In a pre-specified pooled analysis from AstraZeneca’s phase III trial of the diabetes drug Farxiga (dapagliflozin) in patients with heart failure (HF), the medication proved to be the first HF drug to demonstrate mortality benefits for all forms of HF.
HF affects about 64m people worldwide and is associated with significant health problems and risk of death, and is the leading cause of hospitalisation for people 65 and older, reports BioSpace.
The company presented the results at the European Society of Cardiology Congress 2022 in Barcelona last week (26-29 August), while simultaneously publishing it in Nature Medicine. The data demonstrated a drop in risk of cardiovascular (CV) death across pre-specified subgroups, with a mortality benefit with an HF therapeutic in patients with HF across the left ventricular ejection fraction (LVEF) range.
Farxiga is a first-in-class, oral, once-daily SGLT2 inhibitor, a class of drugs originally developed to treat type 2 diabetes. However, the class has demonstrated benefits to patients with chronic kidney and heart disease and helps prevent heart attacks.
“In this patient-level meta-analysis including more than 11 000 patients with heart failure across the full range of ejection fraction, dapagliflozin reduced the risk of both cardiovascular death and heart failure hospitalisation,” said Dr John McMurray, professor of Medical Cardiology and deputy director of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
“These results underpin the valuable role dapagliflozin can play in clinical practice, as we can initiate treatment right away while waiting for ejection fraction to be measured.”
In the pooled analysis, the drug reduced the risk of CV death by 14%, with an absolute risk reduction over the median follow-up of 22 months. It decreased death from any cause by 10% and cut total hospitalisation – first and repeat – for HF by 29%.
It also reduced the composite of death from CV causes, myocardial infarction, or stroke by 10% in patients with HF regardless of LVEF. LVEF is a measurement of the percentage of blood leaving the heart every time it contracts and has several gradations, including HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF) and HF with preserved EF (HFpEF).
In 2021, Farxiga was the company’s primary growth driver when chronic kidney disease (CKD) was added to the label. The drug has been approved in more than 100 countries to improve glycaemic control in adults with type 2 diabetes and for HFreF in patients with and without type 2 diabetes. It received first-in-class approval for CKD in patients with and without type 2 diabetes in the US, European Union, UK, Japan and other countries. The drug brought in $3.005bn in revenue for the year, down 23% compared with the previous year.
If the drug should be approved for a broader treatment of heart failure based on the current results, Ruud Dobber, EVP and president of AstraZeneca’s Biopharmaceuticals Business Unit, said Farxiga’s addressable patient population would jump by 50%.
However, it wouldn’t be without competition for those patients; both Eli Lilly and Boehringer Ingelheim ran clinical studies of their competitive drug Jardiance in similar patients last year.
Eli Lilly reported Jardiance bought in $1.498bn in 2021, up 29% from the previous year.
The study results will probably bring SGLT2 inhibitors to the head of heart failure therapy, said study co-author Scott Solomon, PhD, professor of medicine at Harvard Medical School, Brigham and Women’s Hospital.
Physicians will probably choose Farxiga or Jardiance depending on cost and availability, which will “probably be more important than any potential differences between those therapies”, Solomon said.
Study details
Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER
Pardeep Jhund, Toru Kondo, Jawad Butt, Kieran Docherty, Brian Claggett, Akshay Desai, Muthiah Vaduganathan, Samvel Gasparyan, Olof Bengtsson, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde, Rudolf de Boer, David DeMets, Adrian Hernandez, Silvio Inzucchi, Mikhail Kosiborod, Lars Køber, Carolyn Lam, Felipe Martinez, Marc Sabatine, Sanjiv Shah, Scott Solomon & John McMurray.
Published in Nature on 27 August 2022
Abstract
Whether the sodium–glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and >40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76–0.97; P = 0.01), death from any cause (HR 0.90, 95% CI 0.82–0.99; P = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65–0.78; P < 0.001) and MACEs (HR 0.90, 95% CI 0.81–1.00; P = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient-level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524).
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