraria for consultancy from Lilly USA, Pfizer, Boehringer Ingelheim, Lexicon, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, Intercept, and New Amsterdam. Dr Lewis has received consultant fees from Sanofi. Dr Riddle has received honoraria for consulting from Adocia, Anji, Xeris, DalCor, and Theracos. Dr Voors has received consultancy and speaker fees and research support from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, BMS, Cyrokinetics, Merck, Myokardia, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Metra has received consultant fees from Abbott Structural Heart, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Novo Nordisk, and Roche Diagnostics. Dr Lund has received support from the Karolinska Institutet, the Swedish Research Council (grant 523-2014-2336), and the Swedish Heart Lung Foundation (grants 20150557, 20190310) and grants from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, Novartis, and MSD; has received consulting honoraria from Vifor, AstraZeneca, Bayer, Pharmacosmos, MSD, MedScape, Sanofi, Lexicon, Boehringer Ingelheim, Biopeutics, Novo Nordisk, Edwards Lifesciences, and Alleviant; has received speaker honoraria from MedScape, Radcliffe, AstraZeneca, Novartis, Boehringer Ingelheim, Pharmacosmos, Novo Nordisk, AnaCardio, and Bayer; and has patents with AnaCardio and stock ownership in AnaCardio. Dr Testani has received grants and/or personal fees from 3ive labs, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, AstraZeneca, Novartis, Cardionomic, MagentaMed, Reprieve Inc, FIRE1, W. L. Gore & Associates, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon Pharmaceuticals, preCARDIA, Relypsa, Regeneron, BD, Edwards Lifesciences, and Lilly; and has a patent treatment of diuretic resistance issued to Yale and Corvidia Therapeutics Inc, a patent methods for measuring renalase issued to Yale, and a patent treatment of diuretic resistance pending with Reprieve Inc. Dr Davies is employed by and may have stock or stock options in Lexicon Pharmaceuticals. Dr Pitt has received consulting fees from Lexicon, Bayer, AstraZeneca, Boehringer Ingelheim, Merck, and PhaseBio; has received consulting fees and/or stock options from Viror, KBP Biosciences, Cereno Scientific, Tricida, scPharmaceuticals, SQinnovations, G-3 Pharmaceuticals, ProtonIntel, and Brainstorm Medical; holds U.S. Patent 9931412 on site-specific delivery of eplerenone to the myocardium; and U.S. Patent pending 63/045,783 on histone-modulating agents for the protection and treatment of organ damage. Dr Kosiborod has received research grant funding (payments to institution) from AstraZeneca, Boehringer Ingelheim, and Pfizer; has received consultant/advisory board fees (payments to institution) from 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Regeneron, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support (data analytic center fees/payments to institution) from AstraZeneca and Vifor Pharma; has received honorarium (payments to institution) from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has stock options (personal) in Artera Health and Saghmos Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations., Objectives: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial., Methods: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations., Results: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82)., Conclusions: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)., Competing Interests: Funding Support and Author Disclosures This analysis was funded by Regeneron Pharmaceuticals, Inc. The ODYSSEY OUTCOMES trial was funded by Regeneron Pharmaceuticals, Inc, and Sanofi. The trial was designed by an academic steering committee in conjunction with the sponsors. The sponsors were involved in the collection verification, and analysis of the data provided in the manuscript. All authors participated in the interpretation of the data. Dr Zahger has served as national coordinator for the ODYSSEY OUTCOMES trial and the SCORED trial, both funded by Sanofi; and has served as consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. Dr Schwartz has received research support to the University of Colorado from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company; and is a coinventor of pending U.S. patent 62/806,313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. Drs Du, Manvelian, Pordy, Fazio, and Geba are all employees of and shareholders in Regeneron Pharmaceuticals, Inc. Dr Szarek has received salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron Pharmaceuticals, Inc, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group; has received fees for performing analyses, steering committee fees, and travel support from Sanofi and Regeneron Pharmaceuticals, Inc; has received consulting fees from CiVi, Lexicon, Amarin, and Esperion Therapeutics; has received Data Safety and Monitoring Board membership fees from Resverlogix and Janssen; and is a member of the Journal of the American College of Cardiology Editorial Board. Dr Bhatt has served on the advisory board for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for Angiowave (with stock options), Boston VA Research Institute, Bristol Myers Squibb (with stock), DRS.LINQ (with stock options), High Enroll (with stock), Society of Cardiovascular Patient Care, and TobeSoft; has served as the Inaugural Chair of the American Heart Association Quality Oversight Committee; has served as a consultant for Broadview Ventures and Hims; has served on the Data Monitoring Committee for Acesion Pharma, Assistance Publique–Hôpitaux de Paris, the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), the Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, the Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, the Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and U.S. national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); has served as the Deputy Editor of Clinical Cardiology; has served