The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial

Stephen D. Wiviott, Itamar Raz, Marc P. Bonaca, Ofri Mosenzon, Eri T. Kato, Avivit Cahn, Michael G. Silverman, Sameer Bansilal, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, John PH Wilding, Ingrid AM Gause-Nilsson, Anna Maria Langkilde, Peter A. Johansson, Marc S. Sabatine

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background: Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD). Research design and methods: DECLARE–TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n = 6,971) or multiple risk factors for ASCVD (n = 10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of.0231. Conclusion: The DECLARE–TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE–TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.

Original languageEnglish (US)
Pages (from-to)83-89
Number of pages7
JournalAmerican Heart Journal
Volume200
DOIs
StatePublished - Jun 1 2018

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Sodium-Glucose Transporter 2
Symporters
Cardiovascular Diseases
Type 2 Diabetes Mellitus
Hospitalization
Heart Failure
Myocardial Infarction
Safety
Blood Glucose
Placebos
Glycosuria
Glucose
Diuresis
Risk Reduction Behavior
Random Allocation
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Weight Loss
Research Design
Stroke
Blood Pressure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Wiviott, S. D., Raz, I., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., ... Sabatine, M. S. (2018). The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial. American Heart Journal, 200, 83-89. https://doi.org/10.1016/j.ahj.2018.01.012

The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial. / Wiviott, Stephen D.; Raz, Itamar; Bonaca, Marc P.; Mosenzon, Ofri; Kato, Eri T.; Cahn, Avivit; Silverman, Michael G.; Bansilal, Sameer; Bhatt, Deepak L.; Leiter, Lawrence A.; McGuire, Darren K.; Wilding, John PH; Gause-Nilsson, Ingrid AM; Langkilde, Anna Maria; Johansson, Peter A.; Sabatine, Marc S.

In: American Heart Journal, Vol. 200, 01.06.2018, p. 83-89.

Research output: Contribution to journalArticle

Wiviott, SD, Raz, I, Bonaca, MP, Mosenzon, O, Kato, ET, Cahn, A, Silverman, MG, Bansilal, S, Bhatt, DL, Leiter, LA, McGuire, DK, Wilding, JPH, Gause-Nilsson, IAM, Langkilde, AM, Johansson, PA & Sabatine, MS 2018, 'The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial', American Heart Journal, vol. 200, pp. 83-89. https://doi.org/10.1016/j.ahj.2018.01.012
Wiviott, Stephen D. ; Raz, Itamar ; Bonaca, Marc P. ; Mosenzon, Ofri ; Kato, Eri T. ; Cahn, Avivit ; Silverman, Michael G. ; Bansilal, Sameer ; Bhatt, Deepak L. ; Leiter, Lawrence A. ; McGuire, Darren K. ; Wilding, John PH ; Gause-Nilsson, Ingrid AM ; Langkilde, Anna Maria ; Johansson, Peter A. ; Sabatine, Marc S. / The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial. In: American Heart Journal. 2018 ; Vol. 200. pp. 83-89.
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AU - Wiviott, Stephen D.

AU - Raz, Itamar

AU - Bonaca, Marc P.

AU - Mosenzon, Ofri

AU - Kato, Eri T.

AU - Cahn, Avivit

AU - Silverman, Michael G.

AU - Bansilal, Sameer

AU - Bhatt, Deepak L.

AU - Leiter, Lawrence A.

AU - McGuire, Darren K.

AU - Wilding, John PH

AU - Gause-Nilsson, Ingrid AM

AU - Langkilde, Anna Maria

AU - Johansson, Peter A.

AU - Sabatine, Marc S.

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N2 - Background: Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD). Research design and methods: DECLARE–TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n = 6,971) or multiple risk factors for ASCVD (n = 10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of.0231. Conclusion: The DECLARE–TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE–TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.

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