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

Objective: To describe the pharmacology, clinical efficacy, and safety evidence of sotagliflozin, the first approved dual inhibitor of sodium-glucose cotransporter (SGLT) 1 and SGLT2, in heart failure (HF) management., Data Sources: A literature search of studies published between January 2012 and September 2023 were identified using PubMed, MEDLINE, and clinicaltrials.gov with search terms of "sotagliflozin," "Inpefa," or "LX4211.", Study Selection and Data Extraction: All available studies in English were considered. Studies were included if they investigated drug pharmacology, efficacy, or safety information., Data Synthesis: Two phase 3 trials of sotagliflozin, SOLOIST-WHF and SCORED, evaluated sotagliflozin compared with placebo in patients with type 2 diabetes mellitus (T2DM). SOLOIST-WHF reported a statistically decreased rate of cardiovascular and HF events with sotagliflozin (hazard ratio [HR] = 0.67, 95% CI = 0.52-0.85), while SCORED found a statistically significant decrease in incidence of cardiovascular events in patients with T2DM, chronic kidney disease (CKD), and risk factors for cardiovascular disease in patients in the sotagliflozin group (HR = 0.74, 95% CI = 0.63-0.88)., Relevance to Patient Care and Clinical Practice in Comparison to Existing Agents: While approval of sotagliflozin expands treatment options for patients with HF, the SGLT2 inhibitors, dapagliflozin and empagliflozin, have more data supporting their use in HF, additional risk reduction benefits in patients with CKD, and approval for use in T2DM. Landmark trials of sotagliflozin required a previous diagnosis of T2DM, despite the broader approved indication. Where sotagliflozin will be adopted into the treatment of HF is unclear due to the evidence and benefits of already established SGLT2 inhibitors and the need for comparison with SGLT2 inhibitors., Conclusion: Given the limitations of currently available evidence, including difficulty in fully interpreting the trial results due to changes in primary endpoints, not adjudicating the events, and not reaching the original power calculations, more investigation is warranted to determine the benefit of sotagliflozin compared with SGLT2 inhibitors., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To assesses the cost-effectiveness of sotagliflozin for the treatment of patients hospitalized with heart failure and comorbid diabetes. Materials & methods: A  de novo cost-effectiveness model with a Markov structure was created for patients hospitalized for heart failure with comorbid diabetes. Outcomes of interest included hospital readmissions, emergency department visits and all-cause mortality measured over a 30-year time horizon. Baseline event frequencies were derived from published real-world data studies; sotagliflozin's efficacy was estimated from SOLOIST-WHF. Health benefits were calculated quality-adjusted life years (QALYs). Costs included pharmaceutical costs, rehospitalization, emergency room visits and adverse events. Economic value was measured using the incremental cost-effectiveness ratio (ICER). Results: Sotagliflozin use decreased annualized rehospitalization rates by 34.5% (0.228 vs 0.348, difference: -0.120), annualized emergency department visits by 40.0% (0.091 vs 0.153, difference: -0.061) and annualized mortality by 18.0% (0.298 vs 0.363, difference: -0.065) relative to standard of care, resulting in a net gain in QAYs of 0.425 for sotagliflozin versus standard of care. Incremental costs using sotagliflozin increased by $19,374 over a 30-year time horizon of the patient, driven largely by increased pharmaceutical cost. Estimated ICER for sotagliflozin relative to standard of care was $45,596 per QALY. Conclusion: Sotagliflozin is a cost-effective addition to standard of care for patients hospitalized with heart failure and comorbid diabetes.

