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Following the publication of results from multiple landmark cardiovascular outcome trials of antihyperglycemic medications over the past 8 years, there has been a major shift in the focus of care for people with type 2 diabetes, from control of hyperglycemia to managing cardiovascular risk. Multiple international cardiology and diabetes society guidelines and recommendations now endorse sodium-glucose cotransporter-2 inhibitors and glucagon-like protein-1 receptor agonists as first-line therapies to mitigate cardiovascular risk. The most recent publication is the 2023 European Society of Cardiology guideline on the management of cardiovascular disease in those with type 2 diabetes that, for the first time, recommends use of both classes of medications for the mitigation of cardiovascular risk for those with or at high risk for atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. Here, we review the evidence behind contemporary society guidelines and recommendations for the management of type 2 diabetes and cardiovascular risk.

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 ( I 2 =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., Competing Interests: 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.

Competing Interests: Disclosures N. Sattar has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; he has received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. Dr Neeland has consulted for and/or received speaker honoraria from Boehringer Ingelheim, Eli Lilly and Co, Novo Nordisk, Bayer Pharmaceuticals, and Nestle Health Sciences outside the submitted work. Dr McGuire reports research support for Clinical Trials Leadership from Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, and CSL Behring, as well as honoraria for consultancy from Lilly USA, Pfizer, Boehringer Ingelheim, Lexicon, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, Intercept, and New Amsterdam.

In high-income countries, rates of atherosclerotic complications in type 2 diabetes have declined markedly over time due to better management of traditional risk factors including lipids, blood pressure, and glycemia levels. Population-wide reductions in smoking have also helped lower atherosclerotic complications and so reduce premature mortality in type 2 diabetes. However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Excess weight is also an underrecognized risk factor for chronic kidney disease (CKD). Based on evidence from a range of sources, we explain how excess adiposity must be influencing most risks well before diabetes develops, particularly in younger-onset diabetes, which is linked to greater excess adiposity. We also review potential mechanisms linking excess adiposity to HF and CKD and speculate on how some of the responsible pathways-e.g., hemodynamic, cellular overnutrition, and inflammatory-could be favorably influenced by intentional weight loss (via lifestyle or drugs). On the basis of available evidence, we suggest that the cardiorenal outcome benefits seen with sodium-glucose cotransporter 2 inhibitors may partially derive from their interference of some of these same pathways. We also note that many other complications common in diabetes (e.g., hepatic, joint disease, perhaps mental health) are also variably linked to excess adiposity, the aggregated exposure to which has now increased in type 2 diabetes. All such observations suggest a greater need to tackle excess adiposity earlier in type 2 diabetes., (© 2024 by the American Diabetes Association.)

Competing Interests: Disclosures None.

