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. 2023 Jun 27;81(25):2391-2402.
doi: 10.1016/j.jacc.2023.04.031.

Assessment of Atherothrombotic Risk in Patients With Type 2 Diabetes Mellitus

David D Berg  1 , Filipe A Moura  2 , Andrea Bellavia  2 , Benjamin M Scirica  2 , Stephen D Wiviott  2 , Deepak L Bhatt  3 , Itamar Raz  4 , Erin A Bohula  2 , Robert P Giugliano  2 , Jeong-Gun Park  2 , Mark W Feinberg  5 , Eugene Braunwald  2 , David A Morrow  2 , Marc S Sabatine  2
Affiliations

Assessment of Atherothrombotic Risk in Patients With Type 2 Diabetes Mellitus

David D Berg et al. J Am Coll Cardiol. .

Erratum in

  • Correction.
    [No authors listed] [No authors listed] J Am Coll Cardiol. 2025 Aug 12;86(6):479. doi: 10.1016/j.jacc.2025.06.039. J Am Coll Cardiol. 2025. PMID: 40769677 No abstract available.

Abstract

Background: Risk of atherothrombotic events is not uniform in patients with type 2 diabetes mellitus (T2DM). Tailored risk assessment may help guide selection of pharmacotherapies for cardiovascular primary and secondary prevention.

Objectives: The purpose of this study was to develop a risk model for atherothrombosis in patients with T2DM.

Methods: We developed and validated a risk model for myocardial infarction (MI) or ischemic stroke (IS) in a pooled cohort of 42,181 patients with T2DM from 4 TIMI (Thrombolysis In Myocardial Infarction) clinical trial cohorts. Candidate variables were assessed with multivariable Cox regression, and independent variables (P < 0.05) were retained in the final model. Discrimination and calibration were assessed. Treatment interactions with dapagliflozin (sodium-glucose cotransporter-2 inhibitor) and evolocumab (proprotein convertase subtilisin/kexin type 9 inhibitor) were explored in the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58) and FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trials, respectively.

Results: Sixteen variables were independent predictors of MI or IS. The model identified a >8-fold gradient of MI or IS rates between the top vs bottom risk quintiles in the validation cohort (3-year Kaplan-Meier rate: 14.9% vs 1.4%; P < 0.0001). C-indexes were 0.704 and 0.706 in the derivation and validation cohorts, respectively. The model was well-calibrated in both primary and secondary prevention. Absolute reduction in the rates of MI or IS tended to be greater in patients with higher baseline predicted risk for both dapagliflozin (absolute risk reduction: 2.1% vs 0.2%) and evolocumab (absolute risk reduction: 3.2% vs 1.0%).

Conclusions: We developed and validated a risk score for atherothrombotic events, leveraging 16 routinely assessed clinical variables in patients with T2DM. The score has the potential to improve risk assessment and inform clinical decision-making.

Keywords: atherothrombosis; clinical trials; diabetes mellitus; ischemic stroke; myocardial infarction.

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Conflict of interest statement

Funding Support and Author Disclosures The SAVOR-TIMI 53 and DECLARE-TIMI 58 trials were supported by institutional research grants to Brigham and Women’s Hospital from AstraZeneca. The FOURIER trial was supported by an institutional research grant to Brigham and Women’s Hospital from Amgen. The CAMELLIA-TIMI 61 trial was supported by an institutional research grant to Brigham and Women’s Hospital from Eisai. Drs Berg, Moura, Scirica, Wiviott, Feinberg, Morrow, and Sabatine were supported for the present analysis by the American Heart Association Cardiometabolic Health and Type 2 Diabetes Mellitus Strategically Focused Research Network (20SFRN35120087). Drs Berg, Moura, Bellavia, Scirica, Wiviott, Bohula, Giugliano, Park, Braunwald, Morrow, and Sabatine are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. Dr Berg has received research grant support to his institution from AstraZeneca and Pfizer; has received consulting fees from AstraZeneca, Mobility Bio, Inc, and Youngene Therapeutics; has received honoraria from the Medical Education Speakers Network (MESN) and USV Private Limited; and participates on clinical endpoint committees for studies sponsored by Kowa Pharmaceuticals. Dr Scirica has received institutional research grants to Brigham and Women’s Hospital from Better Therapeutics, Merck, Novo Nordisk, and Pfizer; has received consulting fees from Allergan, Boehringer Ingelheim, Better Therapeutics, Elsevier Practice Update Cardiology, Esperion, Hanmi, Lexicon, and Novo Nordisk; and has equity in Health [at] Scale and Doximity. Dr Wiviott has received grants from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, Janssen, Merck, and Pfizer; has received consulting fees from AstraZeneca, Boston Clinical Research Institute, Icon Clinical, and Novo Nordisk; and his spouse is a former employee of Merck and is a current employee of Flagship Labs 86. Dr Bhatt 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; is Inaugural Chair of the American Heart Association Quality Oversight Committee; has served as a consultant for Broadview Ventures; 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), 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 coleader, 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 of Clinical Cardiology; is Chair of the NCDR-ACTION Registry Steering Committee and VA CART Research and Publications Committee; has a patent for Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); is site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo and Takeda. Dr Raz has received personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Concenter BioPharma and Silkim, Eli Lilly, Merck Sharp and Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FuturRx, InsuLine Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson and Johnson, Novartis, Teva, GlucoMe, and DarioHealth. Dr Bohula has received personal fees from Servier, Kowa, Medscape, Novo Nordisk, Amgen, PriMed, and Merck. Dr Giugliano has received research support from Amgen, Anthos Therapeutics, and Daiichi-Sankyo; has received honoraria for lectures/CME programs for Amgen, Centrix, Daiichi-Sankyo, Dr Reddy’s Laboratories, Medical Education Resources, Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope, and Voxmedia; and has received consultant fees from Amarin, Amgen, Boston Scientific, CryoLife, CSL Behring, CVS Caremark, Daiichi-Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Novartis, Pfizer, PhaseBio Pharmaceuticals, St. Lukes, and Samsung. Dr Braunwald has received research grants through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and has received consultancy fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Cardurion, and Verve. Dr Morrow has received grants to the Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, AstraZeneca, Eisai, The Medicines Company, Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; and has received consultant fees from InCardia, Inflammatix, Merck and Co, Novartis, and Roche Diagnostics. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Merck, Novartis, and Pfizer; and has served as a consultant for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