Background: The SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trials demonstrated that sotagliflozin, an SGLT1 and SGLT2 inhibitor, improves outcomes in individuals with type 2 diabetes who have heart failure (HF) or kidney disease., Objectives: We assessed the efficacy of sotagliflozin on HF clinical outcomes in individuals with differing baseline glycosylated hemoglobin (HbA1c) levels., Methods: We included all adults from SCORED and SOLOIST-WHF. The primary outcome was a composite of cardiovascular death, hospitalizations for HF, and urgent visits for HF. The efficacy of sotagliflozin compared with placebo was evaluated by baseline HbA1c using competing-risk marginal proportional hazards models., Results: We identified 11,744 adults. Individuals with HbA1c ≤7.5% experienced the primary outcome at a lower rate in the sotagliflozin group (11.2 per 100 person-years) than the placebo group (15.5 per 100 person-years) (HR: 0.73; 95% CI: 0.57-0.93). Similarly, individuals with HbA1c of 7.6% to 9.0% experienced the primary outcome at a lower rate in the sotagliflozin group (7.3 per 100 person-years) than the placebo group (9.4 per 100 person-years) (HR: 0.77; 95% CI: 0.63-0.96). These findings were also consistent among individuals with HbA1c >9.0%, with a primary outcome rate in the sotagliflozin group (7.8 per 100 person-years) that was lower than the placebo group (11.6 per 100 person-years) (HR: 0.65; 95% CI: 0.50-0.84). The efficacy of sotagliflozin was consistent by baseline HbA1c level (P for interaction = 0.58)., Conclusions: In individuals with type 2 diabetes and either HF or kidney disease, sotagliflozin reduced HF outcomes irrespective of baseline HbA1c., Competing Interests: Funding Support and Author Disclosures This study was supported by Sanofi and Lexicon Pharmaceuticals, Inc. Dr Aggarwal has served as an investigator in a study funded by the Bristol Myers Squibb-Pfizer Alliance; and has served as a consultant for Lexicon. Dr Bhatt is the Chair of SCORED and of SOLOIST-WHF with research funding paid by Lexicon to Brigham and Women’s Hospital; has served on the Advisory Board of 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 of 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; has served as Inaugural Chair of the American Heart Association Quality Oversight Committee; has served as a consultant for Broadview Ventures and Hims; has served on 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 (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Cochair, 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); has served as Deputy Editor for Clinical Cardiology; has served as chair of the NCDR-ACTION Registry Steering Committee and VA CART Research and Publications Committee; is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon (neither he nor Brigham and Women's Hospital receive any income from this patent); has received research Funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo and Takeda. Dr Szarek receives salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women's Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, and the Yale Cardiovascular Research Group; has received fees for performing analyses, steering committee fees, and travel support from Sanofi and Regeneron; has received consulting fees from CiVi, Esperion, and Amarin; has received Data Safety and Monitoring Board membership fees from Resverlogix and Janssen; and is a member of the JACC editorial board. Dr Cannon has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Merck, Novo Nordisk, and Pfizer; has received consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi; and has served on data and safety monitoring boards for Applied Therapeutics and Novo Nordisk. Dr McGuire has received research support for Clinical Trials Leadership from Boehringer Ingelheim, Merck and Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, and CSL Behring New Amsterdam; and has received honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck and Co, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, GlaxoSmithKline, and Intercept. Dr Inzucchi has served as a consultant and member of clinical trial steering committees for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Merck, Pfizer, and Bayer; and has delivered lectures sponsored by Boehringer Ingelheim, AstraZeneca, and Merck. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Bristol Myers Squibb, Novo Nordisk, and AstraZeneca; and has received funding for consulting from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Novo Nordisk, and AstraZeneca. Drs Davies and Banks are employees of Lexicon Pharmaceuticals Inc, and may hold stocks or stock options in the company. Dr Pitt has received consulting fees from Lexicon, Bayer, AstraZeneca, Boehringer Ingelheim, Merck, and Phasebio; has received consulting fees and/or stock options from Viror, KBP Biosciences, Cereno scientific, Tricida, SCPharmaceuticals, SQinnovations, G-3 Pharmaceuticals, Protonintel, and Brainstorm medical; and holds U.S. Patent 9931412 on site-specific delivery of eplerenone to the myocardium and U.S. Patent pending 63/045,783 on histone-modulating agents for the protection and treatment of organ damage. Dr Steg has received research grants from Amarin, Bayer, Sanofi, and Servier; has received speaker or consultant fees from Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Kowa, Idorsia, Lexicon, Merck, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier; and is a Senior Associate Editor of Circulation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Approximately 25% of patients admitted to hospitals for worsening heart failure (WHF) are readmitted within 30 days., Objectives: The authors conducted a post hoc analysis of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post-WHF) trial to evaluate the efficacy of sotagliflozin versus placebo to decrease mortality and HF-related events among patients who began study treatment on or before discharge from their index hospitalization., Methods: The main endpoint of interest was cardiovascular death or HF-related event (HF hospitalization or urgent care visit) occurring within 90 and 30 days after discharge for the index WHF hospitalization. Treatment comparisons were by proportional hazards models, generating HRs, 95% CIs, and P values., Results: Of 1,222 randomized patients, 596 received study drug on or before their date of discharge. Sotagliflozin reduced the main endpoint at 90 days after discharge (HR: 0.54 [95% CI: 0.35-0.82]; P = 0.004) and at 30 days (HR: 0.49 [95% CI: 0.27-0.91]; P = 0.023) and all-cause mortality at 90 days (HR: 0.39 [95% CI: 0.17-0.88]; P = 0.024). In subgroup analyses, sotagliflozin reduced the 90-day main endpoint regardless of sex, age, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, left ventricular ejection fraction, or mineralocorticoid receptor agonist use. Sotagliflozin was well-tolerated but with slightly higher rates of diarrhea and volume-related events than placebo., Conclusions: Starting sotagliflozin before discharge in patients with type 2 diabetes hospitalized for WHF significantly decreased cardiovascular deaths and HF events through 30 and 90 days after discharge, emphasizing the importance of beginning