Background: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial., Methods: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m 2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis)., Results: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m 2 . Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing., Conclusion: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit., Competing Interests: Conflict of interest SJN reports grants or contracts from Amgen, Anthera Pharmaceuticals, AstraZeneca, Cerenis Therapeutics, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Infraredx, New Amsterdam Pharma, Novartis, Resverlogix, and Sanofi Regeneron; consulting fees from Akcea Therapeutics, Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Kowa, Merck, Novo Nordisk, Pfizer, Sanofi Regeneron, Takeda, Vaxxinity, Silence Therapeutics, and CSL Sequiris; is a named inventor on a patent planned, issued or pending with Amgen; and is President of Cardiac Society of Australia and New Zealand. DLB reports grants or contracts 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 Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89bio, Otsuka, and Alnylam; royalties from Elsevier; consulting fees from Broadview Ventures, Hims, and McKinsey; payment or honoraria from American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, WebMD, Wiley, Society of Cardiovascular Patient Care, and CSL Behring; payment for expert testimony from Arnold and Porter law firm; meeting/travel support from American College of Cardiology, Society of Cardiovascular Patient Care, and American Heart Association; a pending patent for Sotagliflozin; participation on data monitoring or advisory boards for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, AngioWave, Baim Institute, Bayer, Boehringer Ingelheim, Boston Scientific, Cardax, CellProthera, Cereno Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Elsevier Practice Update Cardiology, Janssen, Level Ex, Mayo Clinic, Medscape Cardiology, Merck, Mount Sinai School of Medicine, MyoKardia, NirvaMed, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Population Health Research Institute, and Stasys; leadership or fiduciary roles with American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, TobeSoft, and AHA NYC Chapter; stock or stock options in AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; and other financial or non-financial interests in Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), American Heart Association Quality Oversight Committee (Chair), VA CART Research and Publications Committee (Chair), Contego Medical (Chair, PERFORMANCE 2), conducts unfunded research with FlowCo and Takeda, and is site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Phillips SpectraWAVE, Svelte, and Vascular Solutions. JBB reports grant support from Dexcom, Insulet, MannKind, NovaTarg, Novo Nordisk, Sanofi, Tolerion, and vTv Therapeutics; consulting fees from Novo Nordisk, Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion Inc, Boehringer Ingelheim, CeQur, Cirius Therapeutics Inc, Corcept Therapeutics, CultHealth, Eli Lilly and Company, embecta, GentiBio, Glycadia, Glyscend, Janssen, Mellitus Health, Metsera, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Tandem, Terns Inc, Valo, and Zealand Pharma; payment for expert testimony from Medtronic; participation on data monitoring or advisory boards for Alkahest, Altimmune, AstraZeneca, and Tandem; a leadership or fiduciary role with Association of Clinical and Translational Science; stock or stock options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego and Stability Health; and other financial or other non-financial interests in Dasman Diabetes Center, Kuwait City (scientific advisory board), and ReachMD and Mediflix (audiovisual content development). SDP reports consultation for Abbott, Amarin, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hengrui Pharmaceuticals, Menarini International, MSD, Novo Nordisk, and Sanofi; grant support from AstraZeneca and Boehringer Ingelheim; and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Laboratori Guidotti, MSD, Novartis, Novo Nordisk, and Sanofi.. SEK reports consulting fees from Anji Pharamceuticals, Eli Lilly and Company, Merck, and Novo Nordisk; and payment or honoraria from Novo Nordisk. AML reports grants or contracts from Eli Lilly and Company; consulting fees from Eli Lilly and Company, Novo Nordisk, and Novartis; and meeting/travel support from Novo Nordisk and Eli Lilly and Company. DKM reports research support for clinical trials leadership from Boehringer Ingelheim, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, CSL Behring, and New Amsterdam; and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, and Intercept. MAN reports grants or contracts from Merck, Sharp & Dohme; consulting fees from Boehringer Ingelheim, Berlin-Chemie/Menarini, Eli Lilly and Company, Medtronic, Merck, Sharp & Dohme, Novo Nordisk, Pfizer, Regor, Structure Therapeutics (Gasherbrum), and Sun Pharma; payment or honoraria from Berlin-Chemie/Menarini, Eli Lilly and Company, Medical Learning Institute, Medscape, Merck, Sharp & Dohme, Novo Nordisk, Sanofi, and Sun Pharma; and participation on a data monitoring or advisory board with Inventiva. SEN reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Arrowhead, Amgen, Bristol Myers Squibb, Eli Lilly, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. NS reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; a grant from Roche Diagnostics; and personal fees from Abbott Laboratories, Amgen, Eli Lilly and Company, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi. BZ reports consulting fees from Eli Lilly and Company. SZ reports grants or contracts from NHMRC, Australian Government Department of Health and Aged Care, JDRF Centre of Excellence, and MRFF; consulting fees from Eli Lilly Australia, Boehringer-Ingelheim, MSD Australia, Astra Zeneca, Novo Nordisk, and Sanofi; payment or honoraria from Heart Foundation; meeting/travel support from Australian Diabetes Society 2022, International Diabetes Federation 2022, and KDIGO Implementation Summit on Diabetes Management in CKD; and leadership or fiduciary roles with Melanoma and Skin Cancer Trials Ltd., Australian Clinical Trials Alliance, and Victorian Institute of Forensic Medicine. JB reports consulting fees from Eli Lilly and Company, ReCor, and Medtronic; and participation on advisory boards for ReCor, Medtronic, and Eli Lilly and Company. AB, DM, HN, IP, GW, and RJW are employees and shareholders in Eli Lilly and Company. DD reports consulting fees from Eli Lilly and Company, Sun Pharmaceuticals, and Structure Therapeutics; payment or honoraria from University of Chicago, University of Iowa, and Korean Diabetes Association; meeting/travel support from American Diabetes Association; and stock or stock options in MBX Biosciences., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants., Materials and Methods: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed., Results: Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m 2 , glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants., Conclusion: SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on heart failure (HF) outcomes and cardiovascular (CV) death in patients with varying combinations of type 2 diabetes mellitus (T2DM), HF, and chronic kidney disease (CKD) are uncertain., Objectives: The authors conducted a meta-analysis assessing the effects of SGLT2 inhibitors on HF outcomes and CV death across different patient populations., Methods: Online databases were queried up to November 2022 for primary and secondary analyses of trials of SGLT2 inhibitors in patients with HF, T2DM, or CKD. Outcomes of interest were composite of first heart failure hospitalization (HFH) or CV death (first HFH/CV death), first HFH, and CV death. Data were pooled by means of a random-effects model to derive HRs and 95% CIs., Results: Thirteen trials (n = 90,413) were included. Compared with placebo, SGLT2 inhibitors reduced the risk of first HFH/CV death by 24% in HF (HR: 0.76; 95% CI: 0.72-0.81), 23% in T2DM (HR: 0.77; 95% CI: 0.73-0.81), and 23% in CKD (HR: 0.77; 95% CI: 0.72-0.82). The benefit was consistent in HF with reduced or preserved ejection fraction, HF with or without T2DM, and HF with or without CKD. The benefit was also consistent in T2DM with or without CKD, T2DM without HF, CKD without HF, and in patients with all 3 comorbidities. SGLT2 inhibitors significantly reduced CV death by 16% in HF, 15% in T2DM, and 12% in CKD., Conclusions: SGLT2 inhibitors reduce HF events and CV death in cohorts of HF, T2DM and CKD, and these effects appear consistent in patients with varying combinations of these diseases., Competing Interests: Funding Support and Author Disclosures Dr Anker has received grants or personal fees from Vifor Int, Bayer, Boehringer Ingelheim, Servier, Abbott Vascular, Cardiac Dimensions, Actimed, AstraZeneca, Amgen, Bioventrix, Janssen, Respicardia, V-Wave, Brahms, Cordio, and Occlutech outside of the submitted work. Dr Bakris has received research funding paid to the University of Chicago Medicine from Bayer, Novo Nordisk, and Vascular Dynamics; and has acted as a consultant for and received personal fees from Alnylam, Merck, and Ionisand Relypsa. 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 (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; Inaugural Chair of American Heart Association Quality Oversight Committee; has been a consultant for Broadview Ventures; has served on the 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, 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; and the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; and Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), and Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for Clinical Trial Steering Committee for RE-DUAL PCI (funded by Boehringer Ingelheim) and Executive Committee for AEGIS-II (funded by CSL Behring), and from Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (Clinical Trial Steering Committees), 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), and Wiley (Steering Committee); Deputy Editor, Clinical Cardiology, Registry Steering Committee (Chair) for NCDR-ACTION, Research and Publications Committee (Chair) for VA CART; named on patent for sotagliflozin (no income), assigned to Brigham and Women’s Hospital (no income), who assigned to Lexicon; 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, 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, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); is 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 American College of Cardiology; and has performed unfunded research for FlowCo and Takeda. Dr Fillipatos lectures and/or has committee member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, Bayer, Amgen, and Boehringer Ingelheim; and has received research grants from the European Union. Dr Fonarow has received research support from the National Institutes of Health; and has consulted for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association, National Heart, Lung, and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim and Eli Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, scPharmaceuticals, and Sanofi; serves as a consultant for Amgen, Bayer, Boehringer Ingelheim and Eli Lilly, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, and Roche Diagnostics. Dr Januzzi is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; has consultant/advisory board roles at Amgen, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, and Vifor Pharma; has received financial support for analysis from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr McGuire has had leadership roles in clinical trials for AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co, Novo Nordisk, CSL Behring, and Sanofi USA; and has received consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Lilly USA, Merck & Co, Pfizer, Novo Nordisk, Metavant, Afimmune, and Sanofi. Dr Piña is on the advisory board for Vifor and AstraZeneca; and is on the steering committee of the DIAMOND trial (funded by Vifor). Dr Rosenstock has served on advisory boards for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Terns Pharmaceuticals, and Zealand; and has received research support from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Lexicon, Merck, Novo Nordisk, Novartis, Oramed, Pfizer, and Sanofi. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, 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, Occlutech, and Impulse Dynamics. Dr Verma has received personal fees from AstraZeneca, Sun Pharmaceuticals, and Toronto Knowledge Translation Working Group; has received grants and personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Merck; has received grants from Bristol Myers Squibb; and has received personal fees from Eli Lilly, Janssen, Novartis, Novo Nordisk, and Sanofi. Dr Zieroth has received personal fees for Speakers Bureau and/or consulting in advisory board for Abbott, Akcea AstraZeneca, Amgen, Alnylam, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Servier, and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Pfizer, outside of the submitted work. Dr Butler is a consultant to Abbott, Adrenomed, American Regent, Arca Biopharma, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior CVRx, Cytokinetics, Edwards, Element Science, Fast Biomedical, G3 Pharmaceutical, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova Janssen, Johnson and Johnson, Medtronics, Merck, Occlutech, Nestle, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sanofi, Sequana, SQ Innovation, 3live, and Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials., Competing Interests: Conflict of interest H.G.C.V.S. leads trials with routinely available data, with funding from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. S.J.G. has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, and Sanofi; and serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, and Vifor. M.V. 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. S.S.K. reported grants from the American Heart Association and the National Institutes of Health outside the submitted work. N.L.M. reports research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Healthineers outside the submitted work and honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics, and LumiraDx. Z.A.A. reports institutional research grants to Columbia University—Abbott, Cardiovascular Systems, Inc and serves as a consultant at Abbott, Abiomed, AstraZeneca, and Shockwave. R.J.M. reported receiving personal fees from Novartis International AG, Amgen Inc, Boehringer Ingelheim, Bayer AG, and Merck & Co, Inc and receiving research support and honoraria from Abbott Laboratories, American Regent, Inc, Amgen Inc, AstraZeneca, Bayer AG, Boehringer Ingelheim/Eli Lilly & Company, Boston Scientific Corporation, Cytokinetics, Inc, FAST BioMedical, Gilead Sciences, Inc, Innolife, Medtronic PLC, Merck & Co, Inc, Novartis International AG, Relypsa, Inc, Respicardia, Windtree Therapeutics, Inc, and ZOLL Medical Corporation outside the submitted work. G.C.F. reports research support from the National Institutes of Health and consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. S.V.R. reported receiving institutional research funding from Bayer and the National Heart, Lung, and Blood Institute outside the submitted work. J.A.S. is a consultant to Bayer, Janssen, Merck, Bristol Meyers Squibb, Kineksa, Novartis, Terumo, and United Healthcare. He receives grant support from Janssen, Abbott Vascular, and Bristol Meyers Squibb. He holds the copyright to the Peripheral Artery Questionnaire, Kansas City Cardiomyopathy Questionnaires, and the Seattle Angina Questionnaire. He serves on the Board of Blue Cross/Blue Shield of Kansas City. M.T.R. reports grants from the American College of Cardiology, American Heart Association, Bayer Pharmaceuticals, Familial Hypercholesterolemia Foundation, Ferring Pharmaceuticals, Myokardia, and Patient Centered Outcomes Research Institute; grants and personal fees from Amgen, AstraZeneca, and Sanofi Aventis; personal fees from Janssen Pharmaceuticals, Elsevier Publishers, Regeneron, Roche-Genetech, Eli Lilly, Novo Nordisk, Pfizer, and Signal Path; and is an employee of Verana Health. S.D.A. declares grants or personal fees from Vifor Int, Bayer, Boehringer Ingelheim, Servier, Abbott Vascular, Cardiac Dimensions, Actimed, Astra Zeneca, Amgen, Bioventrix, Janssen, Respicardia, V-Wave, Brahms, Cordio, and Occlutech, outside the submitted work. S.K.J. has received institutional research/grant support from AstraZeneca, Bayer, Janssen, and Novartis. J.B. has served as a consultant to Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Sequana Medical, V-Wave Limited, and Vifor. D.K.M. reports honoraria for clinical trial leadership from Ventyx, Boehringer Ingelheim, Sanofi, Merck & Co, Pfizer, Akebia, AstraZeneca, Novo Nordisk, Esperion, AbbVie, Lilly USA, Eidos, Arena, Dynavax, Lexicon, Otsuka, and CSL Behring, and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, Altimmune, Intercept, Merck & Co, Novo Nordisk, Applied Therapeutics, Metavant, Sanofi, Afimmune, CSL Behring, and Bayer. All other authors report no conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA., Methods: In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term "sleep apnea syndrome." A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA., Results: Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m 2 ; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28-0.96; P = 0.04)., Conclusions: In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA., Clinicaltrials: gov identifier: NCT01986881., (© 2022. Pfizer Inc. and The Author(s).)

