Incremental, Not Monumental, Win for Empagliflozin in Heart Failure With Preserved Ejection Fraction

John Mandrola, MD


August 28, 2021

At the virtual European Society of Cardiology (ESC) Congress 2021, investigators presented (and published) the EMPEROR-Preserved trial of empagliflozin vs placebo in patients with heart failure with preserved ejection fraction (HFpEF).

We have known for weeks that the trial met its primary endpoint of time to first hospitalization for HF or cardiovascular death.

But after seeing the details, I will make the case that this "positive" trial represents an incremental rather than a monumental gain for cardiovascular medicine.

The EMPEROR-Preserved Trial

The EMPEROR-Preserved investigators screened more than 11,000 patients and randomly assigned nearly 6000 patients with HFpEF to 10 mg daily of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin or to placebo. The main reason for exclusion (nearly 80%) was not having a high enough N-terminal pro–B-type natriuretic peptide level.

The average patient age was 72 years, 45% of patients were women, and one third had a left ventricular ejection fraction (LVEF) of 40% to 50%.  For context, the patients enrolled were similar in terms of HF severity to those in the previous major HFpEF trial, PARAGON-HF. The rate of cardiovascular (CV) death and total hospitalizations for HF in the control arms of the two trials were similar.

After slightly more than 2 years, 13.8% of patients in the empagliflozin group experienced CV death or an HF hospitalization compared with 17.1% of the placebo group. The 3.3–percentage point absolute risk reduction translated to a 21% relative risk reduction. The result was statistically robust with a P value of .003.

A 29% lower rate of hospitalization for HF drove the primary endpoint. The 9% relative risk reduction in CV death did not reach statistical significance. There were nearly identical rates of overall death in the two arms (approximately 14%).

The relative reduction in the primary outcome held up in multiple subgroups, including in patients with and without diabetes. There was a consistent effect across EF—except for a blunting of effect for patients with an LVEF of 60% or greater.

There were essentially no differences in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire.

EMPEROR Pooled Analysis of Renal Outcomes

In a separate presentation, also published as a correspondence in the New England Journal of Medicine, the investigators reported a prespecified pooled analysis of renal outcomes in both EMPEROR HF trials (in patients with reduced or preserved EF). The composite renal outcome included a sustained decrease in estimated glomerular filtration rate (eGFR) of greater than 40%, a decrease in the eGFR to less than 10 to 15 mL/min/1.73 m2, or renal replacement therapy.

The pooled analysis found significant heterogeneity of effects based on LVEF. In EMPEROR-Reduced, renal outcomes were nearly halved with empagliflozin (hazard ratio [HR], 0.51; 95% CI, 0.33 - 0.79) whereas in EMPEROR-Preserved, renal outcomes were similar in both treatment groups (HR, 0.95; 95% CI, 0.73 - 1.24).


The EMPEROR-Preserved trial gets to be the first breakthrough in HFpEF. It boasts a statistically robust result for the primary endpoint, and there were no serious safety signals. These are all positives.

And here is another: the SGLT2 inhibitor class has already proven beneficial for patients with diabetes and chronic kidney disease. Many patients with HFpEF also have these conditions, and the results of EMPEROR-Preserved will further strengthen the indication to use empagliflozin in such patients.

That said, we mustn't let the buzz over something new cloud our thinking.

Lower HF hospitalizations without significant reductions in CV death or overall death must be considered a modest effect. Let's not forget that another medical therapy for HF, carvedilol, reduced overall death by 65% in its seminal trial. Although no one expects new therapies to be this good, the point remains that reducing one reason for a hospital admission is a long way from extending life.

Another signal underscoring the modest effect size is the tally of total hospitalizations. Andrew Foy, MD, from Penn State University, with whom I have collaborated on numerous papers, pointed me to the fact that there wasn't a significant reduction in all-cause hospitalizations (HR, 0.93; 95% CI, 0.85 - 1.01).

His take is that being admitted to the hospital—for any reason—is a bad outcome. And that reducing HF admissions is a meaningful endpoint only if it contributes to a reduction in total hospital admissions.

That's going to be near impossible to show in trials like EMPEROR-Preserved. The number of hospitalizations for HF in the empagliflozin group (407) represents about 16% of the total hospitalizations (2566). The ratio is similar in the control arm.

In other words, for older patients with HFpEF and multiple comorbid conditions, admission for HF represents a very small proportion of their hospital admissions.

Indeed, in this trial of nearly 6000 older patients with symptomatic HF, empagliflozin resulted in just 203 fewer hospitalizations over nearly 2 years. That is akin to the proverbial "drop in the bucket."

There are two other sobering findings from EMPEROR-Preserved:

The lack of improvement in renal outcomes in patients with LVEF greater than 40% makes me think the drug acts as an expensive diuretic rather than a disease-modifying agent. But even if that's the case, it would be worthwhile if the drug improved quality of life. Yet there was no significant improvement in the Kansas City Cardiomyopathy score. 


Regulatory bodies will surely approve empagliflozin for the treatment of patients like those enrolled in EMPEROR-Preserved. That's okay. While the average effects are modest, smart clinicians will likely find select patients who may benefit more: a patient with dyspnea, an LVEF of 41%, and chronic kidney disease, perhaps.

But we shouldn't be overly enthusiastic. The core problem in the treatment of patients with HFpEF is their multimorbidity and competing causes of hospital admission and death. That will always be a problem in older, sicker patients.

The lack of significant improvements in CV death, overall death, renal outcomes, quality of life, and total hospitalizations in EMPEROR-Preserved compels clinicians to be highly selective in the use of this costly drug.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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