Clinical Trial

. 2025 Apr;13(4):321-332.

doi: 10.1016/S2213-8587(24)00362-0. Epub 2025 Feb 14.

Effect of sotagliflozin on major adverse cardiovascular events: a prespecified secondary analysis of the SCORED randomised trial

Rahul Aggarwal¹, Deepak L Bhatt², Michael Szarek³, Christopher P Cannon¹, Lawrence A Leiter⁴, Silvio E Inzucchi⁵, Renato D Lopes⁶, Darren K McGuire⁷, Julia B Lewis⁸, Matthew C Riddle⁹, Michael J Davies¹⁰, Phillip Banks¹⁰, Amy K Carroll¹⁰, Benjamin M Scirica¹¹, Kausik K Ray¹², Mikhail N Kosiborod¹³, David Z I Cherney¹⁴, Jacob A Udell¹⁵, Subodh Verma⁴, R Preston Mason¹⁶, Bertram Pitt¹⁷, Ph Gabriel Steg¹⁸

Affiliations

¹ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA.
² Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: dlbhattmd@post.harvard.edu.
³ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA; CPC Clinical Research and University of Colorado Anschutz Medical Campus, Aurora, CO, USA; State University of New York Downstate School of Public Health, Brooklyn, NY, USA.
⁴ Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
⁵ Yale School of Medicine, New Haven, CT, USA.
⁶ Duke University School of Medicine, Durham, NC, USA.
⁷ University of Texas Southwestern Medical Center and Parkland Health, Dallas, Texas, USA.
⁸ Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁹ Oregon Health and Science University, Portland, OR, USA.
¹⁰ Lexicon Pharmaceuticals, The Woodlands, TX, USA.
¹¹ TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹² Department of Primary Care and Public Health, Imperial College London, London, UK.
¹³ Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA.
¹⁴ University Health Network, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON, Canada.
¹⁵ Women's College Hospital and Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, ON, Canada.
¹⁶ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA; Elucida Research, Beverly, MA, USA.
¹⁷ University of Michigan, Ann Arbor, MI, USA.
¹⁸ Université Paris-Cité, INSERM U1148 and AP-HP Hôpital Bichat, Paris, France; French Alliance for Cardiovascular Trials, Paris, France.

PMID: 39961315
DOI: 10.1016/S2213-8587(24)00362-0

Clinical Trial

Effect of sotagliflozin on major adverse cardiovascular events: a prespecified secondary analysis of the SCORED randomised trial

Rahul Aggarwal et al. Lancet Diabetes Endocrinol. 2025 Apr.

. 2025 Apr;13(4):321-332.

doi: 10.1016/S2213-8587(24)00362-0. Epub 2025 Feb 14.

Authors

Affiliations

¹ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA.
² Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: dlbhattmd@post.harvard.edu.
³ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA; CPC Clinical Research and University of Colorado Anschutz Medical Campus, Aurora, CO, USA; State University of New York Downstate School of Public Health, Brooklyn, NY, USA.
⁴ Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
⁵ Yale School of Medicine, New Haven, CT, USA.
⁶ Duke University School of Medicine, Durham, NC, USA.
⁷ University of Texas Southwestern Medical Center and Parkland Health, Dallas, Texas, USA.
⁸ Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁹ Oregon Health and Science University, Portland, OR, USA.
¹⁰ Lexicon Pharmaceuticals, The Woodlands, TX, USA.
¹¹ TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹² Department of Primary Care and Public Health, Imperial College London, London, UK.
¹³ Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA.
¹⁴ University Health Network, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON, Canada.
¹⁵ Women's College Hospital and Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, ON, Canada.
¹⁶ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA; Elucida Research, Beverly, MA, USA.
¹⁷ University of Michigan, Ann Arbor, MI, USA.
¹⁸ Université Paris-Cité, INSERM U1148 and AP-HP Hôpital Bichat, Paris, France; French Alliance for Cardiovascular Trials, Paris, France.

PMID: 39961315
DOI: 10.1016/S2213-8587(24)00362-0

Abstract

Background: Sodium-glucose co-transporter (SGLT)-2 inhibitors have shown consistent benefit in improving heart failure-related outcomes but not ischaemic cardiovascular events such as myocardial infarction or stroke. We assessed if the dual SGLT1/2 inhibitor sotagliflozin improves ischaemic outcomes.