Importance: Evidence-based therapies to reduce atherosclerotic cardiovascular disease risk in adults with type 2 diabetes are underused in clinical practice., Objective: To assess the effect of a coordinated, multifaceted intervention of assessment, education, and feedback vs usual care on the proportion of adults with type 2 diabetes and atherosclerotic cardiovascular disease prescribed all 3 groups of recommended, evidence-based therapies (high-intensity statins, angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs], and sodium-glucose cotransporter 2 [SGLT2] inhibitors and/or glucagon-like peptide 1 receptor agonists [GLP-1RAs])., Design, Setting, and Participants: Cluster randomized clinical trial with 43 US cardiology clinics recruiting participants from July 2019 through May 2022 and follow-up through December 2022. The participants were adults with type 2 diabetes and atherosclerotic cardiovascular disease not already taking all 3 groups of evidence-based therapies., Interventions: Assessing local barriers, developing care pathways, coordinating care, educating clinicians, reporting data back to the clinics, and providing tools for participants (n = 459) vs usual care per practice guidelines (n = 590)., Main Outcomes and Measures: The primary outcome was the proportion of participants prescribed all 3 groups of recommended therapies at 6 to 12 months after enrollment. The secondary outcomes included changes in atherosclerotic cardiovascular disease risk factors and a composite outcome of all-cause death or hospitalization for myocardial infarction, stroke, decompensated heart failure, or urgent revascularization (the trial was not powered to show these differences)., Results: Of 1049 participants enrolled (459 at 20 intervention clinics and 590 at 23 usual care clinics), the median age was 70 years and there were 338 women (32.2%), 173 Black participants (16.5%), and 90 Hispanic participants (8.6%). At the last follow-up visit (12 months for 97.3% of participants), those in the intervention group were more likely to be prescribed all 3 therapies (173/457 [37.9%]) vs the usual care group (85/588 [14.5%]), which is a difference of 23.4% (adjusted odds ratio [OR], 4.38 [95% CI, 2.49 to 7.71]; P < .001) and were more likely to be prescribed each of the 3 therapies (change from baseline in high-intensity statins from 66.5% to 70.7% for intervention vs from 58.2% to 56.8% for usual care [adjusted OR, 1.73; 95% CI, 1.06-2.83]; ACEIs or ARBs: from 75.1% to 81.4% for intervention vs from 69.6% to 68.4% for usual care [adjusted OR, 1.82; 95% CI, 1.14-2.91]; SGLT2 inhibitors and/or GLP-1RAs: from 12.3% to 60.4% for intervention vs from 14.5% to 35.5% for usual care [adjusted OR, 3.11; 95% CI, 2.08-4.64]). The intervention was not associated with changes in atherosclerotic cardiovascular disease risk factors. The composite secondary outcome occurred in 23 of 457 participants (5%) in the intervention group vs 40 of 588 participants (6.8%) in the usual care group (adjusted hazard ratio, 0.79 [95% CI, 0.46 to 1.33])., Conclusions and Relevance: A coordinated, multifaceted intervention increased prescription of 3 groups of evidence-based therapies in adults with type 2 diabetes and atherosclerotic cardiovascular disease., Trial Registration: ClinicalTrials.gov Identifier: NCT03936660.