sodium glucose cotransporter treatment before discharge., Competing Interests: Funding Support and Author Disclosures This study was supported by Sanofi and Lexicon Pharmaceuticals. Dr Pitt has received consulting fees from Lexicon, Bayer, AstraZeneca, Boehringer Ingelheim, Merck, and Phasebio; has received consulting fees and/or stock options from Viror, KBP Biosciences, Cereno Scientific, Tricida, SCPharmaceuticals, SQinnovatiions, G-3 Pharmaceuticals, Protonintel, and Brainstorm medical; holds U.S. Patent 9931412 on site specific delivery of eplerenone to the myocardium; and U.S. Patent pending 63/045,783 on histone-modulating agents for the protection and treatment of organ damage. Dr Bhatt is the Chair of SOLOIST with research funding paid by Lexicon to Brigham and Women’s Hospital; he is 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; is 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; is Inaugural Chair for the American Heart Association Quality Oversight Committee; is a consultant for Broadview Ventures; is on the 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 (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); has received honoraria from 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; is on the RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; is on the AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned it to Lexicon; neither he nor Brigham and Women’s Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, 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, 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, Vascular Solutions; is a trustee for the American College of Cardiology; and has done unfunded research for FlowCo and Takeda. Dr Szarek has received salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol-Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, NovoNordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, and the Yale Cardiovascular Research Group; has received fees for performing analyses, steering committee fees, and travel support from Sanofi and Regeneron; has received consulting fees from CiVi, Esperion, and Amarin; has received Data Safety and Monitoring Board membership fees from Resverlogix and Janssen; and is a member of the JACC editorial board. Dr Cannon has received research grants from Amgen, Better Therapeutics, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer; consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi; and service on the Data and Safety Monitoring Boards for the Veteran’s Administration, Applied Therapeutics, and NovoNordisk. Dr Leiter has received research funding from, has provided CME on behalf of, and/or has acted an adviser to AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier. Dr McGuire has received honoraria for trial leadership from Lexicon, Sanofi, Boehringer Ingelheim, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, CSL Behring; and has received honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Novo Nordisk, CSL Behring, Bayer, GlaxoSmithKline, and Lexicon. Dr Lewis has received consultant fees from Sanofi. Dr Riddle has received honoraria for consulting from Adocia, Anji, Xeris, DalCor, and Theracos. Dr Voors has received consultancy and speaker fees and research support from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, BMS, Cyrokinetics, Merck, Myokardia, Novartis, NooNordisk, and Roche diagnostics. Dr Metra has received personal fees from Actelion, Amgen, Livanova, and Vifor pharma as a member of Executive or Data Monitoring Committees of sponsored clinical trials; from AstraZeneca, Bayer, Boheringer Ingelhelm, Edwards Lifesciences, Novartis for participation in advisory boards and/or speeches at sponsored meetings. Dr Lund has received support from the Karolinska Institutet, the Swedish Research Council [grant 523-2014-2336], and the Swedish Heart Lung Foundation [grants 20150557, 20190310] and grants from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, Novartis, and MSD; consulting honoraria from Vifor, AstraZeneca, Bayer, Pharmacosmos, MSD, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, Servier, Edwards Lifesciences, and Alleviant; and speaker honoraria from Abbott, OrionPharma, MedScape, Radcliffe, AstraZeneca, Novartis, Boehringer Ingelheim, and Bayer; and has patents with AnaCardio and stock ownership in AnaCardio. Dr Komajda has received honoraria from Servier, Novartis, Boehringer Ingelheim, AstraZeneca, Bayer, and Sanofi as adviser/member of clinical trials committees. Dr Testani has received grants and/or personal fees from 3ive labs, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, AstraZeneca, Novartis, Cardionomic, MagentaMed, Reprieve Inc, FIRE1, W. L. Gore & Associates, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon pharmaceuticals, Precardia, Relypsa, Regeneron, BD, Edwards Lifesciences, and Lilly; and has a patent treatment of diuretic resistance issued to Yale and Corvidia Therapeutics Inc, a patent methods for measuring Renalase issued to Yale, and a patent treatment of diuretic resistance pending with Reprieve Inc. Dr Ponikowski has received consultancy fees and speaker honoraria from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Amgen, Servier, Novartis, Bayer, MSD, Pfizer, Impulse Dynamics, Renal Guard Solutions, BMS, AbbottVascular, and the Radcliffe Group. Dr Lopes has received research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis; funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk. Dr Ezekowitz has received research support for trial leadership from Bayer, Merck & Co, Novo Nordisk, Cytokinetics, Applied Therapeutics, American Regent; and honoraria for consultancy from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Otsuka, Bayer, and Novartis. Dr Davies and Mr Sun are employed by and may have stock or stock options in Lexicon Pharmaceuticals, Inc. Dr Verma has received research and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, CMS, HLS, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, and Sanofi; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; served as a consultant or advisory board member for Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Sanofi, Vifor Pharma; has received other research support from AstraZeneca; and honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Steg has received research grants from Amarin, Bayer, Sanofi, and Servier; speaker or consultant fees from Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers-Squibb, Janssen, Kowa, Idorsia, Lexicon, Merck, Novartis, Novo-Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, Servier; and is a Senior Associate Editor of Circulation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug-drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF., Areas Covered: Literature-search-terms in PubMed were 'adverse event/drug-drug interaction' and 'heart failure AND 'dapagliflozin' OR 'empagliflozin' OR 'sotagliflozin.'AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier's gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months.DDI were mainly studied in healthy volunteers for 3-8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron., Expert Opinion: Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable.

