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

Am Heart J. 2018 Jun;200:83-89. doi: 10.1016/j.ahj.2018.01.012. Epub 2018 Feb 7.

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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Benzhydryl Compounds* / administration & dosage
  • Benzhydryl Compounds* / adverse effects
  • Benzhydryl Compounds* / pharmacokinetics
  • Cerebral Infarction / diagnosis
  • Cerebral Infarction / prevention & control
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / diagnosis
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / metabolism
  • Diuresis / drug effects
  • Drug Monitoring / methods
  • Female
  • Glucosides* / administration & dosage
  • Glucosides* / adverse effects
  • Glucosides* / pharmacokinetics
  • Heart Failure* / diagnosis
  • Heart Failure* / mortality
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics
  • Male
  • Middle Aged
  • Myocardial Ischemia / diagnosis
  • Myocardial Ischemia / prevention & control
  • Risk Factors
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacokinetics
  • Treatment Outcome

Substances

  • 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
  • Benzhydryl Compounds
  • Glucosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors

Associated data

  • ClinicalTrials.gov/NCT01730534