Background: In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease., Methods: The DECLARE-TIMI 58 trial was a double-blind, multicentre, randomised, placebo-controlled study. People with type 2 diabetes and either risk factors for or established atherosclerotic cardiovascular disease were randomly assigned (1:1) to receive oral dapagliflozin 10 mg or placebo once daily. In these post-hoc analyses, the effects of dapagliflozin on risks of first non-elective any-cause and cause-specific hospitalisation were assessed with Cox proportional hazards regression models overall and in the subset of participants without prevalent atherosclerotic cardiovascular disease. The risk of total (first plus subsequent) non-elective hospitalisations was assessed with Lin-Wei-Ying-Yang model. Investigator-reported System Organ Class terms were used to classify cause-specific hospitalisations. The trial is registered with ClinicalTrials.gov, NCT01730534., Findings: Between April 25, 2013, and Sept 18, 2018, 17 160 people (6422 [37·4%] women, 10 738 [62·6%] men; mean age 63·9 years [SD 6·8]) were enrolled in the original trial, of whom 10186 (59·4%) had multiple risk factors for but did not have established atherosclerotic cardiovascular disease, and 6835 (39·8%) had both no evidence of atherosclerotic cardiovascular disease and low KDIGO risk. Over a median follow-up of 4·2 years (IQR 3·9-4·4), dapagliflozin was associated with a lower risk of first non-elective hospitalisation for any cause (2779 [32·4%] of 8582 people in the dapagliflozin group vs 3036 [35·4%] of 8578 people in the placebo group; hazard ratio [HR] 0·89 [95% CI 0·85-0·94]) and total (first plus subsequent) non-elective hospitalisations for any cause (risk ratio 0·92 [95% CI 0·86-0·97]). The association between dapagliflozin use and the risk of first non-elective hospitalisation for any cause was consistent in subgroups of participants with (HR 0·92 [95% CI 0·85-0·99] and without (0·87 [0·81-0·94]) atherosclerotic cardiovascular disease at baseline (p interaction=0·31). Compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders (HR 0·91 [95% CI 0·84-1·00]), metabolism and nutrition disorders (0·73 [0·60-0·89]), renal and urinary disorders (0·61 [0·49-0·77]), and due to any other cause excluding these three causes (0·90 [0·85-0·96]). Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders (HR 0·81 [0·67-0·99]) and infections and infastations (HR 0·86 [0·78-0·96])., Interpretation: Dapagliflozin reduced the risk of first and total non-elective hospitalisations for any cause in people with type 2 diabetes, regardless of the presence of atherosclerotic cardiovascular disease, including hospitalisations not directly attributed to cardiac, kidney, or metabolic causes. These findings might have implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition., Funding: AstraZeneca., Competing Interests: Declaration of interests MS reports travel support from AstraZeneca and Novo Nordisk paid to Hadassah Medical Center, Jerusalem, Israel. SDW reports grants from AstraZeneca, Bristol-Myers Squibb, Sanofi, and Amgen; grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen; grants and consulting fees from Merck; and personal fees from Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, St Jude Medical, Xoma, Servier, AstraZeneca, and Bristol-Myers Squibb. SDW's spouse is employed by Merck. IR reports being a member of an advisory board for AstraZeneca, Eli Lilly, Novo Nordisk. Consultancy fees AstraZeneca, Insuline Medical, Concenter BioPharma, and Pluristem; and Speaker's Bureau from AstraZeneca, Eli Lilly and Company, Novo Nordisk, and Sanofi. ELG and SAM are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical, The Medicines Company, and Zora Biosciences. AR and IY report hourly payments from AstraZeneca paid to Hadassah Medical Center and hourly payments from Novo Nordisk. TAZ reports research grants from the Austrian Science Funds and the German Research Foundation, honoraria for serving on advisory boards from Boehringer Ingelheim; personal fees from AstraZeneca, Boehringer Ingelheim, and Sun Pharmaceutical Industries; and educational grants from Eli Lilly. MF, PAJ, IAMG-N, and AML are employees at BioPharmaceuticals Research & Development, AstraZeneca, Gothenburg, Sweden. LAL reports research funding from Astra Zeneca and Lexicon; has provided continuing medical education on behalf of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, and Servier; and has acted as an advisor to AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, and Sanofi. DLB reports being a member of an advisory board for from 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; is a member of the Board of Directors for AngioWave (with stock options), Boston VA Research Institute, Bristol-Myers Squibb (holds stock), DRS.LINQ (with stock options), High Enroll (holds stock), Society of Cardiovascular Patient Care, and TobeSoft; is the Inaugural Chair of the American Heart Association Quality Oversight Committee; consultantcy fees from Broadview Ventures; is a member of Data Monitoring Committees 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, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute; Rutgers University; Honoraria from the American College of Cardiology, Arnold and Porter law firm, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute), Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD, Wiley; is the Deputy Editor of Clinical Cardiology; is the Chair of the NCDR-ACTION Registry Steering Committee; is the Chair of the VA CART Research and Publications Committee; is named on the patent for sotagliflozin, which is 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); 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, 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, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties from Elsevier; is a site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; is a trustee of the American College of Cardiology; and has done unfunded research for FlowCo and Takeda. DKM reports research support for Clinical Trials Leadership from Boehringer Ingelheim, Sanofi, Merck, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, and CSL Behring; and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck, Novo Nordisk, Applied Therapeutics, Metavant, Sanofi, Altimmune and Intercept Pharma, CSL Behring, Bayer, and GlaxoSmithKline. JPHW reports consultancy and speaking engagements contracted via the University of Liverpool, Liverpool, UK (no personal payment) from Alnylam, AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Eli Lilly, Napp, Novo Nordisk, Mundipharma, Pfizer, Rhythm Pharmaceuticals, Saniona, and Ysopia; grants paid to the University of Liverpool from AstraZeneca and Novo Nordisk; and honoraria and lecture fees (personal) from AstraZeneca, Boehringer Ingelheim, Merck, Napp, Novo Nordisk, Mundipharma, Sanofi, and Takeda. AC reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Boehringer Ingelheim, Eli Lilly, Sanofi, Pfizer, and Medial Early-Sign. MSS reports grants and consulting fees from Amgen, AstraZeneca, Intarcia, Janssen Research & Development, Medicines Company, MedImmune, Merck, and Novartis; consulting fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis; and grants from Bayer, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; MSS is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Roche, and Zora Biosciences. OM reports being a member of an advisory board for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, AstraZeneca; research grant support paid to Hadassah Hebrew University Hospital from Novo Nordisk, AstraZeneca; and Speaker's Bureau from AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, and Boehringer Ingelheim., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Increasing rates of obesity and diabetes have driven corresponding increases in related cardiorenal and metabolic diseases. In many patients, these conditions occur together, further increasing morbidity and mortality risks to the individual. Yet all too often, the risk factors for these disorders are not addressed promptly in clinical practice, leading to irreversible pathologic progression. To address this gap, we convened a Task Force of experts in cardiology, nephrology, endocrinology, and primary care to develop recommendations for early identification and intervention in obesity, diabetes, and other cardiorenal and metabolic diseases. The recommendations include screening and diagnosis, early interventions with lifestyle, and when and how to implement medical therapies. These recommendations are organized into primary and secondary prevention along the continuum from obesity through the metabolic syndrome, prediabetes, diabetes, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), atherosclerotic cardiovascular disease (ASCVD) and atrial fibrillation, chronic kidney disease (CKD), and heart failure (HF). The goal of early and intensive intervention is primary prevention of comorbidities or secondary prevention to decrease further worsening of disease and reduce morbidity and mortality. These efforts will reduce clinical inertia and may improve patients' well-being and adherence., Competing Interests: Declaration of competing interest None of the Task Force members received monetary renumeration for their contributions to the creation or writing of this consensus document. See Appendix A for full declarations of competing interests for each author., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Several medications that are proven to reduce cardiovascular events exist for individuals with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease, however they are substantially underused in clinical practice. Clinician, patient, and system-level barriers all contribute to these gaps in care; yet, there is a paucity of high quality, rigorous studies evaluating the role of interventions to increase utilization. The COORDINATE-Diabetes trial randomized 42 cardiology clinics across the United States to either a multifaceted, site-specific intervention focused on evidence-based care for patients with T2DM or standard of care. The multifaceted intervention comprised the development of an interdisciplinary care pathway for each clinic, audit-and-feedback tools and educational outreach, in addition to patient-facing tools. The primary outcome is the proportion of individuals with T2DM prescribed three key classes of evidence-based medications (high-intensity statin, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and either a sodium/glucose cotransporter-2 inhibitor (SGLT-2i) inhibitor or glucagon-like peptide 1 receptor agonist (GLP-1RA) and will be assessed at least 6 months after participant enrollment. COORDINATE-Diabetes aims to identify strategies that improve the implementation and adoption of evidence-based therapies., Competing Interests: Conflict of interest None reported, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, improves cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). This subgroup analysis of FIDELITY, a pre-specified, pooled, individual patient-data analysis of FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049), compared finerenone vs. placebo in patients with and without baseline history of atherosclerotic CV disease (ASCVD)., Methods and Results: Outcomes included a composite CV outcome [CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF)]; CV death or HHF; a composite kidney outcome (kidney failure, sustained estimated glomerular filtration rate decrease ≥57%, or kidney-related death); all-cause mortality; and safety by baseline history of ASCVD.Of 13 026 patients, 5935 (45.6%) had a history of ASCVD. The incidence of the composite CV outcome, CV death or HHF, and all-cause mortality was higher in patients with ASCVD vs. those without, with no difference between groups in the composite kidney outcome. Finerenone consistently reduced outcomes vs. placebo in patients with and without ASCVD (P-interaction for the composite CV outcome, CV death or HHF, the composite kidney outcome, and all-cause mortality 0.38, 0.68, 0.33, and 0.38, respectively). Investigator-reported treatment-emergent adverse events were consistent between treatment arms across ASCVD subgroups., Conclusion: Finerenone reduced the risk of CV and kidney outcomes consistently across the spectrum of CKD in patients with T2D, irrespective of prevalent ASCVD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The majority of cardiovascular randomized controlled trials (RCTs) test interventions in selected patient populations under explicitly protocol-defined settings. Although these 'explanatory' trial designs optimize conditions to test the efficacy and safety of an intervention, they limit the generalizability of trial findings in broader clinical settings. The concept of 'pragmatism' in RCTs addresses this concern by providing counterbalance to the more idealized situation underpinning explanatory RCTs and optimizing effectiveness over efficacy. The central tenets of pragmatism in RCTs are to test interventions in routine clinical settings, with patients who are representative of broad clinical practice, and to reduce the burden on investigators and participants by minimizing the number of trial visits and the intensity of trial-based testing. Pragmatic evaluation of interventions is particularly important in cardiovascular diseases, where the risk of death among patients has remained fairly stable over the past few decades despite the development of new therapeutic interventions. Pragmatic RCTs can help to reveal the 'real-world' effectiveness of therapeutic interventions and elucidate barriers to their implementation. In this Review, we discuss the attributes of pragmatism in RCT design, conduct and interpretation as well as the general need for increased pragmatism in cardiovascular RCTs. We also summarize current challenges and potential solutions to the implementation of pragmatism in RCTs and highlight selected ongoing and completed cardiovascular RCTs with pragmatic trial designs., (© 2022. Springer Nature Limited.)