as the Chair of the NCDR-ACTION Registry Steering Committee and the VA CART Research and Publications Committee; holds a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither Dr Bhatt nor Brigham and Women's Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly and Company, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron Pharmaceuticals, Inc, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee of the American College of Cardiology; and conducted unfunded research for FlowCo and Takeda. Dr Bittner has received grant support from Sanofi, AstraZeneca, DalCor, Esperion, Bayer, Novartis, and Amgen, all paid direct to her institution; and has received personal fees from Sanofi and Pfizer. Dr Budaj has received personal fees and nonfinancial support from Sanofi, Bristol Myers Squibb/Pfizer, Bayer, and AstraZeneca; and has received personal fee from Novartis, Amgen, and Novo Nordisk. Dr Diaz has received research grants from Sanofi, DalCor Pharmaceuticals, the Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, the Montreal Health Innovations Coordinating Center, and Lepetit; and has received personal fees, as a member of the Executive Steering Committee, from Amgen and Cirius. Dr Goodman has received research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly and Comapny, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, and Sanofi; has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly and Company, Esperion Therapeutics, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron Pharmaceuticals, Inc, Sanofi, Servier, Valeo Pharma, the Canadian Heart Research Centre and MD Primer, the Canadian VIGOUR Centre, the Cleveland Clinic Coordinating Centre for Clinical Research, the Duke Clinical Research Institute, the New York University Clinical Coordinating Centre, the PERFUSE Research Institute, and the TIMI Study Group (Brigham Health); and has served as a consultant or on the advisory board (or both) for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Pendopharm, Pfizer, Regeneron Pharmaceuticals, Inc, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma. Dr Jukema has received research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and has received research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Eli Lilly and Company, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr Harrington has received research grants (all data safety and monitoring board related) from AstraZeneca, Janssen, and Bristol Myers Squibb; has served on the advisory board for Gilead (uncompensated) and WebMD; and has served on the board of directors (unpaid) for the American Heart Association and Stanford HealthCare. Dr Moriarty has received research grants to his institution for the participation in the ODYSSEY OUTCOMES trial; has received financial fees for serving as a medical monitor for the trial and associated support for travel related to trial meetings from Sanofi; has received consulting and speaking fees from Regeneron Pharmaceuticals, Inc, and Amgen; has received consulting fees from Esperion, Kaneka, and Stage II innovations; has received speaker fees from Amarin; has received advisor fees from Novartis for serving on their advisory committee; and has received research grants to his institution from Ionis, FH Foundation, GB Life Sciences, Aegerion, Amgen, Kowa, Novartis, and Regeneron Pharmaceuticals, Inc. Dr Scemama is an employee of Sanofi and may hold shares and/or stock options in the company. Dr White has received grant support paid to his institution for serving on a Steering Committee for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, Inc, for the ACCELERATE study from Eli Lilly and Company, for the STRENGTH trial from Omthera Pharmaceuticals, for the CAMELLIA-TIMI study from Eisai, for the HEART-FID study from American Regent, and for the ISCHEMIA Trial and the MINT Trial from the National Institutes of Health; has received grants to his institution and personal fees as Steering Committee member for the dal-GenE study from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial and the SOLOIST-WHF trial from Sanofi Australia Pty Ltd, and for the CLEAR Outcomes Study from Esperion Therapeutics Inc; and has served on the advisory board for CSL Behring and Genentech (an affiliate of F. Hoffmann-La Roche Ltd, “Roche”; Lytics Post-PCI Advisory Board at European Society of Cardiology). Dr Zeiher has received fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi; and has received advisory board and speaker fees from Sanofi, Amgen, Boehringer Ingelheim, Bayer, Novartis, Pfizer, AstraZeneca, and Vifor. Dr Steg has received grants and nonfinancial support (co-Chair of the ODYSSEY OUTCOMES trial; as such, he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (Steering Committee MARINER, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (co-Chair of the ODYSSEY OUTCOMES trial; co-Chair of the SCORED trial; consulting; speaking), Servier (Chair of the CLARIFY registry; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial]; consulting); has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Idorsia, MyoKardia, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, Inc, and AstraZeneca; and has a European application number/patent number, issued on October 26, 2016 (no. 15712241.7), for a method for reducing cardiovascular risk, with all royalties assigned to Sanofi. Dr Kiss has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: Conflict of interest: M.S. reports serving as a consultant or research support (or both) from CiVi, Resverlogix, Lexicon, Baxter, Esperion, Amarin, New Amsterdam, Tourmaline, Sanofi, and Regeneron Pharmaceuticals, Inc. E.R.: No disclosures. P.G.S. reports grants, personal fees, and non-financial support from Sanofi; grants and personal fees from Amarin, Servier, and Bayer; personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Idorsia, Pfizer, and Novartis. J.W.J. receives research grants from The Netherlands Heart Foundation, the Interuniversity Cardiology Institute of The Netherlands, and the European Commission Seventh Framework Programme; and research support from Amgen, Astellas, AstraZeneca, Daiichi Sankyo, Lilly, Merck-Schering-Plough, Novartis, Pfizer, Roche, and Sanofi. M.Sc. is an employee of Roche and may hold shares in the company. D.L.B. discloses the following relationships: Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures, Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, 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), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Author contributions Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solut.