Methods: We did a prespecified secondary analysis of the SCORED trial, which was a double-blind, placebo-controlled, randomised clinical trial enrolling patients (aged ≥18 years) with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate [eGFR] 25-60 mL/min per 1·73 m²), and additional cardiovascular risk factors. Patients at 750 sites in 44 countries were randomly assigned (1:1) to oral sotagliflozin or placebo via an interactive response technology system (block size of four; stratified by heart failure-related criteria and geographical region), with participants, investigators, and study staff, including those who assessed outcomes, masked to group assignment. Sotagliflozin treatment was prescribed at 200 mg once a day, with the dose increased to 400 mg once a day within the first 6 months if tolerated. Matching placebo was prescribed at the same treatment frequency as the intervention regimen. A prespecified secondary outcome was total major adverse cardiovascular events (MACE), which was defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, assessed as first and subsequent events. Other outcomes included total myocardial infarction and total stroke (fatal and non-fatal events) as individual post-hoc endpoints. Outcomes were assessed by intention to treat with competing-risk proportional hazard models in the overall population, and, for total MACE, in prespecified subgroups stratified by baseline demographic and clinical features (sex, age, geographical region, heart failure-related criteria, eGFR, urine albumin-creatinine ratio, and cardiovascular disease history). The SCORED trial was registered at ClinicalTrials.gov, NCT03315143, and was ended early due to loss of funding.

Findings: 10 584 patients were enrolled and randomly assigned to sotagliflozin (n=5292 [50·0%]) or placebo (n=5292 [50·0%]) between Dec 8, 2017 and Jan 20, 2020 (median age 69 years [IQR 63-74]; 4754 [44·9%] female patients and 5830 [55·1%] male patients). 5144 (48·6%) patients had a history of cardiovascular disease, of whom 2108 (19·9% of the total population) had a history of myocardial infarction, 946 (8·9%) had a history of stroke, and 2375 (22·4%) had a history of coronary revascularisation. Patients in the sotagliflozin group had a significantly lower rate of total MACE than those in the placebo group (4·8 events per 100 person-years vs 6·3 events per 100 person-years; hazard ratio [HR] 0·77 [95% CI 0·65-0·91]; p=0·0020). Interaction analyses suggested a consistent effect of sotagliflozin on total MACE among stratified subgroups without evidence of heterogeneity. Additionally, sotagliflozin significantly reduced the rate of myocardial infarction (1·8 events per 100 person-years vs 2·7 events per 100 person-years; HR 0·68 [0·52-0·89]; p=0·0041) and stroke (1·2 events per 100 person-years vs 1·8 events per 100 person-years; HR 0·66 [0·48-0·91]; p=0·012) compared with placebo.

Interpretation: Sotagliflozin reduced MACE, with independent reductions in myocardial infarction and stroke, among patients with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk. The ischaemic benefit on both myocardial infarction and stroke has not been previously observed with other SGLT inhibitors and warrants investigation of combined SGLT1 and SGLT2 inhibition as a possible underlying mechanism.

Funding: Lexicon Pharmaceuticals.

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Conflict of interest statement