Purpose: This review describes the evidence from randomized controlled trials (RCTs) regarding the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular (CV) clinical outcomes when therapy is initiated during acute heart failure (HF)., Summary: SGLT2 inhibitors have become a cornerstone of guideline-directed medical therapy (GDMT) for type 2 diabetes mellitus, chronic kidney disease, and HF. Because of their ability to promote natriuresis and diuresis as well as other potentially beneficial CV effects, use of SGLT2 inhibitors has been investigated when therapy is initiated during hospitalization for acute HF. We identified 5 placebo-controlled RCTs that reported CV clinical outcomes incorporating one or more components of all-cause mortality, CV mortality, CV hospitalization, HF worsening, and hospitalization for HF in patients treated with empagliflozin (n = 3 trials), dapagliflozin (n = 1 trial), and sotagliflozin (n = 1 trial). Nearly all CV outcomes in these trials showed benefit with SGLT2 inhibitor use during acute HF. Incidence of hypotension, hypokalemia, and acute renal failure was generally similar to that with placebo. These findings are limited by heterogeneous outcome definitions, variation in time to SGLT2 inhibitor initiation, and small sample sizes., Conclusion: SGLT2 inhibitors may have a role in inpatient management of acute HF, provided there is close monitoring for fluctuations in hemodynamic, fluid, and electrolyte status. Initiation of SGLT2 inhibitors at the time of acute HF may promote optimized GDMT, continued medication adherence, and reduced risk of CV outcomes., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: The SOLOIST-WHF trial demonstrated efficacy of sotagliflozin in patients with type 2 diabetes mellitus (T2DM) and recent worsening heart failure (HF) regardless of ejection fraction (EF). Selection criteria in trials may limit their generalizability. Therefore, we aimed to investigate eligibility for sotagliflozin based on the SOLOIST-WHF criteria in a real-world HF population., Methods and Results: SOLOIST-WHF criteria were applied to patients stabilized after HF hospitalization in the Swedish HF Registry according to (i) literal scenario (all inclusion/exclusion criteria) or (ii) pragmatic scenario (only criteria likely to influence treatment decisions). Of 5453 inpatients with T2DM and recent worsening HF, 51.4% had reduced EF (HFrEF), 19.1% mildly reduced (HFmrEF), and 29.5% preserved EF (HFpEF). Eligibility (literal) was: 27.2% (32.4% in HFrEF, 24.7% in HFmrEF, 19.7% in HFpEF) and eligibility (pragmatic) was 62.8% (69.1%, 60.3%, 53.4%, respectively). In the literal scenario, criteria limiting eligibility were HF duration <3 months, eGFR <30 ml/min/1.73 m2, age >85 years, acute coronary syndrome <3 months, and insufficiently high N-terminal pro-B-type natriuretic peptide levels. Eligible vs. non-eligible patients had more severe HF, higher cardiovascular (CV) comorbidity burden, higher use of HF treatments, and higher event rates (all-cause death 30.8 vs. 27.2 per 100 patient-years, CV death 19.1 vs. 16.6, and HF hospitalization 36.7 vs. 24.0)., Conclusion: In this large, real-world HF cohort with T2DM, ∼1/3 of patients were eligible for sotagliflozin in the literal and ∼2/3 of patients in the pragmatic scenario. Eligible patients had more severe HF and higher event rates, in particular CV and HF events., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: ≥50%) or/and mildly reduced EF (HFmrEF: 41-49%) regardless of baseline diabetes., Methods: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model., Results: We identified six RCTs, pooling data retrieved from 15,769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p < 0.001, I 2  = 0%). When separately analyzed, benefits of SGLT2i remained significant across HFpEF (N = 8891, HR 0.79, 95% CI: 0.71, 0.87, p < 0.001, I 2  = 0%) and HFmrEF (N = 4555, HR 0.77, 95% CI: 0.67, 0.89, p < 0.001, I 2  = 40%). Consistent benefits were observed also in HFmrEF/HFpEF subgroup without baseline diabetes (N = 6507, HR 0.80, 95% CI: 0.70, 0.91, p < 0.001, I 2  = 0%). Sensitivity analysis including the DELIVER and EMPEROR-Preserved trials found a trend towards significant beneficial effects on CV deaths with no heterogeneity (HR 0.90, 95% CI: 0.79, 1.02, p = 0.08, I 2  = 0%)., Conclusions: This meta-analysis established the place of SGLT2i as a foundational therapy among patients with HF with preserved and mildly reduced EF regardless of diabetes., (Copyright © 2023 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved.)

