Empagliflozin Shows First Clear Benefit in Hard-to-Treat Heart Failure; 27% Drop in HF Hospitalization Risk

Empagliflozin, part of a drug class called sodium glucose co-transporter 2 (SGLT2) inhibitors, offers clear benefits to patients with an increasingly common type of heart failure, the first time a trial has shown this result after a string of failures.

Results for EMPEROR-Preserved, presented Friday during the European Society of Cardiology (ESC) Congress 2021, showed a 21% overall drop in cardiovascular (CV) death and heart failure hospitalization. It marked the first time a therapy produced a “unequivocal” positive result in heart failure with preserved ejection fraction (HFpEF), a condition that accounts for half of the nation’s 5 million heart failure cases but has largely eluded treatment.

Sold as Jardiance by Boehringer Ingelheim and Eli Lilly, empagliflozin has broken ground before—in 2015, results from the EMPA-REG OUTCOME trial stunned the medical world with news that a drug developed to lower blood glucose in type 2 diabetes (T2D) had also produced CV benefits.

Scientists quickly noticed what was driving the numbers—the steep drop in hospitalizations for heart failure, a perennial cost driver in health systems and a target for reform in Medicare. The race was on to see what else empagliflozin and its competitors in the SGLT2 inhibitor class could do. Benefits have been seen across the cardiometabolic spectrum of diabetes, heart failure, and prevention of renal decline. The EMPEROR trials were launched to study empagliflozin’s benefits in heart failure with preserved and reduced ejection fraction (HFrEF).

A wide range of benefit. Empagliflozin produced results across a wide range of left ventricular ejection fraction (LVEF), up to 65%, with similar results for men and women and whether or not patients had diabetes, according to Stefan Anker, PhD, professor at Charité University, Berlin, Germany. He discussed the results of the EMPEROR-Preserved trial during a press briefing ahead of the opening of ESC Congress 2021.

Anker said the primary end point in CV death and hospitalization for heart failure was driven largely by the 27% reduction in heart failure hospitalization, as the reduction in CV mortality (9%) did not reach significance.

Results were published today in the New England Journal of Medicine,¹ and additional results will be published in coming days in other journals. Details of the EMPEROR-Preserved trial were as follows:

• A total of 5988 patients with LVEF of at least 40% were randomized 1:1 in the empagliflozin and placebo groups; 49% had type 2 diabetes, their average ejection fraction was 54%, and 45% were women. The participants’ average age was 72 years. Patients were receiving standard of care, which for the patients with diabetes often included metformin.
• Over a median of 26.2 months, a primary outcome event occurred in 2997 patients (13.8%) of the empagliflozin groups and 511 of 2991 (17.1%) of the placebo group, for an HR of 0.79 (95% CI, 0.69-0.90; P < .001). “This is a highly significant result,” Anker said.
• The number of hospitalizations (first and recurrent) for heart failure in the empagliflozin group was 407; the number in the placebo group was 541 (HR, 0.73; 95% CI, 0.61-0.88, P < .001).
• The rate of decline of estimated glomerular filtration rate (eGFR) was slower in the empagliflozin group compared with the placebo group (–1.25 vs –2.62 mL/min/1.73 m²/year; P < .0001).
• White patients made up 76.3% of the empagliflozin group and 75.4% of the placebo group; Black patients, 4.4% of the empagliflozin group and 4.2% of the placebo group; Asian patients, 13.8% empagliflozin and 13.7% placebo; other or missing race, 5.5% empagliflozin and 6.6% placebo. Asian patients saw greater benefits than other groups (HR, 0.65).
• Adverse events of genital and urinary tract infections and hypotension were reported more frequently.
• Benefits were seen across prespecified subgroups (LVEF 41% to 49%, 50% to 50%, and 60% and higher), although benefits ebbed as LVEF increased. During presentation of the findings, there was discussion whether most of the benefit accrued to patients who now fit a definition of "mildly reduced" LVEF under ESC Guidelines released hours before EMPEROR-Preserved was announced.
• The number of patients needed to treat to prevent 1 event was 31.
• 23% of patients in both arms of the study stopped treatment for reasons other than death, and investigators said this may have affected the CV death results. However, they also stated that a similar disconnect between the CV death and hospitalization results were seen in a study of sacubitril-valsartan during the same period.

Anker said that empagliflozin has the potential to become the new standard of care in HFpEF; prevalence is increasing about 1% a year, in part due to an aging population.

EMPEROR-Preserved succeeds after nearly 20 years of trials in HFpEF that have failed to produce a significant, positive result, he said. “These results represent the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with heart failure and a preserved ejection fraction,” the findings stated.

