Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

doi:10.1161/CIRCULATIONAHA.124.069568

Meta-Analysis

. 2024 Jun 4;149(23):1789-1801.

doi: 10.1161/CIRCULATIONAHA.124.069568. Epub 2024 Apr 7.

Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

Siddharth M Patel^{1

2}, Yu Mi Kang^{1

3}, KyungAh Im^{1

2}, Brendon L Neuen^{2

4

5}, Stefan D Anker⁶, Deepak L Bhatt⁷, Javed Butler^{8

9}, David Z I Cherney¹⁰, Brian L Claggett², Robert A Fletcher⁴, William G Herrington¹¹, Silvio E Inzucchi¹², Meg J Jardine⁴, Kenneth W Mahaffey¹³, Darren K McGuire¹⁴, John J V McMurray¹⁵, Bruce Neal⁴, Milton Packer^{16

17}, Vlado Perkovic⁴, Scott D Solomon², Natalie Staplin¹¹, Muthiah Vaduganathan², Christoph Wanner⁸, David C Wheeler¹⁸, Faiez Zannad¹⁹, Yujie Zhao²⁰, Hiddo J L Heerspink^{4

21}, Marc S Sabatine^#^{1

2}, Stephen D Wiviott^#^{1

2}

Affiliations

¹ TIMI Study Group (S.M.P., Y.M.K., K.I., M.S.S., S.D.W.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
² Cardiovascular Division, Department of Medicine (S.M.P., K.I., B.L.N., B.L.C., S.D.S., M.V., M.S.S., S.D.W.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
³ Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine (Y.M.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
⁴ The George Institute for Global Health, University of New South Wales, Sydney, Australia (B.L.N., R.A.F., M.J.J., B.N., V.P., H.J.L.H.).
⁵ Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia (B.L.N.).
⁶ Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin (S.D.A.).
⁷ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY (D.L.B.).
⁸ Baylor Scott and White Research Institute, Dallas, TX (J.B.).
⁹ Department of Medicine, University of Mississippi School of Medicine, Jackson (J.B.).
¹⁰ Department of Medicine, Division of Nephrology, Toronto General Hospital, Ontario, Canada (D.Z.I.C.).
¹¹ Renal Studies Group, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (W.G.H., N.S.).
¹² Section of Endocrinology, Yale School of Medicine, New Haven, CT (S.E.I.).
¹³ Stanford Center for Clinical Research (SCCR), Department of Medicine, Stanford University School of Medicine, CA (K.W.M.).
¹⁴ University of Texas Southwestern Medical Center, Parkland Health, Dallas (D.K.M.).
¹⁵ British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.).
¹⁶ Baylor University Medical Center, Dallas TX(M.P.).
¹⁷ Imperial College, London, United Kingdom (M.P.).
¹⁸ Department of Renal Medicine, University College London, United Kingdom (D.C.W.).
¹⁹ Université de Lorraine, Inserm Centre d'Investigations Cliniques Plurithématique 1433, and CHRU, Nancy, France (F.Z.).
²⁰ Merck & Co., Inc., Rahway, NJ (Y.Z.).
²¹ Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands (H.J.L.H.).

^# Contributed equally.

PMID: 38583093
PMCID: PMC11149938
DOI: 10.1161/CIRCULATIONAHA.124.069568

Meta-Analysis

Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

Siddharth M Patel et al. Circulation. 2024.

. 2024 Jun 4;149(23):1789-1801.

doi: 10.1161/CIRCULATIONAHA.124.069568. Epub 2024 Apr 7.

Authors

Affiliations

¹ TIMI Study Group (S.M.P., Y.M.K., K.I., M.S.S., S.D.W.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
² Cardiovascular Division, Department of Medicine (S.M.P., K.I., B.L.N., B.L.C., S.D.S., M.V., M.S.S., S.D.W.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
³ Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine (Y.M.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
⁴ The George Institute for Global Health, University of New South Wales, Sydney, Australia (B.L.N., R.A.F., M.J.J., B.N., V.P., H.J.L.H.).
⁵ Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia (B.L.N.).
⁶ Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin (S.D.A.).
⁷ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY (D.L.B.).
⁸ Baylor Scott and White Research Institute, Dallas, TX (J.B.).
⁹ Department of Medicine, University of Mississippi School of Medicine, Jackson (J.B.).
¹⁰ Department of Medicine, Division of Nephrology, Toronto General Hospital, Ontario, Canada (D.Z.I.C.).
¹¹ Renal Studies Group, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (W.G.H., N.S.).
¹² Section of Endocrinology, Yale School of Medicine, New Haven, CT (S.E.I.).
¹³ Stanford Center for Clinical Research (SCCR), Department of Medicine, Stanford University School of Medicine, CA (K.W.M.).
¹⁴ University of Texas Southwestern Medical Center, Parkland Health, Dallas (D.K.M.).
¹⁵ British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.).
¹⁶ Baylor University Medical Center, Dallas TX(M.P.).
¹⁷ Imperial College, London, United Kingdom (M.P.).
¹⁸ Department of Renal Medicine, University College London, United Kingdom (D.C.W.).
¹⁹ Université de Lorraine, Inserm Centre d'Investigations Cliniques Plurithématique 1433, and CHRU, Nancy, France (F.Z.).
²⁰ Merck & Co., Inc., Rahway, NJ (Y.Z.).
²¹ Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands (H.J.L.H.).