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) improve the risk for heart and kidney failure. However, their effects on major atherosclerotic cardiovascular events (MACE) are less clear. Although outcomes trials of drugs for diabetes were not powered to prove superiority, the totality of trial data yields an estimate of ∼11% relative reduction for MACE (HR 0.89, 95%CI 0.82-0.96) and neutral on stroke (HR 0.92, 95%CI 0.79-1.08). In animal models, SGLT-2i favorably affects plaque size, composition, and inflammatory pathways; human data in this regard are lacking. Ongoing trials are evaluating SGLT-2i efficacy in heart failure, kidney disease, and postmyocardial infarction populations, independent of diabetes status., Competing Interests: Disclosure A.J. Nelson—nothing to disclose; Josephine Harrington—completed work for this article while grant (T32HL069749); A.A. Kolkailah—was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number T32HL12547. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health; N.J. Pagidipati - Grants from Amgen, Novartis, Novo Nordisk, Boehringer Ingelheim, Eli Lilly & Co, Cleerly, Eggland’s Best, and Verily Life Sciences; personal fees from Boehringer Ingelheim, Eli Lilly & Co, Novo Nordisk, Novartis; D.K. McGuire - Personal fees from Boehringer Ingelheim, Sanofi US, Merck., Merck Sharp and Dohme., Eli Lilly & Co USA, Novo Nordisk, AstraZeneca, Lexicon Pharmaceuticals, Eisai, Pfizer, Metavant, Applied Therapeutics, Afimmune, Bayer, CSL Behring and Esperion., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Among individuals with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM) is common and confers increased risk for morbidity and mortality. Differentiating risk is key to optimize efficiency of treatment selection. Our objective was to develop and validate a model to predict risk of major adverse cardiovascular events (MACE) comprising the first event of cardiovascular death, myocardial infarction (MI), or stroke for individuals with both T2DM and ASCVD., Methods: Using data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), we used Cox proportional hazards models to predict MACE among participants with T2DM and ASCVD. All baseline covariates collected in the trial were considered for inclusion, although some were excluded immediately because of large missingness or collinearity. A full model was developed using stepwise selection in each of 25 imputed datasets, and comprised candidate variables selected in 20 of the 25 datasets. A parsimonious model with a maximum of 10 degrees of freedom was created using Cox models with least absolute shrinkage and selection operator (LASSO), where the adjusted R-square was used as criterion for selection. The model was then externally validated among a cohort of participants with similar criteria in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. Discrimination of both models was assessed using Harrell's C-index and model calibration by the Greenwood-Nam-D'Agostino statistic based on 4-year event rates., Results: Overall, 1491 (10.2%) of 14,671 participants in TECOS and 130 (9.3%) in the ACCORD validation cohort (n = 1404) had MACE over 3 years' median follow-up. The final model included 9 characteristics (prior stroke, age, chronic kidney disease, prior MI, sex, heart failure, insulin use, atrial fibrillation, and microvascular complications). The model had moderate discrimination in both the internal and external validation samples (C-index = 0.65 and 0.61, respectively). The model was well calibrated across the risk spectrum-from a cumulative MACE rate of 6% at 4 years in the lowest risk quintile to 26% in the highest risk quintile., Conclusion: Among patients with T2DM and prevalent ASCVD, this 9-factor risk model can quantify the risk of future ASCVD complications and inform decision making for treatments and intensity., (© 2022. The Author(s).)

Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the "Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes" trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs., (© 2022. The Author(s).)

Cardiovascular disease is a leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus. These high-risk patients benefit from aggressive risk factor management, with blood pressure and low-density lipoprotein-cholesterol treatment, glycemic control, kidney protection, and lifestyle intervention. There are several recommendation and guideline documents across cardiology, endocrinology, nephrology, and general medicine professional societies from the United States and Europe with recommendations for cardiovascular risk reduction in patients with type 2 diabetes mellitus. Although there are some noteworthy differences, particularly in risk stratification, low-density lipoprotein-cholesterol and blood pressure treatment targets, and the use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, overall there is considerable alignment across recommendations from different professional societies., Competing Interests: Funding Support and Author Disclosures Dr Kelsey is supported by National Institute of Health (NIH) training grant 5T32HL069749-18. Dr Granger has received research grants from AKROS, Apple, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Duke Clinical Research Institute, the U.S. Food and Drug Administration, GlaxoSmithKline, Janssen Pharmaceutical Products, L.P., Medtronic Foundation, Novartis Pharmaceuticals, and Pfizer; and has received consulting fees from Abbvie, Abiomed, Anthos Therapeutic, LLC, Bayer Corporation, Boehringer Ingelheim, Boston Scientific Corporation, Bristol Myers Squibb, CeleCor Therapeutics, Correvio, Espero BioPharma, Janssen Pharmaceutica Products, L.P., Medscape, LLC, Medtronic Inc, Merck, Novo Nordisk, Novartis Pharmaceutical Company, Pfizer, Phillips, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr Green has received research support from Boehringer Ingelheim/Lilly, Sanofi/Lexicon, Merck, and Roche; and has received consulting fees from Boehringer Ingelheim/Lilly Alliance, NovoNordisk, AstraZeneca, Pfizer, and Hawthorne Effect/Omada. Dr Peterson has received research support from Amgen Inc, Janssen Pharmaceutical Products, Bristol Myers Squibb, and Esperion; and has received consulting fees from Janssen Pharmaceutical Products, Boehringer Ingelheim, Novartis, and Cerner. Dr McGuire has received honoraria for clinical trial leadership from Boehringer Ingelheim, Sanofi Aventis, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, and CSL Behring; and has received honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Metavant, Sanofi Aventis, and Afimmune. Dr Pagidipati has received research grants from Amgen, Inc., AstraZeneca, Baseline Study LLC, Boehringer Ingelheim, Duke Clinical Research Institute, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk Pharmaceutical Company, Regeneron Pharmaceuticals, Inc, Sanofi-S.A., and Verily Sciences Research Company; and has received consulting fees from AstraZeneca, Boehringer Ingelheim, Esperion Therapeutics, Eli Lilly & Company, and Novo Nordisk Pharmaceutical Company. Dr Nelson has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c., Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models., Results: In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06-1.19], 1.08 [1.04-1.13], and 1.17 [1.11-1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05)., Conclusions: Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%., (© 2022 by the American Diabetes Association.)

Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have well-documented cardioprotective effects but are underused, partly because of high cost. We aimed to develop a machine learning-based decision support tool to individualize the atherosclerotic cardiovascular disease (ASCVD) benefit of canagliflozin in type 2 diabetes., Research Design and Methods: We constructed a topological representation of the Canagliflozin Cardiovascular Assessment Study (CANVAS) using 75 baseline variables collected from 4,327 patients with type 2 diabetes randomly assigned 1:1:1 to one of two canagliflozin doses (n = 2,886) or placebo (n = 1,441). Within each patient's 5% neighborhood, we calculated age- and sex-adjusted risk estimates for major adverse cardiovascular events (MACEs). An extreme gradient boosting algorithm was trained to predict the personalized ASCVD effect of canagliflozin using features most predictive of topological benefit. For validation, this algorithm was applied to the CANVAS-Renal (CANVAS-R) trial, comprising 5,808 patients with type 2 diabetes randomly assigned 1:1 to canagliflozin or placebo., Results: In CANVAS (mean age 60.9 ± 8.1 years; 33.9% women), 1,605 (37.1%) patients had a neighborhood hazard ratio (HR) more protective than the effect estimate of 0.86 reported for MACEs in the original trial. A 15-variable tool, INSIGHT, trained to predict the personalized ASCVD effects of canagliflozin in CANVAS, was tested in CANVAS-R (mean age 62.4 ± 8.4 years; 2,164 [37.3%] women), where it identified patient phenotypes with greater ASCVD canagliflozin effects (adjusted HR 0.60 [95% CI 0.41-0.89] vs. 0.99 [95% CI 0.76-1.29]; Pinteraction = 0.04)., Conclusions: We present an evidence-based, machine learning-guided algorithm to personalize the prescription of SGLT2 inhibitors for patients with type 2 diabetes for ASCVD effects., (© 2022 by the American Diabetes Association.)

Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57-1.11) for MACE-4; 0.90 (95% CI, 0.50-1.61) for cardiovascular death; and 0.80 (95% CI, 0.51-1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls., (© 2022. The Author(s).)

Objective: Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD., Research Design and Methods: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial., Results: Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29-3.29]). Similar phenotypes and outcomes were identified in EXSCEL., Conclusions: In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs., (© 2021 by the American Diabetes Association.)

Purpose of Review: The cardiovascular benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) have increased the focus of type 2 diabetes mellitus (T2DM) care on comprehensive cardiovascular risk reduction. Herein, we review the results of the cardiovascular outcomes trials of SGLT2i and GLP-1 RA, discuss the concepts of relative vs. absolute risk reduction in the context of these trials, and highlight the importance of individualized risk assessment when applying trial results to clinical practice., Recent Findings: To enable personalized treatment approaches, multiple clinical risk scores have been developed to assess risk of atherosclerotic cardiovascular disease (ASCVD) outcomes and hospitalization for heart failure (HHF) in patients with T2DM. In addition, circulating biomarkers of myocardial injury (cardiac troponin) and hemodynamic stress (natriuretic peptides) have been shown to further refine risk prediction of these clinically important cardiovascular complications. When making decisions about whether to initiate SGLT2i and GLP-1 RA, clinicians should consider the anticipated relative and absolute treatment benefits from these antihyperglycemic therapies. Clinicians can use available clinical and biomarker-based risk tools when counseling patients about their individual cardiovascular risk profiles and when estimating absolute treatment benefits from SGLT2i and GLP-1 RA., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A recent meta-analysis of sodium-glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials., Hypothesis: The apparent heterogeneity of the meta-analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials., Methods: We performed a meta-analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV (NCT01986881), CANVAS Program (NCT01032629 and NCT01989754), DECLARE-TIMI 58 (NCT01730534), and EMPA-REG OUTCOME (NCT01131676)., Results: Data from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51-0.65]) and with a highly consistent effect across the trials (Q statistic p = .64; I 2  = 0.0%)., Conclusions: Our meta-analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.

Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown., Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR)., Design, Setting, and Participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018., Interventions: Dapagliflozin vs placebo., Main Outcomes and Measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF., Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher., Conclusions and Relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria., Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.

Background: Results of cardiovascular outcome trials (CVOTs) suggest Asians may derive greater benefit than Whites from newer classes of antihyperglycemic medications., Purpose: To provide summary hazard ratio (HR) estimates for cardiovascular efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) stratified by race (Asian vs. White)., Data Sources: A systematic review performed in PubMed from 1 January 2015 to 8 December 2020., Study Selection: Randomized placebo-controlled CVOTs of SGLT2is and GLP-1RAs that reported HRs (95% CIs) for 1 ) major adverse cardiovascular event (MACE) in patients with diabetes and 2 ) cardiovascular (CV) death/hospitalization for heart failure (HHF) in patients with HF and reduced ejection fraction (HFrEF)., Data Extraction and Synthesis: HRs (95% CIs) for selected outcomes in Asians and Whites were extracted from each trial, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects meta-analyses were performed to examine differences between the selected outcomes in Asians versus Whites., Results: In four SGLT2i trials in type 2 diabetes, the MACE outcome HR (95% CI) in 3,298 Asians versus 20,258 Whites was 0.81 (0.57, 1.04) vs. 0.90 (0.80, 1.00), respectively ( P interaction = 0.46). In two SGLT2i trials in patients with HFrEF, the CV death/HHF outcome HR in 1,788 Asians versus 5,962 Whites was 0.60 (0.47, 0.74) vs. 0.82 (0.73, 0.92), respectively ( P interaction = 0.01). In six GLP-1RA trials, the MACE outcome HR in 4,195 Asians versus 37,530 Whites was 0.68 (0.53, 0.84) vs. 0.87 (0.81, 0.94), respectively ( P interaction = 0.03)., Limitations: Lack of individual patient-level data, relatively short duration of trial observation, and lack of granular categorization of race within broadly defined Asian subgroups., Conclusions: Compared with Whites, Asians may derive greater CV death/HHF benefit from SGLT2is in patients with HFrEF, and MACE benefit from GLP-1RAs in patients with type 2 diabetes., (© 2021 by the American Diabetes Association.)

Objective: International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients., Research Design and Methods: In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction., Results: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37-0.69) did not differ from that for patients with ASCVD ( P interaction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA 1c , weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher ( P < 0.001)., Conclusions: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population., (© 2021 by the American Diabetes Association.)

Type 2 diabetes mellitus is a progressive chronic disease and is an established risk factor for cardiovascular disease. Until recently, the cardiovascular safety and efficacy of antihyperglycemic drugs remained uncertain. However, after the changes in regulatory guidance in 2008, a wealth of data has been generated, expanding the focus of the treatment of diabetes from blood glucose control to the prevention of macro-and microvascular complications and improvement in mortality. This article will review cardiovascular outcome trials of antihyperglycemic agents and provide overview of ongoing trials., (Copyright © 2020. Published by Elsevier Inc.)

Aim: To assess the associations between baseline glucose-lowering agents (GLAs) and cardiorenal outcomes with dapagliflozin versus placebo in the DECLARE-TIMI 58 study., Materials and Methods: DECLARE-TIMI 58 assessed the cardiorenal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. This post hoc analysis elaborates the efficacy and safety outcomes by baseline GLA for treatment effect and GLA-based treatment interaction., Results: At baseline, 14 068 patients (82.0%) used metformin, 7322 (42.7%) sulphonylureas, 2888 (16.8%) dipeptidyl peptidase-4 inhibitors, 750 (4.4%) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and 7013 (40.9%) insulin. Dapagliflozin reduced the composite of cardiovascular death (CVD) and hospitalization for heart failure (HHF) versus placebo regardless of baseline GLA, with greater benefit in the small group of patients with baseline use of GLP-1 RAs (HR [95% CI] 0.37 [0.18, 0.78] vs. 0.86 [0.75, 0.98] in GLP-1 RA users vs. non-users, P interaction = .03). The overall HR for major adverse cardiovascular events (CVD, myocardial infarction or ischaemic stroke) was 0.93 (95% CI 0.84, 1.03) with dapagliflozin versus placebo, with no interaction by baseline GLA (P interaction > .05). The renal-specific outcome was reduced with dapagliflozin versus placebo in the overall cohort (HR [95%CI] 0.53[0.43-0.66]), with no interaction by baseline GLA (P interaction > .05). All of these outcomes were similar in those with versus those without baseline metformin use., Conclusions: The effects of dapagliflozin on cardiorenal outcomes were generally consistent regardless of baseline GLA, with consistent benefits regardless of baseline metformin use. The potential clinical benefit of combining sodium-glucose co-transporter-2 inhibitors with GLP-1 RAs, given some evidence of cardiovascular risk reduction with both classes, should be explored further., (© 2020 John Wiley & Sons Ltd.)

