PMID- 29898853
OWN - NLM
STAT- In-Process
LR  - 20190414
IS  - 1097-6744 (Electronic)
IS  - 0002-8703 (Linking)
VI  - 200
DP  - 2018 Jun
TI  - The design and rationale for the Dapagliflozin Effect on Cardiovascular Events
      (DECLARE)-TIMI 58 Trial.
PG  - 83-89
LID - S0002-8703(18)30038-3 [pii]
LID - 10.1016/j.ahj.2018.01.012 [doi]
AB  - 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 alpha 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.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Wiviott, Stephen D
AU  - Wiviott SD
AD  - TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, 
      MA. Electronic address: swiviott@partners.org.
FAU - Raz, Itamar
AU  - Raz I
AD  - The Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel.
FAU - Bonaca, Marc P
AU  - Bonaca MP
AD  - TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, 
      MA.
FAU - Mosenzon, Ofri
AU  - Mosenzon O
AD  - The Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel.
FAU - Kato, Eri T
AU  - Kato ET
AD  - Kyoto University Hospital, Kyoto, Japan.
FAU - Cahn, Avivit
AU  - Cahn A
AD  - The Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel.
FAU - Silverman, Michael G
AU  - Silverman MG
AD  - Cardiology Division, Massachusetts General Hospital, Boston, MA.
FAU - Bansilal, Sameer
AU  - Bansilal S
AD  - Zena and Michael A Weiner Cardiovascular Institute, Icahn School of Medicine at
      Mount Sinai, New York, NY.
FAU - Bhatt, Deepak L
AU  - Bhatt DL
AD  - TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, 
      MA.
FAU - Leiter, Lawrence A
AU  - Leiter LA
AD  - Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto,
      Ontario, Canada.
FAU - McGuire, Darren K
AU  - McGuire DK
AD  - Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, 
      TX.
FAU - Wilding, John Ph
AU  - Wilding JP
AD  - Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool,
      United Kingdom.
FAU - Gause-Nilsson, Ingrid Am
AU  - Gause-Nilsson IA
AD  - AstraZeneca Gothenburg, Molndal, Sweden.
FAU - Langkilde, Anna Maria
AU  - Langkilde AM
AD  - AstraZeneca Gothenburg, Molndal, Sweden.
FAU - Johansson, Peter A
AU  - Johansson PA
AD  - AstraZeneca Gothenburg, Molndal, Sweden.
FAU - Sabatine, Marc S
AU  - Sabatine MS
AD  - TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, 
      MA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01730534
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180207
PL  - United States
TA  - Am Heart J
JT  - American heart journal
JID - 0370465
EDAT- 2018/06/15 06:00
MHDA- 2018/06/15 06:00
CRDT- 2018/06/15 06:00
PHST- 2017/08/04 00:00 [received]
PHST- 2018/01/28 00:00 [accepted]
PHST- 2018/06/15 06:00 [entrez]
PHST- 2018/06/15 06:00 [pubmed]
PHST- 2018/06/15 06:00 [medline]
AID - S0002-8703(18)30038-3 [pii]
AID - 10.1016/j.ahj.2018.01.012 [doi]
PST - ppublish
SO  - Am Heart J. 2018 Jun;200:83-89. doi: 10.1016/j.ahj.2018.01.012. Epub 2018 Feb 7.