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a class of oral antiglycemic agents that have emerged as a new therapeutic strategy for heart failure (HF) with reduced ejection fraction (HFrEF) and, potentially, for HF with preserved ejection fraction (HFpEF)., Areas Covered: Ongoing efforts to clarify the exact mechanisms of action of SGLT2 inhibitors (SGLT2i) reveal that glycosuria and osmotic diuresis, resulting from the blockade of renal receptors, is not the sole pathophysiological mechanism. Nevertheless, the underlying mechanisms, accounting for their cardiovascular beneficial effects which have been clearly demonstrated in clinical trials, remain unclear. The aim of this review is to summarize the primary outcomes of large-scale studies regarding the use of SGLT2i in HF and provide an overview of the potential pathways involved in the SGLT2i-mediated cardioprotection., Expert Opinion: SGLT2i exhibit favorable pleiotropic effects, which extend beyond their primary indication as pharmaceutical agents intended for glycemic control. Given their unique pathophysiological profile, these agents have revolutionized the management of HF, while in the near future, it is possible that evolving research in the field may unfold further perspectives on their potential use in the treatment of other chronic conditions.

Aims: Sodium-glucose co-transporter inhibitors (SGLT2i) are emerging as a new treatment for heart failure (HF) after demonstrating favorable clinical outcomes in several randomized controlled trials (RCTs). In this meta-analysis, we assessed the safety of SGLT2i in the trials that prespecified heart failure in their inclusion criteria., Materials and Methods: We searched the databases for RCTs comparing SGLT2i to placebo in heart failure patients. The primary outcome was the incidence of serious adverse events (SAEs). A sensitivity analysis according to the class of HF was also performed., Results: The incidence of SAEs was significantly lower in the SGLT2i group (OR, 0.85; 95% CI, 0.77-0.92; P, 0.0002) and SAEs remained significantly lower after performing the sensitivity analysis (OR, 0.82; 95% CI, 0.75-0.89; P, <0.00001). Genital infections, urinary tract infections (UTIs), and hypotension were significantly higher in the SGLT2i group., Conclusions: SGLT2i remain a safe option for patients with HF with a lower incidence of SAEs. However, since they increase the risk of genital infection, UTIs and hypotension, the risks vs benefits in each patient should be weighed when making a prescribing decision., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Heart failure with mildly reduced ejection fraction (HFmrEF) is associated with comparable poor outcomes as other subtypes of heart failure and remains a medical unmet need due to the paucity of effective therapies. According to large cardiovascular (CV) outcome trials in patients with heart failure, sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduce CV mortality and hospitalizations for heart failure in patients with heart failure across the spectrum of left ventricular ejection fraction (LVEF). There has been a lack of dedicated trials in HFmrEF. However, several large outcome trials in heart failure that enrolled patients with HFmrEF could provide a hint on the role of SGLT2is in this subgroup. This review focuses on CV effects of three major SGLT2is-dapagliflozin, empagliflozin, and sotagliflozin-in patients with HFmrEF. A narrative review of trials investigating the efficacy of each medication in treating heart failure with LVEF > 40% is provided with a focus on their LVEF subgroup analyses. The purpose of this review is to discuss the current state of evidence regarding the potential of SGLT2is in HFmrEF management. Current limited evidence suggests that SGLT2is might be a favourable treatment modality for patients with HFmrEF to reduce hospitalization for heart failure and CV mortality. This conclusion needs to be further supported by clear HFmrEF subgroup analysis of the existing trials. Further outcome trials involving sufficient patients with different subtypes of HFmrEF are needed to confirm and assess CV benefits of SGLT2is in HFmrEF. Possible mechanisms by which SGLT2is exert their cardioprotective effect are also described briefly., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently been recommended as a foundational therapy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) because of their favourable effects on mortality, clinical events and quality of life. While clinical practice guidelines have recommended dapagliflozin or empagliflozin in all patients with HFrEF, or sotagliflozin in those with HFrEF and concomitant diabetes, the timing and practical integration of these drugs in clinical practice is less well defined. We propose that these drugs are candidates for early, upfront administration to patients with newly diagnosed HFrEF and for patients hospitalized with HF. Growing evidence has established early benefits, with clinically meaningful reductions in clinical events that reach statistical significance within days to weeks, following dapagliflozin, empagliflozin or, in diabetic patients, sotagliflozin initiation. Secondly, although major clinical trials have tested these drugs in patients already receiving background HF therapy, secondary analyses showed that their efficacy is independent of that. Third, SGLT2 inhibitors are generally safe and well tolerated, with clinical trial data reporting minimal effects on blood pressure, glycaemia-related adverse events, and no excess in acute kidney injury. Rather, they exert renal protective effects and reduce risk of hyperkalaemia, properties that favour initiation, tolerance and persistence of renin-angiotensin system inhibitors and mineralocorticoid receptor antagonists. This review supports the early initiation of dapagliflozin and empagliflozin (or sotagliflozin limited to patients with diabetes) to rapidly improve clinical outcome and quality of life of HFrEF patients., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Despite the availability of established treatments, heart failure (HF) is associated with a poor prognosis and its management is suboptimal, highlighting the need for new options for treatment and prevention. Patients with type 2 diabetes (T2D) often experience cardiovascular (CV) complications, with HF being one of the most frequent. Consequently, several CV outcome trials have focused on glucose-lowering therapies and their impact on CV outcomes. An established treatment for T2D, sodium-glucose cotransporter-2 inhibitors (SGLT-2is; canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) have demonstrated beneficial effects on CV outcomes in long-term studies of patients with T2D with established CV disease and/or a broad range of CV risk factors. Recent studies have extended these findings to patients with HF, with and without T2D, finding that SGLT-2is (particularly dapagliflozin and empagliflozin) are effective therapeutic interventions for the treatment and prevention of HF. This narrative review article discusses the use of SGLT-2is in the treatment and prevention of HF in patients with and without T2D. Dapagliflozin was the first SGLT-2i to receive US Food and Drug Administration (FDA) approval for treatment of HF, to reduce the risk of CV death and hospitalization for HF in adults with HF with reduced ejection fraction (HFrEF) with and without T2D. Recently, the FDA also approved empagliflozin for this indication. Given the new HFrEF indications for dapagliflozin and empagliflozin, and the likelihood of similar approvals for other SGLT-2is, cardiology guidelines are beginning to integrate SGLT-2is into a standard-of-care treatment regimen for patients with HFrEF. The utility of SGLT-2is in HF with preserved EF (HFpEF) shows promise based on data from the EMPEROR-Preserved study of empagliflozin in patients with HFpEF. Further clinical trial evidence may lead to more widespread use and further integration of SGLT-2is into standard-of-care regimens for the treatment and management of HF in patients with and without T2D., (© 2022. The Author(s).)