Background: SGLT2 inhibitors and GLP-1 receptor agonists both improve cardiovascular and kidney outcomes in patients with type 2 diabetes. We sought to evaluate whether the benefits of SGLT2 inhibitors are consistent in patients receiving and not receiving GLP-1 receptor agonists., Methods: We conducted a collaborative meta-analysis of trials included in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium, restricted to participants with diabetes. Treatment effects from individual trials were obtained from Cox regression models and pooled using inverse variance weighted meta-analysis. The two main cardiovascular outcomes assessed included major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), and hospitalisation for heart failure or cardiovascular death. The main kidney outcomes assessed were chronic kidney disease progression (≥40% decline in estimated glomerular filtration rate [eGFR], kidney failure [eGFR <15 mL/min/1·73 m 2 , chronic dialysis, or kidney transplantation], or death due to kidney failure), and the rate of change in eGFR over time. Safety outcomes were also assessed., Findings: Across 12 randomised, double-blind, placebo-controlled trials, 3065 (4·2%) of 73 238 participants with diabetes were using GLP-1 receptor agonists at baseline. SGLT2 inhibitors reduced the risk of major adverse cardiovascular events in participants both receiving and not receiving GLP-1 receptor agonists (hazard ratio [HR] 0·81, 95% CI 0·63-1·03 vs 0·90, 0·86-0·94; p-heterogeneity=0·31). Effects on hospitalisation for heart failure or cardiovascular death (0·76, 0·57-1·01 vs 0·78, 0·74-0·82; p-heterogeneity=0·90) and chronic kidney disease progression (0·65, 0·46-0·94 vs 0·67, 0·62-0·72; p-heterogeneity=0·81) were also consistent regardless of GLP-1 receptor agonist use, as was the effect on the chronic rate of change in eGFR over time (heterogeneity=0·92). Fewer serious adverse events occurred with SGLT2 inhibitors compared with placebo, irrespective of GLP-1 receptor agonist use (relative risk 0·87, 95% CI 0·79-0·96 vs 0·91, 0·89-0·93; p-heterogeneity=0·41)., Interpretation: The effects of SGLT2 inhibitors on cardiovascular and kidney outcomes are consistent regardless of the background use of GLP-1 receptor agonists. These findings suggest independent effects of these evidence-based therapies and support clinical practice guidelines recommending the use of these agents in combination to improve cardiovascular and kidney metabolic outcomes., Funding: National Health and Medical Research Council of Australia and the Ramaciotti Foundation., Competing Interests: Declaration of interests BLN reports fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Alexion, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, Janssen, the limbic, Medscape, Novo Nordisk, and Travere Therapeutics with all honoraria paid to The George Institute for Global Health. RAF has received studentship awards from the HDR-UK-Turing Wellcome Programme in Health Data Science. SDA reports grants and personal fees from Vifor and Abbott Vascular; and personal fees for consultancies, trial committee work or lectures, or a combination, from Actimed, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Occlutech, Pfizer, Regeneron, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave; and is the named co-inventor of two patent applications regarding MR-proANP (patent numbers DE 102007010834 and DE 102007022367), but he does not benefit personally from the related issued patents. DLB is on an advisory board for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; is on the board of directors for American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS. LINQ (stock options), High Enroll (stock); is a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; is on a data monitoring committee for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (chair for the PEITHO trial), Cleveland Clinic, Contego Medical (chair for the PERFORMANCE 2 trial), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; and for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, Rutgers University (for the National Institutes for Health-funded MINT trial); receives honoraria from the American College of Cardiology (senior associate editor for Clinical Trials and News for ACC.org; chair for the American College of Cardiology Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi and Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; for the RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; and the AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief for Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief for the Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor and associate editor), K2P (co-chair for interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education steering committees), MJH Life Sciences, Oakstone CME (course director for Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (Continuing Medical Education steering committees), Wiley (steering committee), and Clinical Cardiology (deputy editor); is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon (neither DLB nor Brigham and Women's Hospital receive any income from this patent); receives research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; receives