Dapaglifozin ‘DECLARED’ Effective in the Reduction of Heart Failure Hospitalizations in Diabetic Population DECLARE-TIMI 58: Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

The DECLARE–TIMI 58 trial, published in the New England Journal of Medicine and presented at AHA 2018 showed that in patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin was non-inferior for reduction of MACE as compared to placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure.

Dapagliflozin, a selective inhibitor of sodium–glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, had a relatively undefined cardiovascular profile. In the trial, Dr. Stephen D. Wiviott and his colleagues aimed to assess the cardiovascular (CV) safety of this drug in patients with type 2 diabetes mellitus (DM2) and either established CV disease (CVD) or multiple risk factors. A total number of 17,160 patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease were randomized in a 1:1 ratio to receive either dapaglifozin 10 mg (n = 8,582) or matching placebo (n = 8,578). The median duration of follow up was 4.2 years. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m² of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.

In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE. The investigators reported that the primary outcome of major adverse cardiac events (MACE) for dapagliflozin vs. placebo was 8.8% vs. 9.4%, hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03, p < 0.01 for noninferiority; p = 0.15 for superiority. When it came to the secondary outcomes for dapagliflozin vs. placebo, the reduction in HbA1c with dapagliflozin was 0.42%, the rate of CV death or heart failure (HF) hospitalization was 4.9% vs. 5.8% (p = 0.005), HF hospitalization: 2.5% vs. 3.3% (p < 0.005),and  all-cause mortality rates were 6.2% vs. 6.6% (p > 0.05). Additionally, >40% decrease in GFR, end-stage renal disease, or death due to renal or CV causes had rates of 4.3% vs. 5.6% (p < 0.05).Diabetic ketoacidosis was more common with dapagliflozin than with placebo, as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events. The incidence of diabetic ketoacidosis, genital infections and amputation were 0.3% vs. 0.1% (p = 0.02), 0.9% vs. 0.1% (p < 0.001) and 1.4% vs. 1.3% (p = 0.53) respectively.

The results of this trial showcased that dapagliflozin was superior to placebo in the improvement of glycemic control and non-inferior but not superior for reduction of MACE in patients with Type 2 diabetes and high cardiovascular risk. Moreover, there was a reduction in heart failure (HF) hospitalizations, and also a salutary effect on renal outcomes. Unlike canagliflozin, there was no safety signal regarding increased amputations. Wiviot et al. concluded that these are important findings, and more or less consistent with findings noted with other selective inhibitors of sodium–glucose cotransporter 2 (SGLT-2) inhibitors. This trial thus established the CV safety profile of dapagliflozin for use in patients with type 2 DM. Furthermore, the reduction in HF hospitalization was noted even among patients with prior HF and has been noted for the other SGLT-2 inhibitors.

Commenting on the findings of the study, the investigators stated, “The DECLARE–TIMI 58 trial also adds substantially to the literature on current safety concerns for this class of drugs, which are based on relatively sparse previous data. There have been conflicting reports of a possible increased risk of stroke, amputation, and fractures with various SGLT2 inhibitors. We saw no evidence, despite a focused collection of events, of a higher risk of stroke, amputations, or fractures with dapagliflozin than with placebo. Likewise, despite the observation of an excess of cases of bladder cancer in earlier, smaller studies of dapagliflozin, we observed a lower rate of bladder cancer with dapagliflozin than with placebo.”