A Broken Heart: Empagliflozin Falls Flat after Acute Myocardial Infarction

Authors:
Amy Hu, PharmD
Kathleen Pincus, PharmD, BCPS, BCACP, CDCES

Reviewers:
Kelsey Norman, PharmD, BCCP, BCACP, BCPS
John Shilka, PharmD, BCPS, BCACP
Carrie Yu, PharmD

Citation: Butler J, Jones WS, Udell JA, et al. Empagliflozin after Acute Myocardial Infarction. N Eng J Med. 2024;390(16):1455-1466. 

The Problem

Heart disease has killed more Americans since 1950 than any other health condition.¹  Despite advances in the management of acute myocardial infarction (MI), up to 38% of patients will experience signs of heart failure (HF).  Many will have a reduced left ventricular ejection fraction (LVEF), leading to increased mortality and, long-term, HF complications.² Sodium-glucose cotransporter 2 (SGLT2) inhibitors have well-documented cardiovascular benefits and are indicated for the treatment of HF, chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM).^3,4 However, data regarding their usefulness after an acute MI are limited.

What’s Known

Myocardial infarction includes ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), both of which are managed with a combination of procedural intervention and pharmacotherapy. The American College of Cardiology/American Heart Association 2013 STEMI and 2014 NSTEMI guidelines recommend percutaneous coronary intervention (PCI) alongside early initiation of beta-blockers, dual-antiplatelet therapy (aspirin plus a P2Y12 inhibitor), and a high-intensity statin. Early initiation of an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker if intolerant and add-on mineralocorticoid receptor antagonists are also strongly recommended in higher-risk patients, especially those with LVEF ≤40%. These guideline-recommended treatments have several compelling benefits, reducing mortality and preventing recurrent cardiovascular events.^5,6

In contrast, previous trials of SGLT2 inhibitors use in this population have been inconclusive. The DAPA-MI trial demonstrated positive outcomes in a win-ratio analysis of a series of seven hierarchal composite outcomes (death, hospitalization for heart failure [hHF], nonfatal MI, atrial fibrillation/flutter, T2DM, New York Heart Association Functional Classification at last visit, and body weight decrease of ≥5% at last visit) in adults with MI and impaired LVEF (win ratio 1.34, 95% confidence interval [CI] 1.20 to 1.50; p<0.001). However, the original intended primary outcome of time to cardiovascular death and hHF (the primary outcome was changed during a blinded interim analysis due to a small number of events) was not significantly reduced (HR: 0.95, 95% CI 0.64-1.40). This trial excluded patients with baseline diabetes or HF and was only conducted in Sweden and the United Kingdom, perhaps limiting its generalizability.⁷

What’s New

The EMPACT-MI study was an international randomized controlled trial that tested empagliflozin on a primary composite outcome of all-cause death and hHF in adults following an acute MI who were at risk of HF.⁸ Patients hospitalized for an acute MI with either a newly developed LVEF <45% or signs and symptoms of congestion prompting treatment received either empagliflozin 10mg daily or placebo plus standard of care within 14 days after admission. Patients also needed to have at least one additional risk factor associated with the primary outcome, such as age ≥65 years, LVEF <35%, history of MI, estimated glomerular filtration rate (GFR) <60 mL/min/1.73m², or high-risk comorbid conditions (e.g., atrial fibrillation, T2DM). Patients with a previous diagnosis of HF or who planned to take SGLT2 inhibitors were excluded.

Table 1: Baseline Characteristics

Characteristic	Empagliflozin Group (N=3260)	Placebo Group (N=3262)
Age – year (SD)	63.6 (11.0)	63.7 (10.8)
Female sex	24.9%	24.9%
White race (patient-reported)	83.7%	83.4%
Revascularization procedure for the index MI	89.3%	89.2%
Lowest LVEF
≤25%	3.9%	3.9%
≥25 to <35%	22.1%	21.4%
≥35 to <45%	52.9%	52.6%
≥45 to <55%	13.4%	14.3%
≥55%	7.0%	6.9%
Signs and symptoms of congestion requiring treatment	56.8%	57.1%
Cardiovascular disease history
Previous MI	11.9%	14.1%
Atrial fibrillation	11.0%	11.1%
T2DM	31.7%	32.1%
Hypertension	69.4%	69.8%

Participants were followed for a median of 17.9 months. Empagliflozin did not significantly decrease the time-to-event for hHF or death (HR: 0.90, 95% CI: 0.76-1.06, P=0.21). See Table 2 for additional results.