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m 2 To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications., (© 2020 by the American Diabetes Association and the National Kidney Foundation.)

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk., Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk., Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa., Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins., Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization., Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%)., Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (<25, ≥25-<30, ≥30-<35 and ≥35 kg/m 2 ), and CV and kidney outcomes with GLP-1 RA versus placebo were analysed. All baseline BMI data from LEADER (n = 9331) and SUSTAIN 6 (n = 3290) were included (91% and 92% of patients with overweight or obesity, respectively). In SUSTAIN 6, nominally significant heterogeneity of semaglutide efficacy by baseline BMI was observed for CV death/myocardial infarction/stroke (major adverse CV events, primary outcome of both; P interaction = .02); otherwise, there was no statistical heterogeneity for either GLP-1 RA versus placebo across BMI categories for key CV and kidney outcomes. The lack of statistical heterogeneity from these cardiorenal outcomes implies that liraglutide and semaglutide may be beneficial for many patients and is probable not to depend on their baseline BMI, but further study is needed., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Whether glycaemic control is associated with cardiovascular outcomes in patients with type 2 diabetes (T2D) is unclear. Consequently, we assessed the relationship between glycated haemoglobin (HbA 1c ) and cardiovascular outcomes in a placebo-controlled randomized trial which demonstrated no cardiovascular effect of sitagliptin in patients with T2D and atherosclerotic vascular disease., Methods and Results: Secondary analysis of 14 656 TECOS participants with time to event analyses using multivariable Cox proportional hazard models. During a median 3.0 (interquartile range 2.3-3.8) year follow-up, 456 (3.1% of 14 656) patients had first hospitalization for heart failure (HF), 1084 (11.5%) died, 1406 (9.6%) died or were hospitalized for HF, and 1689 (11.5%) had a non-HF cardiovascular event (cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, or hospitalization for unstable angina). Associations between baseline or time-varying HbA 1c and cardiovascular outcomes were U-shaped, with the lowest risk when HbA 1c was around 7%. Each one-unit increase in the time-varying HbA 1c above 7% was associated with an adjusted hazard ratio (HR) of 1.21 [95% confidence interval (CI) 1.11-1.33] for first HF hospitalization, 1.11 (1.03-1.21) for all-cause death, 1.18 (1.09-1.26) for death or HF hospitalization, and 1.10 (1.02-1.17) for non-HF cardiovascular events. Each one-unit decrease in the time-varying HbA 1c below 7% was associated with an adjusted HR of 1.35 (95% CI 1.12-1.64) for first HF hospitalization, 1.37 (1.16-1.61) for death, 1.42 (1.23-1.64) for death or HF hospitalization, and 1.22 (1.06-1.41) for non-HF cardiovascular events., Conclusion: Glycated haemogobin exhibits a U-shaped association with cardiovascular outcomes in patients with T2D and atherosclerotic vascular disease, with nadir around 7%., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT00790205., (© 2020 European Society of Cardiology.)

Background: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established., Methods: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure., Results: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo., Conclusions: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.)., (Copyright © 2020 Massachusetts Medical Society.)

Importance: Recent randomized clinical trials have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce cardiovascular events in at-risk individuals with type 2 diabetes. Despite these findings, GLP-1RAs are underused in eligible patients, particularly by cardiologists., Observations: To date, randomized clinical trials of albiglutide, dulaglutide, liraglutide, and injectable semaglutide have reported favorable cardiovascular outcomes. Most recently approved for clinical use, oral semaglutide has a favorable safety profile and is currently undergoing regulatory evaluation and further study for cardiovascular outcomes. Professional society guidelines now recommend GLP-1RA therapy for cardiovascular risk mitigation in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) or multiple ASCVD risk factors, independent of glucose control or background antihyperglycemic therapy (other diabetes medications being used). Additional conditions suitable for GLP-1RA therapy include obesity and advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2), for which cardiovascular risk-reducing options are limited. Out-of-pocket costs and secondary advantages (eg, weight loss) may inform shared decision-making discussions regarding potential therapies. GLP-1RA therapy has a favorable safety profile. Its most common adverse effect is gastrointestinal upset, which typically wanes during the early weeks of therapy and may be mitigated by starting at the lowest dose and escalating as tolerated. Depending on baseline glycemic control, sulfonylureas and insulin may need to be decreased before GLP-1RA initiation; without concurrent use of insulin or sulfonylureas, GLP-1RAs are not associated with hypoglycemia. Multidisciplinary follow-up and collaborative care with primary care physicians and/or endocrinologists are important., Conclusions and Relevance: Findings from this review suggest that GLP-1RAs are safe, are well tolerated, and improve cardiovascular outcomes, largely independent of their antihyperglycemic properties, but they remain underused by cardiologists. This review provides a practical resource for cardiologists for initiating GLP-1RAs and managing the therapy in patients with type 2 diabetes and established ASCVD or high risk for ASCVD.

Purpose of Review: Results from cardiovascular (CV) outcome trials have revealed important insights into the CV safety and efficacy of glucose-lowering agents, including dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA)., Recent Findings: Among patients with T2DM, DPP-4i have no significant effect on risk of major adverse CV events (MACE: CV death, myocardial infarction, or stroke) with mixed results regarding risk for heart failure (HF). While sitagliptin and linagliptin have neutral effects on HF risk, saxagliptin significantly increases the risk of HF. The CV safety of the GLP-1RA class of medications has been clearly demonstrated, and select agents, such as liraglutide, semaglutide, albiglutide, and dulaglutide, reduce the risk of MACE in patients with T2DM and established CV disease. CV outcome trials have demonstrated CV safety but not incremental efficacy for DPP-4i in most cases. Select GLP-1RA have proven efficacy for MACE and should be considered by cardiologists for CV risk mitigation in the care of patients with T2DM and established CV disease.

Objective: Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m 2 ) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532)., Research Design and Methods: Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA 1c , and adverse events (AEs) including hypoglycemia., Results: A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m 2 ; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA 1c , without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories., Conclusions: Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA 1c and no difference in AEs were observed., (© 2020 by the American Diabetes Association.)