Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction

Remo H.M. Furtado, Marc P. Bonaca, Itamar Raz, Thomas A. Zelniker, Ofri Mosenzon, Avivit Cahn, Julia Kuder, Sabina A. Murphy, Deepak L. Bhatt, Lawrence A. Leiter, Darren K McGuire, John P.H. Wilding, Christian T. Ruff, Jose C. Nicolau, Ingrid A.M. Gause-Nilsson, Martin Fredriksson, Anna Maria Langkilde, Marc S. Sabatine, Stephen D. Wiviott

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. METHODS: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. RESULTS: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). CONCLUSIONS: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Original languageEnglish (US)
Pages (from-to)2516-2527
Number of pages12
JournalCirculation
Volume139
Issue number22
DOIs
StatePublished - May 28 2019

Fingerprint

Type 2 Diabetes Mellitus
Myocardial Infarction
Sodium-Glucose Transporter 2
Hospitalization
Cardiovascular Diseases
Heart Failure
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Numbers Needed To Treat
Risk Reduction Behavior
Placebos
Clinical Trials

Keywords

  • myocardial infarction
  • sodium-glucose transporter 2 inhibitors
  • type 2 diabetes mellitus

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Furtado, R. H. M., Bonaca, M. P., Raz, I., Zelniker, T. A., Mosenzon, O., Cahn, A., ... Wiviott, S. D. (2019). Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction. Circulation, 139(22), 2516-2527. https://doi.org/10.1161/CIRCULATIONAHA.119.039996

Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction. / Furtado, Remo H.M.; Bonaca, Marc P.; Raz, Itamar; Zelniker, Thomas A.; Mosenzon, Ofri; Cahn, Avivit; Kuder, Julia; Murphy, Sabina A.; Bhatt, Deepak L.; Leiter, Lawrence A.; McGuire, Darren K; Wilding, John P.H.; Ruff, Christian T.; Nicolau, Jose C.; Gause-Nilsson, Ingrid A.M.; Fredriksson, Martin; Langkilde, Anna Maria; Sabatine, Marc S.; Wiviott, Stephen D.

In: Circulation, Vol. 139, No. 22, 28.05.2019, p. 2516-2527.

Research output: Contribution to journalArticle

Furtado, RHM, Bonaca, MP, Raz, I, Zelniker, TA, Mosenzon, O, Cahn, A, Kuder, J, Murphy, SA, Bhatt, DL, Leiter, LA, McGuire, DK, Wilding, JPH, Ruff, CT, Nicolau, JC, Gause-Nilsson, IAM, Fredriksson, M, Langkilde, AM, Sabatine, MS & Wiviott, SD 2019, 'Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction', Circulation, vol. 139, no. 22, pp. 2516-2527. https://doi.org/10.1161/CIRCULATIONAHA.119.039996
Furtado, Remo H.M. ; Bonaca, Marc P. ; Raz, Itamar ; Zelniker, Thomas A. ; Mosenzon, Ofri ; Cahn, Avivit ; Kuder, Julia ; Murphy, Sabina A. ; Bhatt, Deepak L. ; Leiter, Lawrence A. ; McGuire, Darren K ; Wilding, John P.H. ; Ruff, Christian T. ; Nicolau, Jose C. ; Gause-Nilsson, Ingrid A.M. ; Fredriksson, Martin ; Langkilde, Anna Maria ; Sabatine, Marc S. ; Wiviott, Stephen D. / Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction. In: Circulation. 2019 ; Vol. 139, No. 22. pp. 2516-2527.
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title = "Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction",
abstract = "BACKGROUND: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. METHODS: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. RESULTS: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16{\%} and the absolute risk by 2.6{\%} (15.2{\%} versus 17.8{\%}; hazard ratio [HR], 0.84; 95{\%} CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1{\%} versus 7.1{\%}; HR, 1.00; 95{\%} CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6{\%} versus 12.8{\%}; HR, 0.98; 95{\%} CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9{\%} (8.6{\%} versus 10.5{\%}; HR, 0.81; 95{\%} CI, 0.65-1.00; P=0.046) and 0.6{\%} (3.9{\%} versus 4.5{\%}; HR, 0.85; 95{\%} CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). CONCLUSIONS: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.",
keywords = "myocardial infarction, sodium-glucose transporter 2 inhibitors, type 2 diabetes mellitus",
author = "Furtado, {Remo H.M.} and Bonaca, {Marc P.} and Itamar Raz and Zelniker, {Thomas A.} and Ofri Mosenzon and Avivit Cahn and Julia Kuder and Murphy, {Sabina A.} and Bhatt, {Deepak L.} and Leiter, {Lawrence A.} and McGuire, {Darren K} and Wilding, {John P.H.} and Ruff, {Christian T.} and Nicolau, {Jose C.} and Gause-Nilsson, {Ingrid A.M.} and Martin Fredriksson and Langkilde, {Anna Maria} and Sabatine, {Marc S.} and Wiviott, {Stephen D.}",
year = "2019",
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TY - JOUR

T1 - Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction

AU - Furtado, Remo H.M.

AU - Bonaca, Marc P.

AU - Raz, Itamar

AU - Zelniker, Thomas A.

AU - Mosenzon, Ofri

AU - Cahn, Avivit

AU - Kuder, Julia

AU - Murphy, Sabina A.

AU - Bhatt, Deepak L.

AU - Leiter, Lawrence A.

AU - McGuire, Darren K

AU - Wilding, John P.H.

AU - Ruff, Christian T.

AU - Nicolau, Jose C.

AU - Gause-Nilsson, Ingrid A.M.

AU - Fredriksson, Martin

AU - Langkilde, Anna Maria

AU - Sabatine, Marc S.

AU - Wiviott, Stephen D.

PY - 2019/5/28

Y1 - 2019/5/28

N2 - BACKGROUND: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. METHODS: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. RESULTS: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). CONCLUSIONS: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

AB - BACKGROUND: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. METHODS: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. RESULTS: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). CONCLUSIONS: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

KW - myocardial infarction

KW - sodium-glucose transporter 2 inhibitors

KW - type 2 diabetes mellitus

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