Declaration of interests RA is involved in research funded by the Bristol Myers Squibb–Pfizer alliance, Novartis, Amarin, and Lexicon Pharmaceuticals. He has previously served as a consultant for Lexicon. DLB receives research funding from Lexicon Pharmaceuticals paid to the Icahn School of Medicine at Mount Sinai for his role as Chair of the SCORED trial and discloses the following relationships: advisory board membership for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors membership for the American Heart Association New York City, Angiowave, Bristol Myers Squibb, DRS.LINQ, and High Enroll (and holds stock or stock options with Angiowave, Bristol Myers Squibb, DRS.LINQ, and High Enroll); consulting for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; data monitoring committee participation 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, Contego Medical (Chair, PERFORMANCE 2 trial), Duke Clinical Research Institute, Mayo Clinic, Icahn School of Medicine at Mount Sinai (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; and for the ALLAY-HF trial, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the MINT trial, funded by the US National Institutes of Health [NIH]); honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; and Chair, American College of Cardiology 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; for RE-DUAL PCI Clinical Trial Steering Committee membership funded by Boehringer Ingelheim; for AEGIS-II Executive Committee membership funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), the Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (continuing medical education steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, the Population Health Research Institute (for the COMPASS Operations Committee, Publications Committee, Steering Committee, and US National Co-Leader, funded by Bayer), WebMD (continuing medical education steering committees), and Wiley (steering committee); other support from Clinical Cardiology (Deputy Editor); a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned the patent to Lexicon Pharmaceuticals; neither DLB nor Brigham and Women's Hospital receive any income from this patent); 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 Pharmaceuticals, Eli 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 from Elsevier (Editor, Braunwald's Heart Disease); a role as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; a role as Trustee of the American College of Cardiology; and unfunded research with FlowCo. MS serves as a consultant for and/or has received research support from Lexicon Pharmaceuticals, Amarin, NewAmsterdam, Silence, Sanofi, Regeneron, and Tourmaline. MS also receives salary support from CPC, a non-profit academic research organisation affiliated with the University of Colorado, that receives or has received research grant or consulting funding between July, 2021 and July, 2024 from the following organisations: Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma Godo Kaisha, Amgen, Anthos Therapeutics, ARCA biopharma, Arrowhead Pharmaceuticals, AstraZeneca Pharma India, AstraZeneca UK, Bayer, Bayer Aktiengesellschaft, Bayer Pharma, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, Bristol Myers Squibb, Cleerly, Colorado Department of Public Health and Environment, Congress, Cook Regentec, CSL Behring, Eidos Therapeutics, EPG Communication Holdings, Esperion Therapeutics, Faraday Pharmaceuticals, HeartFlow, Insmed, Ionis Pharmaceuticals, IQVIA, Janssen Pharmaceuticals, Janssen Research & Development, Janssen Scientific Affairs, Lexicon Pharmaceuticals, Medpace, Medscape, Merck Sharp & Dohme, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, PPD Development, Prothena Biosciences, Regeneron, Regents of the University of Colorado (University of Colorado Denver), Sanifit Therapeutics, Sanofi, Silence Therapeutics, Stanford University, Stealth BioTherapeutics, Brigham and Women's Hospital, Thrombosis Research Institute, Tourmaline Bio, University of Colorado, University of Colorado Denver, University of Pittsburgh, VarmX, Verve Therapeutics, and WraSer. CPC 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 Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Eli Lilly, Janssen, Lexicon Pharmaceuticals, Merck, Pfizer, Rhoshan, and Sanofi; and has served on data and safety monitoring boards for Applied Therapeutics and Novo Nordisk. LAL has received research funding from, has provided continuing medical education on behalf of, and/or has acted an adviser to Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion, HLS Therapeutics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi. SEI 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 and AstraZeneca. RDL 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. DKM has received research support for clinical trials leadership from Boehringer Ingelheim, Merck, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Eli Lilly, Lexicon Pharmaceuticals, CSL Behring, and NewAmsterdam Pharma; and has received honoraria for consultancy from Eli Lilly, Boehringer Ingelheim, Merck, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, GlaxoSmithKline, and Intercept. JBL has received consultant fees from Sanofi. MCR has received honoraria for consulting from Adocia, Anji, Xeris, DalCor, and Theracos. MJD, AKC, and PB are employees of Lexicon Pharmaceuticals, and may hold stocks or stock options in the company. BAS reports institutional research grants to Brigham and Women's Hospital from Better Therapeutics, Merck, Novo Nordisk, and Pfizer; consulting fees from Allergan, Boehringer Ingelheim, Better Therapeutics, Elsevier Practice Update Cardiology, Esperion Therapeutics, Hanmi Pharmaceutical, Lexicon Pharmaceuticals, and Novo Nordisk; and equity in Health at Scale and Doximity. DZIC has received honoraria from Boehringer Ingelheim–Eli Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi Tanabe, AbbVie, Janssen, Amgen, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL Behring, Otsuka, Novartis, Youngene, Lexicon Pharmaceuticals, Inversago, GlaxoSmithKline, and Novo Nordisk, and has received operational funding for clinical trials from Boehringer Ingelheim–Eli Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring, Novo Nordisk, and Bayer. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving grants and/or research support and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management, and Sanofi. JAU discloses advisory board roles for Boehringer Ingelheim, Novavax, Novo Nordisk, and Sanofi; speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, and Eli Lilly; and research funding to his institution from Amgen, Bayer, Boehringer Ingelheim, and Novartis. RPM has received research funding or consulting fees from Amarin, Lexicon Pharmaceuticals, Esperion, and HLS Therapeutics. BP has received consulting fees from Lexicon Pharmaceuticals, Bayer, AstraZeneca, Boehringer Ingelheim, Merck, and Phasebio; has received consulting fees from and/or holds stock options from Viror, KBP Biosciences, Cereno Scientific, Tricida, scPharmaceuticals, SQ Innovation, G-3 Pharmaceuticals, Protonintel, and Brainstorm Medical; and holds a US patent (number 9931412) on site-specific delivery of eplerenone to the myocardium and US patent, pending (number 63/045,783) on histone-modulating agents for the protection and treatment of organ damage. PGS 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 Pharmaceuticals, Merck, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier; and is a Senior Associate Editor of Circulation. All other authors declare no competing interests.

Comment in

Sodium-glucose co-transporter inhibitors-who would have guessed?
Norhammar A, Ritsinger V. Norhammar A, et al. Lancet Diabetes Endocrinol. 2025 Apr;13(4):268-270. doi: 10.1016/S2213-8587(25)00001-4. Epub 2025 Feb 14. Lancet Diabetes Endocrinol. 2025. PMID: 39961316 No abstract available.

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Effect of sotagliflozin on major adverse cardiovascular events: a prespecified secondary analysis of the SCORED randomised trial

Affiliations

Effect of sotagliflozin on major adverse cardiovascular events: a prespecified secondary analysis of the SCORED randomised trial

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

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Associated data

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