Heart failure (HF) is a major health problem with a significant impact on morbidity, mortality, quality of life and healthcare costs. Despite the positive impact of disease-modifying therapies developed over the last four decades, HF mortality and hospitalization remain high. We aim at reviewing the evidence supporting the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, as a novel strategy for HF with reduced ejection fraction (HFrEF) treatment. The consistent observation of a reduction in HF hospitalizations in type-2 diabetes cardiovascular safety trials EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS raised the hypothesis that SGLT-2 inhibitors could have an impact in HF treatment. This hypothesis was first confirmed in 2019 with the DAPA-HF publication showing that dapagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations and cardiovascular mortality. This was reinforced by the EMPEROR-Reduced publication in 2020 showing that empagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations. Both studies established SGLT-2 inhibitors as a fourth pillar of HFrEF prognosis-modifying therapy, in addition to the gold standard triple neurohormonal modulation/blockade., (Copyright © 2021 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background and aim: Dapagliflozin inhibits the sodium-glucose cotransporter protein 2 (SGLT-2), while sotagliflozin, belonging to a new class of dual-acting SGLT-1/SGLT-2 inhibitors, has garnered considerable attention due to its efficacy and safety. Both Dapagliflozin and sotagliflozin play a significant role in treating worsening heart failure in diabetes/nondiabetes patients with heart failure. Therefore, this article was to analyze and compare the cost per outcome of both drugs in preventing one event in patients diagnosed with diabetes-related heart failure. Method: The Cost Needed to Treat (CNT) was employed to calculate the cost of preventing one event, and the Number Needed to Treat (NNT) represents the anticipated number of patients requiring the intervention treatment to prevent a single adverse event, or the anticipated number of patients needing multiple treatments to achieve a beneficial outcome. The efficacy and safety data were obtained from the results of two published clinical trials, DAPA-HF and SOLOISTWHF. Due to the temporal difference in the drugs' releases, we temporarily analyzed the price of dapagliflozin to calculate the price of sotagliflozin within the same timeframe. The secondary analyses aimed to assess the stability of the CNT study and minimize differences between the results of the RCT control and trial groups, employing one-way sensitivity analyses. Result: The final results revealed an annualized Number Needed to Treat (aNNT) of 4 (95% CI 3-7) for preventing one event with sotagliflozin, as opposed to 23 (95% CI 16-55) for dapagliflozin. We calculated dapagliflozin's cost per prevented event (CNT) to be $109,043 (95% CI $75,856-$260,755). The price of sotagliflozin was set below $27,260, providing a favorable advantage. Sensitivity analysis suggests that sotagliflozin may hold a cost advantage. Conclusion: In this study, sotagliflozin was observed to exhibit a price advantage over dapagliflozin in preventing one events, cardiovascular mortality, or all-cause mortality in patients with diabetes. [ABSTRACT FROM AUTHOR]

