ESC 2021 – Jardiance blows Entresto out of the water

A 21% reduction in the risk of cardiovascular death or hospitalisation paves the way for Jardiance's approval in heart failure with preserved ejection fraction.

Is there anything the SGLT2 inhibitors cannot do? Lilly and Boehringer Ingelheim’s Jardiance now looks set to add heart failure with preserved ejection fraction to its repertoire, on the back of impressive data from the Emperor-Preserved trial.

The study found a 21% reduction in the risk of cardiovascular death or hospitalisation for heart failure, the composite primary outcome, with Jardiance plus standard of care versus standard of care alone. This far exceeds the 13% benefit seen with Novartis’s Entresto in its HFpEF study, Paragon.

Emperor-Preserved’s lead author, Professor Stefan Anker of Charité University, Berlin, described the data as “very powerful”, highlighting during an ESC press conference that Jardiance is the first drug to have shown an unequivocal benefit on major heart failure outcomes in HFpEF.

Notably, the benefit was consistent across diabetics and non-diabetics.

Full results from Emperor-Preserved (N=5,988, NCT03057951)
  Jardiance + SOC SOC alone Stats
CV death & HF hospitalisations* 415 events 511 events HR=0.79; CI=0.69-0.90; p=0.0003
First HF hospitalisations** 259 hospitalisations 352 hospitalisation HR=0.71; CI=0.60-0.83
CV death** 219 deaths 244 deaths HR=0.91; CI=0.76-1.09
*Primary endpoint; **component of primary endpoint. CI=confidence interval; HR=hazard ratio. Source: ESC & Professor Stefan Anker, NEJM article.

Still, the study, presented today and published simultaneously in the NEJM, was not perfect. The primary endpoint win was driven by a 29% lower risk of heart failure hospitalisation, while the 9% fall in the risk of cardiovascular death did not hit statistical significance.

Professor Anker played down the importance of this miss, stressing that reducing hospitalisations was an important goal in HFpEF patients. “This is a time to celebrate, now we have something that can very strongly reduce the burden of these problems.”

Chairing the session, Dr Carlos Aguiar of Hospital Santa Cruz in Carnaxide, Portugal, agreed that Emperor-Preserved would be a game-changer. “As a physician treating patients with heart failure, I can testify that this is something I feel will definitely be changing our practice, and quite quickly.”

Broad label?

The question now is whether Jardiance can get a broad label in HFpEF, which is characterised by a left ventricular ejection fraction (LVEF) of 50% or higher. Patients with an LVEF of 40% or less are said to have heart failure with reduced ejection fraction, or HFrEF, while an LVEF of 41-49% denotes heart failure with mildly reduced ejection fraction, or HFmrEF.

Emperor-Preserved enrolled patients with an LVEF of 40% or greater, meaning that it captured some patients with HFmrEF. So one concern could be that the benefit was driven by the HFmrEF population rather than true HFpEF patients.

A subgroup analysis found a benefit on the primary endpoint across three different LVEF baskets: <50%, 50-59%, and 60% or more. However, the result was not so clear cut in the over 60% group, where the upper bound of the confidence interval crossing 1.00. As noted in an accompanying editorial in the NEJM: “There may be a decrement of benefit in patients with the highest ejection fractions.”

Still, Jardiance certainly looks more impressive than Entresto in HFpEF, with the usual caveats about cross-trial comparisons.

And despite Paragon narrowly missing hitting statistical significance, Novartis managed to get Entresto approved in some HFpEF patients; namely those with a LVEF “below normal”, with some debate about what this would actually mean in practice.

If Jardiance does manage to score a broader HFpEF label than Entresto, which looks likely, the Lilly/Boehringer drug could address all of the six million heart failure patients in the US; the SGLT2 inhibitor also got the US nod last week for heart failure with reduced ejection fraction.

Evaluate Pharma's consensus predicts Jardiance sales almost doubling by 2026, to sell around $5bn that year. 

It might not be game over for Entresto in HFpEF just yet, though. Professor Milton Packer of Baylor University Medical Center, Dallas, believes that the two drugs could have synergistic effects. “If I had a patient with HFpEF, would I use both drugs in combination? The answer is yes,” he told the ESC press conference.

Class effect

The Emperor-Preserved results also raise the possibility of a class effect in HFpEF with the SGLT2s, particularly after Lexicon’s SGLT1/2 inhibitor sotagliflozin showed a benefit in a pooled analysis of the Soloist and Scored trials.

Professor Anker was cautious about jumping to this conclusion, though. “I think it’s a bit premature to conclude this after one study. We should wait for the next big trial to report next year.”

That “next big trial” is the Deliver study of Astrazeneca’s Farxiga, to which all eyes now turn.

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