Dapagliflozin approved for heart failure across LVEFs

The Medicines and Healthcare products Regulatory Agency (MHRA) has granted a licence extension for FORXIGA (dapagliflozin) in Great Britain for symptomatic chronic heart failure (HF) across the full spectrum of left ventricular ejection fraction (LVEF).

The approval means potentially a further 250,000 patients across the full spectrum of LVEF >40 percent, including HF with reduced, mildly reduced, and preserved ejection fraction (HFrEF, HFmrEF, HFpEF) will be eligible for treatment in England and Wales.

AstraZeneca’s oral dapagliflozin drug

AstraZeneca’s dapagliflozin is an oral, once-daily selective inhibitor of human sodium-glucose co-transporter 2 (SGLT2). It is already approved in Great Britain for the treatment of insufficiently controlled type 2 diabetes (T2D), symptomatic chronic HFrEF and chronic kidney disease (CKD).

“Dapagliflozin has been clinically shown to reduce hospitalisations and cardiovascular deaths in heart failure,” commented Dr John McMurray, Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK. “[The] approval from the MHRA is a significant moment for patients living with heart failure in Great Britain, particularly for those with a preserved ejection fraction, who until now, have had few treatment options,” added Dr McMurray.

Clinical trial data assessing dapagliflozin for chronic heart failure

The MHRA’s decision is based on results from the DELIVER Phase III trial, which showed that dapagliflozin met its primary endpoint in reducing the composite outcome of cardiovascular (CV) death or worsening HF by 18 percent (16.4 percent in the dapagliflozin group and 19.5 percent in the placebo group over a median follow-up of 2.3 years [hazard ratio {HR} =0.82 {95 percent CI 0.73-0.92}; p<0.001, absolute risk reduction (ARR) 3.1 percent]). The treatment effect was consistent across the LVEF range, without evidence of attenuation of effect by LVEF.

In the DELIVER Phase III trial, data was only collected on serious adverse events (AEs) that led to discontinuation of dapagliflozin or placebo and other select AEs, as a result of the extensive safety data on dapagliflozin and established safety profile. Overall, serious AEs, including death, were reported in 43.5 percent of patients (n=1361) in the dapagliflozin group and in 45.5 percent of patients (n=1423) in the placebo group. AEs that led to discontinuation of dapagliflozin or placebo were reported in 5.8 percent of patients (n=182) in the dapagliflozin group and in 5.8 percent of patients (n=181) in the placebo group.

Data analysis of the Phase III trials

Pre-specified, patient level, pooled analysis of the DELIVER and Dapagliflozin And Prevention of Adverse-outcomes in HF (DAPA-HF) Phase III trials demonstrated that dapagliflozin reduced the risk of CV death by 14 percent (HR = 0.86 [95 percent CI 0.76-0.97]; p=0.01, ARR 1.5 percent) over the median follow-up of 22 months, death from any cause by 10 percent (HR = 0.90 [95 percent CI 0.82-0.99]; p=0.03, ARR 1.5 percent), total (first and repeat) hospitalisation for HF by 29 percent (rate ratio [RR] = 0.71 [95 percent CI 0.65-0.78]; p<0.001, ARR 6 percent) and the composite of death from CV causes, myocardial infarction, or stroke by 10 percent (HR = 0.90 [95 percent CI 0.81-1.00]; p=0.045, ARR 1.3 percent) in patients with HF irrespective of LVEF.

Ed Piper, Medical and Scientific Affairs Director at AstraZeneca UK noted: “We’re delighted that the MHRA has authorised dapagliflozin. We continue to work with NICE and the SMC to ensure that patients living with heart failure can access dapagliflozin as quickly as possible.”