Evidence for reducing cardiovascular and renal events with sotagliflozin is uncertain among type 2 diabetes mellitus (T2DM) patients. To gather more evidence, this meta-analysis assesses the beneficial effects of sotagliflozin, a dual sodium--glucose cotransporter 1 and 2 inhibitor, in reducing the cardiovascular and renal events in diabetic patients with or without chronic kidney disease (CKD). Scopus, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were the databases used to search. The studies published from January 1, 2018, to January 30, 2022, were considered. The eligibility of studies was assessed independently. The data were collected in a modified Cochrane data extraction form. The included studies' quality was assessed with the Cochrane risk-of-bias tool. The quality of evidence for renal and cardiovascular outcomes was evaluated using GRADEpro software. The number of events of urgent visits to the hospital and requiring hospitalization was reduced (RR: 0.73; 95% CI: 0.69, 0.78; P value <0.00001). The mortality rate because of cardiovascular events was decreased with sotagliflozin (RR: 0.73; 95% CI: 0.67, 0.80; P value <0.00001). Patients taking sotagliflozin had a drastic decline in the number of deaths due to stroke and non-fatal myocardial infarction. Yet, there is no difference between the groups in terms of changes in mortality due to other causes or the glomerular filtration rate (GFR). Sotagliflozin demonstrated effectiveness in reducing the mortality rate related to heart failure and cardiovascular events when the dose was increased from 200 mg to 400 mg. Despite this, evidence is still needed to prove the renal protective action. [ABSTRACT FROM AUTHOR]

Aim: To assesses the cost–effectiveness of sotagliflozin for the treatment of patients hospitalized with heart failure and comorbid diabetes. Materials & methods: A de novo cost–effectiveness model with a Markov structure was created for patients hospitalized for heart failure with comorbid diabetes. Outcomes of interest included hospital readmissions, emergency department visits and all-cause mortality measured over a 30-year time horizon. Baseline event frequencies were derived from published real-world data studies; sotagliflozin’s efficacy was estimated from SOLOIST-WHF. Health benefits were calculated quality-adjusted life years (QALYs). Costs included pharmaceutical costs, rehospitalization, emergency room visits and adverse events. Economic value was measured using the incremental cost–effectiveness ratio (ICER). Results: Sotagliflozin use decreased annualized rehospitalization rates by 34.5% (0.228 vs 0.348, difference: -0.120), annualized emergency department visits by 40.0% (0.091 vs 0.153, difference: -0.061) and annualized mortality by 18.0% (0.298 vs 0.363, difference: -0.065) relative to standard of care, resulting in a net gain in QAYs of 0.425 for sotagliflozin versus standard of care. Incremental costs using sotagliflozin increased by $19,374 over a 30-year time horizon of the patient, driven largely by increased pharmaceutical cost. Estimated ICER for sotagliflozin relative to standard of care was $45,596 per QALY. Conclusion: Sotagliflozin is a cost-effective addition to standard of care for patients hospitalized with heart failure and comorbid diabetes.

Background: As an antidiabetic agent, sotagliflozin was recently approved for heart failure (HF). However, its cardiovascular benefits in type 2 diabetic mellitus (T2DM) patients with HF or cardiovascular (CV) risk factors have not been systematically evaluated. The aim of this study is to evaluate the cardiovascular benefits and safety of sotagliflozin in T2DM patients with HF or CV risk factors using Bayesian network meta-analysis. Methods: Data were retrieved from PubMed, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Library from their inception to 16 August 2023. Randomized controlled trials (RCTs) comparing sotagliflozin with a placebo, dapagliflozin, and empagliflozin in adult T2DM patients with HF or CV risks for at least 12 weeks were included in the study. Data analysis was conducted using R 4.2.3 and Stata 17.0. Cardiovascular efficacy outcomes included HF events (hospitalization or urgent visits for HF), MACE (deaths from CV causes, hospitalizations for HF, nonfatal myocardial infarctions, and strokes), cardiovascular death, the decrease in SBP, and weight loss. Safety outcomes are urinary tract infection, diarrhea, and diabetic ketoacidosis. Results: Eleven studies with 30,952 patients were included. Compared to dapagliflozin and empagliflozin, 200 mg of sotagliflozin showed the best effect in reducing HF events [OR (95% CI), 0.79 (0.66, 0.94) and 0.90 (0.63, 1.27)]. Compared to dapagliflozin, 200 mg of sotagliflozin [OR (95% CI), 0.76 (0.66, 0.87)] was superior in preventing MACE. Compared to empagliflozin, 200 mg of sotagliflozin [OR (95% CI), 1.46 (1.04, 2.05)] was inferior in preventing CV death. Sotagliflozin showed a poorer SBP decreasing effect than empagliflozin and dapagliflozin [MD (95% CI), 1.30 (0.03, 2.56) and 2.25 (0.35, 4.14), respectively]. There was no significant difference between sotagliflozin and other interventions in weight loss. Sotagliflozin exhibited no increased risk for diabetic ketoacidosis or urinary tract infection among all interventions, however, it showed a mild risk for diarrhea than placebo [OR (95% CI), 1.47 (1.28, 1.69)]. Conclusion: Sotagliflozin displayed moderate CV benefits and acceptable safety. Sotagliflozin can be one of the recommended options for T2DM patients with HF or CV risk factors, which will be important for evidence-based use of sotagliflozin as well as decision-making of T2DM medication. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a chronic disorder that decreases heart function and causes a person to be less tolerant to exercise, have a lower quality of life, and prone to death. Novel therapeutic strategies are still needed despite improvements in HF management. Sotagliflozin is a promising medication for the treatment of HF, which is a dual sodium-glucose cotransporter 1 as well as 2 (SGLT1 and SGLT2) inhibitor. The purpose of this in-depth study is to assess sotagliflozin's effectiveness and safety in the treatment of HF. The effects of sotagliflozin on different facets of HF pathophysiology, such as blood flow, myocardial remodeling, and neurohormonal stimulation, are discussed in preclinical and clinical investigations. Sotagliflozin has been shown to be effective in lowering the risk of HF hospitalization and heart attack in patients with HF with either type 2 diabetic mellitus (T2DM) and chronic kidney disease (CKD), according to numerous randomized trials, including the most recent SOLOIST-WHF or SCORED trials. Sotagliflozin's simultaneous inhibition of SGLT1 along with SGLT2 creates a special pharmacological profile that addresses both the metabolic as well as non-metabolic problems seen in HF. This review provides a comprehensive summary of various aspects related to sotagliflozin and heart failure, including the pathophysiology in heart failure, US-FDA approved treatment for HF, mechanism of action, pharmacokinetic, pharmacodynamics data of sotagliflozin, reported adverse drug reactions (ADRs), and ongoing clinical trials.

