Dapagliflozin reduces heart failure hospitalization in T2D
Dapagliflozin reduced the risk of hospitalization for heart failure (HHF) in patients with type 2 diabetes (T2D) who had established or multiple risk factors for atherosclerotic cardiovascular disease (CVD), according to results of the DECLARE-TIMI 58* trial presented at AHA 2018. However, it did not reduce the incidence of major adverse cardiovascular events (MACE)**.
“Dapagliflozin reduced cardiovascular death and heart failure, was safe with regard to MACE, and appeared to reduce renal events. This was consistent regardless of baseline atherosclerotic disease or heart failure,” said primary investigator Dr Stephen Wiviott from Brigham and Women’s Hospital, Boston, Massachusetts, US.
A total of 17,160 patients (mean age 64 years, 37 percent female) with T2D (HbA1c 6.5–12 percent and creatinine clearance ≥60 mL/min) with established (secondary prevention population; n=6,974) or multiple risk factors for atherosclerotic CVD (primary prevention population; n=10,186) were randomized to receive either the SGLT-2*** inhibitor dapagliflozin (10 mg/day; n=8,582) or placebo (n=8,578). Over the median 4.2-year follow-up period, 1,559 patients experienced MACE, while 913 patients experienced HHF or cardiovascular death. Patients had a mean diabetes duration of 11 years, mean HbA1c 8.3 percent, and mean eGFR# 85 mL/min/1.73 m2, and 41 percent had established CVD.
Despite dapagliflozin demonstrating noninferiority to placebo for MACE risk in the primary safety analysis (hazard ratio [HR], 0.93, 95 percent confidence interval [CI], 0.84–1.03; upper boundary of 95 percent CI <1.3; p<0.001 for noninferiority), there was no significant reduction in MACE incidence between dapagliflozin and placebo recipients (8.8 percent vs 9.4 percent; p=0.17 for superiority). [AHA 2018, LBS.02, abstract 19485; N Engl J Med 2018;doi:10.1056/NEJMoa1812389]
However, dapagliflozin recipients had a 17 percent reduced risk of the composite of HHF and cardiovascular death (4.9 percent vs 5.8 percent, HR, 0.83, 95 percent CI, 0.73–0.95; p=0.005), driven primarily by the reduction in HHF (HR, 0.73), as the risk of cardiovascular death was similar between dapagliflozin and placebo recipients (HR, 0.98).
Patients without established CVD had comparable MACE incidence regardless of whether they received dapagliflozin or placebo (HR, 1.01), while incidence of cardiovascular death and HHF was reduced in dapagliflozin recipients with and without established CVD (HR, 0.83 and 0.84, respectively).
Fewer patients on dapagliflozin experienced renal events (≥40 percent reduction in eGFR to <60 mL/min/1.73 m2, new incidence of end-stage renal disease, or cardiovascular or renal-related death) than those on placebo (4.3 percent vs 5.6 percent, HR, 0.76; p<0.001), while all-cause mortality occurred at a comparable rate between groups (6.2 percent vs 6.6 percent, HR, 0.93; p=0.20).
Treatment-emergent serious adverse events (AEs) were less frequent in dapagliflozin recipients (34.1 percent vs 36.2 percent; p<0.001), though drug discontinuation due to treatment-emergent AEs was more common in this group (8.1 percent vs 6.9 percent; p=0.01).
The rate of major hypoglycaemia was lower among dapagliflozin recipients than those on placebo (0.7 percent vs 1.0 percent; p=0.02) as was bladder cancer (0.3 percent vs 0.5 percent; p=0.02), while dapagliflozin recipients had higher rates of genital infections (0.9 percent vs 0.1 percent; p<0.001) and diabetic ketoacidosis (0.3 percent vs 0.1 percent; p=0.02) than placebo recipients.
“Notably, compared to prior studies, there was no difference in amputation or fracture with dapagliflozin,” said Wiviott.
Zoning in on heart failure prevention
“Heart failure consistently has been one of the most common, if not the most common complication in patients with diabetes,” said study discussant Professor Javed Butler from the University of Mississippi, Mississippi, US. Patients with diabetes who develop heart failure have an exceptionally high risk of mortality, making any strategies to prevent heart failure in this population “a welcome addition”.
“The majority of patients [in this trial] did not have a history of heart failure, so the prevention of new clinical heart failure is notable,” said Wiviott and co-authors.
The three CV outcome trials (EMPA-REG OUTCOME##, CANVAS###, and DECLARE-TIMI 58) suggest the potential of SGLT-2 inhibitors for incident heart failure risk reduction regardless of their impact on MACE among patients similar to those enrolled in the trials, while further research is needed to identify their impact on other populations such as those with T2D and no cardiovascular risk factors, said Butler.
“It [is] imperative for us to include risk reduction for heart failure and progression of chronic kidney disease [CKD] for comprehensive management of these patients and any … improvement efforts for management of patients with diabetes that does not include heart failure and CKD is likely to fall short of the potential benefit for these patients,” he said.
Expanding the use of SGLT-2 inhibitors
According to Wiviott, consistent effects are noted when assessing the three CV outcome trials including a modest reduction in MACE, which appears confined to patients in secondary prevention, as well as robust reductions in heart failure and kidney-related events that was not dependent on baseline CV status.
“This extends the benefit of this class of agents from the secondary prevention realm – patients with established CVD – to patients in primary prevention – those at risk, which is a much bigger population of patients,” he said.