Loading ...

Empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, did not show significant benefit in reducing a first heart failure (HF) hospitalization or death from any cause in patients at high risk for HF after an acute myocardial infarction (MI), in the randomized EMPACT-MI trial. 

The results were presented April 6 here at the American College of Cardiology (ACC) Scientific Sessions 2024 and simultaneously published online in the New England Journal of Medicine. 

However, a prespecified secondary analysis, also simultaneously published online in Circulation, showed the risks for a first HF hospitalization and total HF hospitalizations were significantly lower with empagliflozin versus placebo among vulnerable patients. 

"If you look at the components of the primary endpoint, there was no significant difference in all-cause mortality," Javed Butler, MD, Baylor Scott & White Research Institute, Dallas, Texas, told attendees. "However, in the secondary analysis, there was a statistically significant 23% relative risk reduction in the first HF hospitalization and a highly statistically significant 33% reduction in total HF hospitalizations (first and recurrent combined) in these patients."

"We certainly showed that starting empagliflozin in this patient population was safe," Deepak Bhatt, MD, MPH, director of Mount Sinai Heart and Valentin Fuster, MD, professor of cardiovascular medicine at the Icahn School of Medicine at Mount Sinai Health System in New York City and an executive committee member for the study, told theheart.org | Medscape Cardiology.

"We had thought there would be a larger effect on hospitalization for HF, but I think what might have happened in the post-acute coronary syndrome population with a high rate of revascularization and evidence-based medical therapy is that left ventricular function improved even in the placebo arm, somewhat blunting the ability of SGLT2 inhibition to provide incremental benefits," said Bhatt. "With longer-term follow-up, perhaps there would have been a larger absolute benefit."

Regardless, Bhatt feels that "for patients with diabetes, it remains an excellent drug to use across the spectrum of risk, including in patients with recent acute coronary syndrome." 

EMPACT-MI was a double-blind, randomized, placebo-controlled trial involving patients hospitalized for an acute MI within 14 days before randomization. At time of enrollment, 57% of patients had congestion requiring treatment and about 78% had a new reduction in left ventricular ejection fraction; 35% met both criteria. 

A total of 3260 patients received 10 mg empagliflozin daily and 3262 received placebo. Seventy-five percent of patients were men, half were over the age of 65, and 31% had diabetes. 

The primary endpoint was a composite of HF hospitalization or death from any cause in a time-to-first-event analysis during a median follow-up of 17.9 months. Overall, 565 patients had a primary endpoint event.

Results showed that empagliflozin did not reduce the risk of the composite primary endpoint event. A first hospitalization for HF or death from any cause occurred in 267 (8.2%) versus 298 (9.1%) of patients in the empagliflozin versus placebo groups, respectively, with incidence rates of 5.9 and 6.6 events per 100 patient-years (hazard ratio, 0.90; 95% CI, 0.76 - 1.06; P = .21). 

However, Butler told attendees, there was a significant 23% relative risk reduction in first HF hospitalization, and for total HF hospitalizations (first and recurrent HF hospitalizations combined) there was a highly significant 33% relative risk reduction. 

Among patients who were not taking HF therapies such as diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor/neprilysin inhibitors at the time of their initial hospital discharge, those taking empagliflozin were significantly less likely to start such therapies within 6 months compared with those receiving placebo.

The safety profile for empagliflozin was consistent with its known safety profile, and no significant differences in risk of renal adverse events compared with placebo were noted.

Researchers also performed a meta-analysis of all HF trials with SGLT2 inhibitors including HF, diabetes, chronic kidney disease, and acute MI, which is in press in The Lancet Diabetes & Endocrinology. 

"The meta-analyses showed about a 29% reduction in risk for first HF hospitalization and a 30% reduction in total HF hospitalizations, results that were completely consistent with what we found in EMPACT-MI," Butler said. "So, the totality of evidence for HF benefit with empagliflozin suggests the benefit of empagliflozin for HF reduction in patients post-acute MI without prior HF."

"Challenging Trial"

"I'm excited because of the totality of evidence," said session panelist James Januzzi, MD. 

EMPACT-MI was "obviously a challenging trial," he added. "However, as a trialist, I see a neutral primary endpoint, but then a really remarkable set of secondary follow-on findings. How do we find a path through these findings, and is there some way to identify those patients where treatment with an SGLT2 inhibitor would potentially be of benefit, despite the overall neutral result of the study?"

Butler acknowledged that he doesn't yet know whether SGLT2 inhibitor use is justified in perhaps some but not all patients at high risk and that the responder analysis may provide answers. 

He noted that the investigators had to deal with many issues during the trial, including COVID, wars, and the fact that outpatient events were not included in the primary endpoint. "However, these results are so consistent that at the least, I'm very comfortable in saying that in patients post-MI the use of empagliflozin reduces the risk of HF," he remarked.

Panelist Michelle Albert, MD, asked how empagliflozin use might be equitably implemented in different patient populations, given the lack of diversity in the trial population with regard to sex and lack of information on race/ethnicity and socioeconomic status. 

Butler agreed that diverse enrollment "is really, really important." Non-White enrollment was only about 17%, and largely made up of Asian patients, he said. Although efforts are being made to increase enrollment among different populations, he said, "this remains a challenge."

"With the growing body of evidence demonstrating the benefits of SGLT2 inhibitors such as empagliflozin, this study adds to the population of patients who may benefit from this drug — those who are particularly vulnerable to heart failure following an acute MI," said Carine Hamo, MD, when commenting on the study for theheart.org | Medscape Cardiology. Hamo is an HF cardiologist at NYU Langone Heart and assistant professor in the Department of Medicine, the Leon H. Charney Division of Cardiology at NYU Grossman School of Medicine in New York City.

"Because the trial did not meet the primary endpoint, the results of the secondary analysis focusing specifically on HF endpoints remain exploratory," she added. 

Furthermore, she said, "Because this trial used a pragmatic study design, the inclusion/exclusion criteria, as well as the data collected, were limited to data that are readily available in standard clinical care. As such, the study did not include collection of mechanistic data that may explain the results. Thus, the mechanism by which empagliflozin reduces heart failure risk following MI remains to be elucidated." 

The EMPACT trial was supported by Boehringer Ingelheim and Eli Lilly. Bhatt and Butler have reported financial relationships with multiple pharmaceutical and biotech companies. Hamo has reported no relevant financial relationships.