Aim: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: ≥50%) or/and mildly reduced EF (HFmrEF: 41–49%) regardless of baseline diabetes. Methods: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model. Results: We identified six RCTs, pooling data retrieved from 15,769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p

Background: Heart failure is prevalent worldwide. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective in heart failure patients with reduced ejection fraction, whether SGLT2i are effective in heart failure with preserved ejection fraction (HFpEF) remains to be determined. Methods: All relevant citations in the PubMed, Embase and Cochrane databases were identified from inception to September, 2022. The primary outcome was a composite endpoint of cardiovascular death and hospitalization for heart failure (HHF). A subgroup analysis was performed according to diabetes mellitus status and the ejection fraction. Secondary endpoints were cardiovascular death, hospitalization for heart failure and all cause death. Results: Seven studies involving 11,604 patients were included in the metaanalysis. Compared with placebo, sodium-glucose cotransporter 2 inhibitors reduced the incidence of the primary outcome by 24%, with an odds ratio (OR) and 95% confidence interval (CI) 0.76 [0.69, 0.84]. For secondary outcomes, sodium-glucose cotransporter 2 inhibitors were associated with a lower incidence of hospitalization for heart failure, but not cardiovascular or all-cause death; the OR and 95% CI were 0.73 [0.66, 0.82], 0.92 [0.81, 1.04], 0.96 [0.88, 1.05], respectively. Conclusions: This study proves the clinical efficacy of SGLT2i for treatment of HFpEF patients with or without diabetes, which was mainly driven by prevention of HHF rather than cardiovascular or all-cause death. [ABSTRACT FROM AUTHOR]

Purpose of Review: Focused review highlighting select studies presented at the 2022 American College of Cardiology (ACC) Scientific Sessions. Recent Findings: Included studies assessed the impact of a low-sodium diet on heart failure outcomes (SODIUM-HF); outcomes of pregnant patients with chronic hypertension treated with antihypertensive therapies (CHAP); cardiovascular outcomes in patients with type 2 diabetes and renal impairment treated with sotagliflozin (SCORED); a safety and efficacy study investigating SLN360, a short interfering RNA targeting lipoprotein(a) (APOLLO); a supermarket and web-based intervention targeting nutrition for cardiovascular risk reduction (SuperWIN); a superiority trial comparing myocardial injury following very mild perioperative hypothermia versus aggressive warming after non-cardiac surgery (PROTECT); and 3-year efficacy outcomes of renal denervation on blood pressure reduction from the SPYRAL HTN-ON MED pilot study. Summary: Research presented at the 2022 ACC Scientific Sessions underscores the new potential and meaningful impact of cardiovascular disease prevention and management interventions. [ABSTRACT FROM AUTHOR]

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The article analyzes the new results of randomized clinical trials on the use of sodium-glucose co-transporter-2 inhibitors in patients with cardiovascular diseases, heart failure with and without type 2 diabetes. The data of the latest studies (EMPEROR reduced, VERTIS CV, SOLOIST-WHF, SCORED) are presented in more detail.

Given the mode of action of the drug, this is not surprising - but would also position omecamtiv mecarbil as a possible add-on therapy in patients with severe systolic dysfunction, in whom hypotension is often a complicating issue for conventional treatment. While the COVID-19 sensitivity analysis was meaningful in view of reported associations of the pandemic with reduced HF hospitalization rates 8 that may particularly impact recurrent HF events in the trial, how such analyses will be viewed in guidelines remains unknown. Perhaps most tantalizing are the implications of SOLOISTWHF for the safe initiation of SGLT inhibitors in hospitalized patients, as well as possible benefit in patients with HF and preserved LVEF. Biography: Dr Lam is a Senior Consultant at NHCS specializing in heart failure and recognized globally for expertise in heart failure with preserved ejection fraction. [Extracted from the article]

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Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials. [ABSTRACT FROM AUTHOR]