Hi, I'm Dr Varun Sundaram, Associate Professor of Medicine at Case Western Reserve University, Cleveland and Section Chief of Advanced Heart Failure at Cleveland VA Medical Centre and part of University Hospital's Harrington Heart and Vascular Institute.

How does the pathophysiology of HFrEF with concurrent obesity potentially create a therapeutic opportunity for GLP-1RAs?

So HFrEF, that is heart failure with reduced ejection fraction, and obesity is kind of different than heart failure with preserved ejection fraction and obesity where GLP-1, multiple trials with GLP-1 receptor agonist have shown to have clinical benefits.

The reason being, GLP-1 receptor agonist can increase heart rate and prior small trials have shown a signal of harm in patients with heart failure with reduced ejection fraction. So it's not the same as HFpEF is not just the efficacy but even safety has to be confirmed in patients with heart failure with reduced ejection fracture.

What was the study design and patient population?

The study is a pharmacoepidemiological study from 170 veteran affairs medical centers in the United States. So we identified among one and a half million diabetic patients close to 190,000 patients with HFrEF and identified those who have prescribed for GLP-1 receptor agonists for diabetes and a comparative group and followed up long-term or immediate follow up of 3.3 years to look for a composite outcome which is heart failure hospitalisation or mortality.

What were the key findings?

We observed that our study cohort was more sicker than the previous trial which tested HFrEF patient populations which is a pre-specific analysis from SELECT. This is a much more sicker HFrEF patient population because, 1: almost twice as number of patients were on loop diuretics in our study population compared to the pre-specific analysis of SELECT, and the heart failure hospitalisation and mortality rates were almost fourfold higher. So clearly a sicker cohort where we were testing the association between GLP-1 receptor use and outcomes.

What we observed was during the immediate follow up of close to 38 months we accrued more than 600 heart failure events. And what we noticed was there was no increased risk of heart failure hospitalisation or mortality with GLP-1 receptor agonists, demonstrating possible safety in this patient population.

But the important thing to note is these are diabetes management doses, and what we observed also was a heterogeneity of treatment effect with increasing body mass index showing that GLP-1 may be working even at diabetes management doses, at those with higher body mass index. A hypothesis generating finding which needs confirmation of randomised evidence.

How do the findings from PRAISE-HFrEF complement what we're learning about GLP-1RAs from other cardiovascular outcome trials like SURMOUNT-CV or FLOW?

The SELECT trial enrolled patients, it was not a heart failure trial where it was a vascular disease trial and they had a pre-specified analysis of patients analysing those who had documented heart failure with reduced ejection fraction. But because it's not a heart failure trial, they did not mandate these heart failure patients to have active heart failure symptoms prior to randomisation.

As a consequence, the event rates in the trial were very low because these patients were less sick or just milder disease. Our patient population was more advanced disease or more sicker: a clinically severe HFREF with obesity. So using a Bayesian approach or Bayesian lens, integrating results from SELECT trial and the PRAISE-HFrEF, we could argue that GLP-1 receptor agonist for treatment of obesity may be safe across the spectrum of heart failure with reduced ejection fraction.

But whether modifying or targeting obesity with GLP-1 receptor agonists is going to modify heart failure outcomes is something we don't know or our study failed to answer that question. That needs a randomised trial.

What are the next steps?

The next step is it's quite imperative that we perform a well-done randomised trial to document safety confirming the SELECT and our study findings, and more so efficacy at weight loss doses in patients with heart failure with reduced ejection fraction and obesity with GLP-1 receptor agonists.