“All the previous trials have [shown] between 5% and 14% reductions. And now here we have more than 20%, a 21% reduction—a highly significant result,” he said. “I think this is for the patient with HFpEF that quite often has to go to the hospital, and hospitalizations are dramatically impacting on their life. This is a time to celebrate for them that we now have something that can very strongly reduce the burden of these problems.”

Why did EMPEROR-Preserved succeed where so many other drugs have failed? Milton D. Packer, MD, of Baylor University Medical Center, who last year presented the EMPEROR-Reduced study, was asked if the drug’s unique mechanism of action may play a role—it targets a protein that allows blood sugar to be excreted through the urine and has many other subtle benefits. “We know that heart failure and a preserved ejection fraction can result from myocardial inflammation, and that SGLT2 inhibitors exert powerful anti-inflammatory effects in the heart,” Packer said.

EMPEROR-Pooled and renal outcomes. In a related presentation, published as correspondence in the New England Journal of Medicine,² Packer presented pooled results of renal outcomes of from EMPEROR-Preserved and EMPEROR-Reduced. The combined trials, similar in design, involved 9718 patients who underwent randomization between April 2017 and April 2000.

The HR for serious renal outcomes was 0.51 (95% CI, 0.33-0.79) in the EMPEROR-Reduced trial and 0.95 (95% CI, 0.73-1.24) in the EMPEROR-Preserved trial. The EMPEROR study authors stated that in each trial, “the effect of empagliflozin was consistent across the components of the primary outcome and across all prespecified subgroups, including patients with and patients without diabetes.”

The investigators also found differences in the annualized decline in eGFR between the EMPEROR-Reduced trial than in the EMPEROR-Preserved trial. “Our finding that ejection fraction influences the effects of empagliflozin on major renal outcomes is noteworthy, given that empagliflozin lowered the incidence of hospitalizations for heart failure to a similar extent in the EMPEROR-Reduced and in the EMPEROR-Preserved trials.”

Comparison with other trials. Anker presented a table that outlined how results for EMPEROR-Preserved achieved clear superiority in HFpEF, while other trials fell short, including PARAGON-HF, the CV outcomes trial for sacubitril-valsartan (Entresto, Novartis). This angiotensin receptor–neprilysin inhibitor just missed its end point for superiority in 2019 (Packer was an investigator for that trial).

Earlier this year, FDA granted sacubitril-valsartan an expanded indication to treat an additional group of patients in the range above an LVEF of 40%, based on a combination of studies.

Packer said EMPEROR-Preserved and EMPEROR-Pooled show empagliflozin’s benefits are greater than those of sacubitril-valsartan. The findings demonstrate the benefits of empagliflozin across a broad range of patients,” he said, “specifically those with the ejection fraction of > 60% to 65%.”

Still, when asked, Packer said he would combine use empagliflozin alongside sacubitril-valsartan for patients with HFpEF in certain circumstances.

“If I had a patient with heart failure and preserved ejection fraction, would I use both drugs in combination? The answer is yes,” Packer said. “Remember, these patients are already getting other drugs—they’re getting beta blockers; they're getting mineralocorticoid receptor antagonists. We do use all of these drugs in combination, because we want to maximize benefits.”

Will SGLT2 inhibitors have a class effect in HFpEF? It’s too soon to say, Anker said. Another study, DELIVER, is examining dapagliflozin in heart failure, and a pooled analysis from studies of the SGLT1/2 inhibitor sotagliflozin found benefits in HFpEF, but plans for a dedicated heart failure study lost funding.

An editorial in the New England Journal of Medicine suggests cardiologists will be waiting to see what’s next. “Ultimately, the EMPEROR-Preserved trial should contribute to a change in clinical practice, given the paucity of therapeutic options available for patients with heart failure and a preserved ejection fraction,” wrote Mark H. Drazner, MD.³

But Packer said increasing uptake of empagliflozin or SGLT2 inhibitors generally in the United States will require cooperation from third-party payers. “The major barrier to uptake of SGLT2 inhibitors for heart failure is that third-party payers are reluctant to provide coverage,” he said. “I do not understand their decision not to cover the use of these drugs for use by patients who can benefit from them.”

References

1. Anker SD, Butler J, Filippatos G, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. Published online August 27, 2021. doi:10.1056/NEJMoa2107038
2. Packer MD, Butler J, Zannad F, et al. Empagliflozin and major renal outcomes in heart failure. N Engl J Med. Published online August 27, 2021. doi:10.1056/NEJMc2112411
3. Drazner MH. SGLT2 inhibition in heart failure with a preserved ejection fraction—a win against a formidable foe. N Engl J Med. Published online August 27, 2021. doi:10.1056/NEJMe2113008