DAPA-HF heralds new era of heart failure treatment with dapagliflozin
The sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin significantly reduces the risk of death and hospitalization in patients with heart failure (HF) with reduced ejection fraction (rEF) regardless of whether they have type 2 diabetes mellitus (T2DM), the DAPA-HF trial has shown.
“SGLT2 inhibitors, including dapagliflozin, were previously shown to reduce the risk of HF in patients with T2DM. The DAPA-HF trial investigated whether dapagliflozin is also useful in treating HF, even in patients without T2DM,” said principal investigator Professor John McMurray of the University of Glasgow, Glasgow, UK, at the European Society of Cardiology (ESC) Congress 2019 and World Congress of Cardiology (WCC) 2019.
“The most important finding of the DAPA-HF trial is the benefit of dapagliflozin in patients without diabetes. This is truly a HF treatment and not just a drug for diabetes,” said McMurray.
The DAPA-HF trial recruited 4,744 HFrEF patients with (n=2,139) or without diabetes (n=2,605) from 20 countries. The patients were randomized to receive dapagliflozin 10 mg once daily or placebo, in addition to standard-of-care therapy.
At baseline, a majority of patients in both groups were on a diuretic (93 percent in the dapagliflozin group vs 94 percent in the placebo group) and a beta-blocker (96 percent in both groups). Seventy-one percent and 56 percent of patients in both groups were on a mineralocorticoid receptor antagonist and an angiotensin-converting enzyme inhibitor, respectively, while 28 percent vs 27 percent were on an angiotensin-receptor blocker and 11 percent were on an angiotensin receptor-neprilysin inhibitor (ARNI).
After a median follow-up of 18.2 months, a significant 26 percent relative risk reduction and 4.9 percent absolute risk reduction was observed with dapagliflozin vs placebo in the primary composite endpoint of cardiovascular (CV) death, HF hospitalization and urgent HF visit (16.3 percent vs 21.2 percent; hazard ratio [HR], 0.74; 95 percent confidence interval [CI], 0.65 to 0.85; p=0.00001; number needed to treat, 21).
“Importantly, the benefits were consistent regardless of T2DM status at baseline [HR for T2DM patients, 0.75; 95 percent CI, 0.63 to 0.90; HR for patients without T2DM, 0.73; 95 percent CI, 0.60 to 0.88],” highlighted McMurray. “Consistent benefits were observed across other important subgroups, including in patients with or without ARNI use [HR, 0.75 (95 percent CI, 0.50 to 1.13) and 0.74 (95 percent CI, 0.65, 0.86), respectively].”
Analysis of individual components of the primary endpoint showed significant reductions with dapagliflozin vs placebo in rates of worsening HF events (ie, HF hospitalization or urgent HF visit) (10.0 percent vs 13.7 percent; HR, 0.70; 95 percent CI, 0.59 to 0.83; p<0.001) as well as CV death (9.6 percent vs 11.5 percent; HR, 0.82; 95 percent CI, 0.69 to 0.98; p=0.03).
“Moreover, the risk of all-cause mortality was reduced by 17 percent with dapagliflozin vs placebo [HR, 0.83; 95 percent CI, 0.71 to 0.97; p=0.022],” said McMurray. “Worsening of renal function was noted in 1.2 percent vs 1.6 percent of the patients, respectively [HR, 0.71; 95 percent CI, 0.44 to 1.16; p=0.17].”
In terms of HF symptoms, more patients receiving dapagliflozin vs placebo had improvements as assessed by the Kansas City Cardiomyopathy Questionnaire (mean change from baseline to 8 months, +6.1 vs +3.3; p<0.001; ≥5 points improvement, 58 percent vs 51 percent; odds ratio [OR], 1.15; 95 percent CI, 1.08 to 1.23; p<0.001; ≥5 points deterioration, 25 percent vs 33 percent; OR, 0.84; 95 percent CI, 0.78 to 0.90; p<0.001).
The adverse event (AE) profile was generally comparable between the dapagliflozin and placebo groups. No significant differences were noted for volume depletion (7.5 percent vs 6.8 percent; p=0.4) and renal dysfunction (6.5 percent vs 7.2 percent; p=0.36). Major hypoglycaemia, as well as lower limb amputation and fracture, were infrequent in both groups.
“Dapagliflozin was well tolerated. Rates of treatment discontinuation due to AEs were low in both groups [4.7 percent with dapagliflozin vs 4.9 percent with placebo; p=0.79],” noted McMurray.
“Results of the DAPA-HF trial mark a new era of HF treatment,” said discussant Professor Marco Metra of the University of Brescia, Brescia, Italy. “Notably, the curves of the primary endpoint and worsening HF events diverged early. The HRs of the primary and key secondary endpoints in DAPA-HF were comparable to, if not better than, those in major positive trials of HFrEF pharmacological therapy in recent years.”