royalties from Elsevier (editor for Braunwald's Heart Disease); is a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; is a trustee for the American College of Cardiology; and has conducted unfunded research with FlowCo. JB reports consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pharmacosmos, Pharmain, Pfizer, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. DZIC has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, and Novo-Nordisk; and received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, and Novo-Nordisk. WGH reports funding from the UK Medical Research Council, Kidney Research UK, and Health Data Research UK; and grants to the University of Oxford from Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial. SEI reports serving as an advisor or consultant to Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Merck, Pfizer, and Bayer; and delivering lectures sponsored by Boehringer Ingelheim and AstraZeneca. MJJ is supported by an National Health and Medical Research Council investigator grant; is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and MSD; and has received fees for advisory, steering committee, or scientific presentations, or a combination, from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, Chinook, CSL, Janssen, Medscape, MSD, Occuryx, Roche, and Vifor, with any consultancy, honoraria, or travel support paid to her institution. C-CL is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co. KWM has received research support from Afferent, Amgen, Apple, AstraZeneca, Cardiva Medical, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, National Institutes of Health, Novartis, Sanofi, St Jude, and Tenax; and has served as a consultant (speaker fees for continuing medical education events only) for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi Tanabe, Myokardia, the National institutes for Health, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and the University of California, San Francisco. DKM has received honoraria for trial leadership from Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, CSL Behring, Eidos, and NewAmsterdam; and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, CSL Behring, Bayer, Altimmune, Intercept, Alynlam, and Pfizer. JJVM has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of Continuing Medical Education, Hikma Pharmaceuticals, Imagica health, Intas Pharma, JB Chemicals & Pharma, Lupin Pharma, Medscape or Heart. Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners. BN has received grants for CANVAS and CREDENCE; is on an advisory board and has received honoraria and travel reimbursement all from Janssen and all paid to his institution; has received research support from the Australian National Health and Medical Research Council Principal Research Fellowship and Janssen; and has served on advisory boards or has had involvement in continuing medical education programmes for Janssen, with any consultancy, honoraria, or travel support paid to his institution; and has institutional relationships with AbbVie, Actelion, and Janssen. MP reports consulting to 89bio, AbbVie, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, MSD, Novartis, Reata, Relypsa, and Salamandra. VP serves as a board director for St Vincent's Health Australia, Victor Chang Cardiac Research Institute, and Mindgardens; and has received honoraria for Steering Committee roles, scientific presentations, or advisory board attendance, or a combination, from Abbvie, Amgen, Astra Zeneca, Bayer, Baxter, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pharmalink, Pfizer, Reata, Travere, Relypsa, Roche, Sanofi, Servier, and Tricida. MSS reports research grant support through the Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis, Merck, Novartis, Pfizer, Saghmos Therapeutics, and Verve Therapeutics; and consulting for Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Dr Reddy's Laboratories, Merck, Moderna, Novo Nordisk, Precision BioSciences, and Silence Therapeutics. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health and the National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. NS reports institutional grant support from Boehringer Ingelheim, Lilly, and Novo Nordisk. MS serves as a consultant for, or has received research support from, or both, Lexicon, Esperion, Amarin, NewAmsterdam, Silence, Sanofi, Tourmaline, and Regeneron Pharmaceuticals. MV has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. CW reports personal fees from Boehringer Ingelheim, AstraZeneca, Eli Lilly and Company, MSD, and Bayer. DCW reports honoraria or consultancy fees, or both, from Amgen, AstraZeneca (ongoing), Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Mundipharma, MSD, Napp, Dohme, Takeda, Vifor Fresenius, and Zydus. SDW reports research grants from Amgen, AstraZeneca, Janssen, Merck, and Pfizer; and consulting fees or honoraria from Icon Clinical and Novo Nordisk, Varian, and Harvard Medical School. SDW's spouse, Dr Caroline Fox is an employee of Vertex, and former employee of Flagship Pioneering and Merck. MSS and SDW are members of the TIMI Study Group, which has received institutional grant support through Brigham and Women's Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Saghmos Therapeutics, Softcell Medical, The Medicines Company, Verve Therapeutics, and Zora Biosciences. FZ reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, NovoNordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; having stock options at G3Pharmaceutical; having equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and being the founder of Cardiovascular Clinical Trialists. HJLH has received grants or contracts from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Novo Nordisk, Novartis, and Travere Therapeutics; and payment or honoraria for speaking from AstraZeneca and Novo Nordisk. EMA and NJ declare no competing interests., (Copyright © Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)