^# Contributed equally.

PMID: 38583093
PMCID: PMC11149938
DOI: 10.1161/CIRCULATIONAHA.124.069568

Abstract

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear.

Methods: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups).

Results: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I²=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (P_interaction=0.02).

Conclusions: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.

Keywords: diabetes mellitus; heart failure; meta-analysis; metabolic syndrome; renal insufficiency, chronic; sodium-glucose cotransporter-2 inhibitors.

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Conflict of interest statement

Disclosures Drs Patel, Kang, Im, Sabatine, and Wiviott are members of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., and Zora Biosciences. Dr Patel reports consulting fees from Janssen. Dr Neuen 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, and Travere Therapeutics with all honoraria paid to The George Institute for Global Health. Dr Anker reports grants and personal fees from Vifor and Abbott Vascular, and personal fees for consultancies, trial committee work, or lectures 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. Named co-inventor of 2 patent applications regarding MR-proANP (DE 102007010834 and DE 102007022367), but he does not benefit personally from the related issued patents. Dr Bhatt discloses the following relationships: advisory boards 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, and Stasys; boards 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 [Portico Re-sheathable Transcatheter Aortic Valve System US IDE Trial]), funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial [Pulmonary Embolism International Thrombolysis Trial]), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Arter Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation–Atrial Fibrillation], funded by Daiichi Sankyo; for the ABILITY-DM trial (Randomized Comparison of Abluminus DSE+ Sirolimus-Eluting Stents Versus Everolimus-Eluting Stents in Coronary Artery Disease Patients With Diabetes Mellitus Global), funded by Concept Medical; for ALLAY-HF (Safety and Efficacy of the Alleviant System for No-Implant Interatrial Shunt Creation in Patients With Chronic Heart Failure), funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the National Institutes of Health–funded MINT Trial [Myocardial Ischemia and Transfusion]); 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 [Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting] steering committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] 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 [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], 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 [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), 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 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, 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, Vascular Solutions; trustee: American College of Cardiology; Unfunded Research: FlowCo. Dr Butler 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. Dr Cherney 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. Dr Claggett has received consulting fees from Amgen, Cardurion, Corvia, and Novartis. Dr Anand reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from Amgen, ARCA, Boston Scientific Corporation, Boehringer Ingelheim, LivaNova, and Zensun outside the submitted work. D. Herrington 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. Dr Inzucchi reports serving as an advisor or consultant to Boehringer Ingelheim, AstraZeneca, Bayer, Novo Nordisk, Merck, Pfizer, Lexicon, Abbott, VTV Therapeutics, and Esperion, and delivering lectures sponsored by Boehringer Ingelheim and AstraZeneca. Dr Jardine is supported by a 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; has received fees for advisory, steering committee and scientific presentations 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. Dr Mahaffey’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. Dr McGuire has received honoraria for trial leadership from Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, CSL Behring, and 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. Dr McMurray 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 Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma. Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica health, Intas Pharma, J.B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/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 Ltd. Dr Nunez has received personal fees from or is on advisory boards for Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Cytokinetics, Novartis, Novo Nordisk, Rovi, and Vifor Pharma. Dr Neal has received grants for CANVAS and CREDENCE, advisory board, honoraria, travel reimbursement, all from Janssen and all paid to his institution. He has received research support from the Australian National Health and Medical Research Council principal research fellowship and from Janssen, and he has served on advisory boards or has had involvement in continuing medical education programs for Janssen, with any consultancy, honoraria, or travel support paid to his institution. He also notes institutional relationships with AbbVie, Actelion, and Janssen. Dr Packer reports consulting to 89bio, Abbvie, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Reata, Relypsa, and Salamandra. Dr Staplin has consulted for and received speaker fees from Abbott Laboratories, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. Dr Perkovic has received fees for advisory boards, steering committee roles and travel support from AstraZeneca, Bayer, and Janssen, with all honoraria paid to his employer. Dr Solomon 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/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. Dr Staplin reports institutional grant support from Boehringer Ingelheim, Lilly, and Novo Nordisk. Dr Vaduganathan 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. Dr Wanner reports personal fees from Boehringer Ingelheim, AstraZeneca, Eli Lilly, and Company, MSD, and Bayer. Dr Wheeler reports honoraria and consultancy fees from Amgen, AstraZeneca (ongoing), Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Merck Sharp, Napp, and Dohme, Takeda, Vifor Fresenius, and Zydus. Dr Zannad 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, USa2, having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, Eshmoun Clinical research and being the founder of Cardiovascular Clinical Trialists. Dr Zhao is an employee of Merck & Co, Inc. and holds Merck stock. Dr Heerspink 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; payment or honoraria for speaking from AstraZeneca and Novo Nordisk. Dr Sabatine reports research grant support through Brigham and Women’s Hospital from Abbott; Amgen; Anthos Therapeutics, Inc.; AstraZeneca; Boehringer Ingelheim; Daiichi-Sankyo; Ionis; Merck; Novartis; Pfizer; Saghmos Therapeutics; Verve Therapeutics, and consulting for Amgen; Anthos Therapeutics, Inc.; AstraZeneca; Beren Therapeutics; Boehringer Ingelheim; Dr. Reddy’s Laboratories; Merck; Moderna; Novo Nordisk; Precision BioSciences; and Silence Therapeutics. Dr Wiviott reports research grants from Amgen, AstraZeneca, Janssen, Merck, and Pfizer, consulting fees or honoraria from Icon Clinical and Novo Nordisk, Varian and Harvard Medical School. Dr Wiviott’s spouse, Dr Caroline Fox, is an employee of Vertex, and a former employee of Flagship Pioneering and Merck.