Figures

FIGURE 1
FIGURE 1. Cumulative Incidence of Myocardial Infarction or Ischemic Stroke by Risk Category
Risk categories are defined by predicted 3-year risk of myocardial infarction or ischemic stroke. Kaplan-Meier event rates at 3 years are shown. The shaded areas are superimposed to improve interpretation of calibration, and do not represent confidence limits derived from statistical hypothesis testing. Cumulative incidence by risk category was consistent in the derivation and validation cohorts, demonstrating appropriate risk stratification and calibration of the risk model.
FIGURE 2
FIGURE 2. Model Discrimination in Primary and Secondary Prevention
The cumulative incidence of myocardial infarction or ischemic stroke is shown by quintiles of predicted risk in patients with (secondary prevention) and without (primary prevention) established ASCVD. Kaplan-Meier event rates at 3 years are noted. Discrimination was consistent in primary and secondary prevention cohorts, with strong gradients of risk for myocardial infarction or ischemic stroke in the derivation and validation cohorts for both subgroups. ASCVD = atherosclerotic cardiovascular disease.
FIGURE 3
FIGURE 3. Calibration Plots in the Validation Cohort
Calibration was assessed by comparing predicted 3-year risk with observed 3-year Kaplan-Meier event rates. The dots represent the observed rates vs predicted risk of each risk decile in the validation cohort. The blue line represents the least squares regression line through these 10 data points, with the linear slope and 95% CI provided. The red line represents the theoretical line of perfect calibration (slope = 1.00). In the bottom panel, the red line is not visible because the slope of the blue line is superimposed. The model was well-calibrated in the primary and secondary prevention subgroups despite substantial differences in their overall risk profiles.
FIGURE 4
FIGURE 4. Treatment Benefit of Dapagliflozin and Evolocumab by Baseline Predicted Risk
To test for relative differences in the treatment effect of dapagliflozin vs placebo in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58) and of evolocumab vs placebo in FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) according to baseline predicted risk, interaction terms were included in the Cox model. To compare absolute differences in the treatment effect of these therapies according to baseline predicted risk, 3-year Kaplan-Meier event rates for myocardial infarction (MI) or ischemic stroke in patients treated with dapagliflozin or evolocumab, respectively, were subtracted from the 3-year Kaplan-Meier (KM) event rates in patients treated with placebo across risk categories. Although there were consistent relative risk reductions (RRRs) in MI or ischemic stroke across baseline risk categories, there was increasing absolute risk reduction (ARR) with increasing baseline risk.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Thrombolysis In Myocardial Infarction Risk Score for Atherothrombosis in Diabetes
The TIMI Risk Score for Atherothrombosis in Diabetes is a novel clinical risk model for predicting atherothrombotic events (fatal or nonfatal myocardial infarction or ischemic stroke) in patients with T2DM. The model includes 16 routinely assessed clinical variables. ARR = absolute risk reduction; CABG = coronary artery bypass grafting; DECLARE-TIMI 58 = Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58; eGFR = estimated glomerular filtration rate; FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; LDL = low-density lipoprotein; MI = myocardial infarction; PCI = percutaneous coronary intervention; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; TIMI = Thrombolysis In Myocardial Infarction; UACR = urine albumin-to-creatinine ratio.
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References

    1. Sarwar N, Gao P, Seshasai SR, et al. for the Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–2222. - PMC - PubMed
    1. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med. 2014;370:1514–1523. - PubMed
    1. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999–2010. N Engl J Med. 2013;368:1613–1624. - PubMed
    1. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6:148–158. - PMC - PubMed
    1. Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7:776–785. - PubMed

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