Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. DOI: 10.1056/NEJMoa1911303

The DAPA-HF trial published in New England Journal of Medicine in November 2019 was probably the most important cardiology trial of the last year. After many years of lacklustre progress in the development of new heart failure medication, this trial found that dapagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), which was previously used only for the treatment of diabetes, reduces cardiovascular death, worsening heart failure, and overall mortality when used on top of optimal medical therapy in patients with heart failure with reduced ejection fraction (HFrEF).

The study lasted about 18 months and involved more than 4,700 people with heart failure with reduced EF <40% who were symptomatic in classes II-IV, according to the New York Heart Association (NYHA). The patients were randomised to dapagliflozin or placebo on top of standard care.

The benefit was seen across all subgroups - and most importantly, in patients with diabetes as well as in patients without diabetes. Death from any cause was reduced by 2.3%, which is unheard of in the era of modern medicine, where incremental progress in mortality is typically measured in tenths of a per cent. The primary outcome of cardiovascular death or heart failure was reduced from 21.2% to 16.3%, and cardiovascular death was reduced from 11.5% to 9.6%. There were fewer hospitalisations, fewer urgent clinic appointments for heart failure, and better symptomatic improvement in the dapagliflozin group.

There were some earlier trials with SGLT2 drugs, such as EMPA-REG and CANVAS trials which suggested cardiovascular benefit, but these trials did not investigate specifically patients with HFrEF or patients with and without diabetes. These trials were designed to prove the cardiovascular safety of new diabetic drugs, and unexpectedly, it turned out that SGLT inhibitors were not only safe in cardiac patients, but it appeared that they improved cardiovascular outcomes.

The mechanism of benefit for dapagliflozin is not clear; a reduction in cardiac preload or afterload, a diuretic effect, improved intracellular metabolism or local endocrine effect are all possible.

Dapagliflozin provided the same benefits in patients with and without diabetes, and it is therefore no longer solely a diabetes drug. Patients with HFrEF on dapaglifozin died less, were hospitalised less, and felt better. SGLT2 inhibitors may well become one of the cornerstones of HFrEF treatment.