Figures

**Figure 1.**
**Overall effect of sodium-glucose cotransporter-2 inhibition on the major adverse cardiovascular events composite.** The forest plot depicts the treatment effect of SGLT2 inhibitors on major adverse cardiovascular events composite at the level of the individual trials, by trial type, and in the overall study population. ASCVD indicates atherosclerotic cardiovascular disease; CANVAS Program, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure), DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; EMPA-REG Outcome; 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; FE, fixed effects; RE, random effects; SGLT2, sodium-glucose cotransporter-2; and VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial.

**Figure 2.**
**Overall effect of sodium-glucose cotransporter-2 inhibition on individual components.** These forest plots depict the treatment effect of SGLT2 inhibitors on the individual components of the major adverse cardiovascular events composite, at the level of the individual trials, by trial type, and in the overall study population. A, The treatment effect on cardiovascular death. B, The effect on myocardial infarction. C, The effect on stroke. ASCVD indicates atherosclerotic cardiovascular disease; CANVAS Program, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure), DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; EMPA-REG Outcome; 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; FE – fixed effects; RE, random effects; SGLT2, sodium-glucose cotransporter-2; and VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial.

**Figure 3.**
**Cardiovascular death subtypes across trial populations (placebo arms only).** The pie charts show the distribution of subtypes of cardiovascular death in the placebo arms of each trial grouped by trial type. ASCVD indicates atherosclerotic cardiovascular disease; CV, cardiovascular; and MI, myocardial infarction.

**Figure 4.**
**Overall effect of sodium-glucose cotransporter-2 inhibition on subtypes of cardiovascular death.** These forest plots depict the treatment effect of SGLT2 inhibitors on subtypes of cardiovascular death. ASCVD indicates atherosclerotic cardiovascular disease; RE, random effects; and SGLT2, sodium-glucose cotransporter-2.

**Figure 5.**
**Overall effect of sodium-glucose cotransporter-2 inhibition by subgroups for the major adverse cardiovascular events composite and cardiovascular death. A**, The treatment effect of SGLT2 inhibitors on the MACE composite across subgroups. B, The treatment effect on cardiovascular death across subgroups. ASCVD indicates atherosclerotic cardiovascular disease; eGFR, estimated glomerular filtration rate; MACE, major adverse cardiovascular events; SGLT2i, sodium-glucose cotransporter-2; and UACR, urine albumin-to-creatinine ratio.

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References

1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. ; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720 - PubMed
1. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925 - PubMed
1. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al. ; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389 - PubMed
1. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, et al. ; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–1435. doi: 10.1056/NEJMoa2004967 - PubMed
1. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al. ; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424. doi: 10.1056/NEJMoa2022190 - PubMed

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[1] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. ; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720 - PubMed

[2] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. ; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720 - PubMed

[3] Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925 - PubMed

[4] Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925 - PubMed

[5] Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al. ; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389 - PubMed

[6] Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al. ; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389 - PubMed

[7] Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, et al. ; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–1435. doi: 10.1056/NEJMoa2004967 - PubMed

[8] Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, et al. ; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–1435. doi: 10.1056/NEJMoa2004967 - PubMed

[9] Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al. ; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424. doi: 10.1056/NEJMoa2022190 - PubMed

[10] Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al. ; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424. doi: 10.1056/NEJMoa2022190 - PubMed

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Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

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Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

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