Table 2: Primary and Secondary Outcomes* 

Endpoint	Empagliflozin Group (N=3260)	Placebo Group (N=3262)	Effect  (95% CI)^
Primary composite endpoint
First hHF or death from any cause	8.2%	9.1%	0.90 (0.76-1.06)
First hHF	3.6%	4.7%	0.77 (0.60-0.98)
Death from any cause	5.2%	5.5%	0.96 (0.78-1.19)
Key secondary endpoints
Total number of nonelective hospitalizations for any cause or death from any cause, n	998	1138	0.87 (0.77-1.0)#
Total number of hospitalizations for MI or death from any cause, n	276	274	1.06 (0.83-1.35)#
Other secondary and exploratory endpoints
Death from CV causes, n (%)	132 (4.0)	131 (4.0)	1.03 (0.81-1.31)
Total number hHF, n	148	207	0.67 (0.51-0.89)#

Given the established safety profile of empagliflozin, the investigators only collected serious adverse events and special adverse events. The rate of serious adverse events was similar in the two groups (23.7-24.7%) and 3.8% of patients in both groups discontinued the assigned treatment due to an adverse event. Reported special adverse events that occurred more frequently in the empagliflozin group compared to placebo included ketoacidosis (0.05 events per 100 patient-years vs 0.02), lower limb amputation (0.19 vs. 0.11), and hepatic injury (0.19 vs. 0.05).

Our Critical Appraisal

The findings from this study demonstrate that empagliflozin, and likely SGLT2 inhibitors as a class, do not significantly reduce all-cause death, but may decrease the incidence of hHF following acute MI. The strengths of this study include wide enrollment of patients who may benefit from treatment post-MI based on a high risk of HF, without excluding patients with common comorbidities. Unlike DAPA-MI, nearly a third of patients in EMPACT-MI had T2DM. Most participants were already on at least one guideline therapy at baseline (e.g., angiotensin antagonist, beta-blocker, statin, dual antiplatelet therapy) and there was similar adherence to study regimens in both arms. Consistent with contemporary practice, nearly 90% of participants had revascularization for MI with a median time from diagnosis of 0 days (IQR: 0-0). The investigators used remote follow-up via telephone or Web-based applications, and this resulted in a very high rate of study follow-up (99%).

Limitations include a short follow-up timeframe compared to most other landmark SGLT2 inhibitor trials. A small but meaningful percentage (7.2%) of patients in the placebo group initiated open-label SGLT2 inhibitors in the follow-up. Similar to DAPA-MI, there was a lower rate of primary events than expected, which necessitated an increase in target enrollment. This was also complicated by the COVID-19 pandemic and regional wars that took place when the trial was conducted from 2020 to 2023. 

Prior to this trial, it was reasonable to expect SGLT2 inhibitors to benefit patients at risk of HF following an MI, similar to the current use of ACEi.  In historical trials in the 1990s, ACEi use post-MI significantly reduced all-cause death and hHF. However, the differences in outcomes, comparing ACEi and SGLT2 inhibitor trials, may be related to the enrollment of patients with more reduced LVEF (e.g., ≤40%) and the frequency of PCI.  In the 1990s, PCI was not performed as frequently as present day.^2,9

It is interesting to speculate whether the results would have been different had major adverse cardiovascular events (MACE) been used as the primary composite outcome. All-cause death and hHF are relevant clinical endpoints, but MACE has been commonly used in other post-MI trials.  

The Bottom Line

The current body of evidence suggests that there is a marginal benefit of adding SGLT2 inhibitors to current guideline-recommended treatments in post-MI in patients at risk for HF. This may be because the incremental benefit of SGLT2 inhibitors is relatively small in an age of nearly universal PCI. It is uncertain whether the benefits of SGLT2 inhibitors would be realized over a longer time horizon (e.g., five years). Nonetheless, given their positive safety profile and approved indications in T2DM, CKD, and HF, the SGLT2 inhibitors can still be considered in many patients – but there is no urgency to initiate therapy (e.g., within 24 hours) following an MI.

The Key Points

• Patients with an acute MI and newly reduced LVEF or symptoms of HF are at nearly double the risk of death and at much higher risk of hospitalization for HF
• Empagliflozin did not improve mortality when added on to guideline-recommended therapies and did not significantly reduce a composite endpoint of time to all-cause death and hHF in patients after an MI with reduced LVEF or signs of congestion 
• SGLT2 inhibitors, like empagliflozin, are likely useful in patients who have  approved indications for an SGLT2 inhibitor, but there is not an urgent need to initiate them after an MI.

FINAL NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Board Prep and Recertification Program.  To learn more, visit the APhA Geriatric Board Prep and Recertification website and sign up for the Evidence-Based Practice Series.

References