https://orcid.org/0000-0001-6484-7743
Introduction
Sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated significant cardiorenal benefits in patients with diabetes, heart failure (HF), and chronic kidney disease (CKD). However, adding incremental benefit to the well-established post-myocardial infarction (MI) treatment regimen presents a greater challenge.
EMPACT-MI trial
The EMPACT-MI trial investigated the efficacy and safety of empagliflozin, an SGLT2 inhibitor, in reducing the composite endpoint of HF hospitalization or all-cause mortality when added to standard post-MI therapy.1 The study enrolled acute MI patients with either a newly developed left ventricular ejection fraction (LVEF) <45% or signs and symptoms of congestion requiring treatment, along with one additional HF risk factor. Compared with the DAPA-MI trial, the EMPACT-MI targeted a patient population at a higher risk of developing HF following acute MI to investigate the potential benefits of empagliflozin in a more vulnerable population.2,3
Baseline characteristics and outcomes
The EMPACT-MI trial enrolled over 6500 participants with a mean age of 64 years, among which 75% presented with ST-segment elevation myocardial infarction (STEMI), and 80% had an LVEF <45%. At the 18-month follow-up, the primary composite endpoint of HF hospitalization or all-cause mortality was observed in 8.2% of the empagliflozin group and 9.1% of the placebo group (Hazard ratio 0.90; 95% confidence interval, 0.76–1.06; P = 0.21), with comparable rates of adverse events between the two groups.
Interpretation
SGLT2 inhibitors are known to promote natriuresis and glycosuria, exerting a haemodynamic effect through a reduction in preload and afterload. Consequently, confirming the safety profile of SGLT2 inhibitors in acute clinical settings, including acute coronary syndrome (ACS), provides additional reassurance regarding their use in these scenarios.
The development of HF following ACS is influenced by multiple factors, with timely and successful percutaneous coronary intervention (PCI) being a crucial determinant in minimizing myocardial injury and improving clinical outcomes. In the contemporary era of widespread PCI utilization, novel therapeutic interventions face substantial challenges in demonstrating incremental benefits beyond the established standard of care. The EMPACT-MI demonstrated that early initiation of SGLT2 inhibitor did not have an additive impact on cardiovascular (CV) events. Additional risk factors for HF post-MI include the extent and severity of coronary artery disease, time to PCI, infarct size, baseline LVEF, and comorbidities, and the proposed mechanism of action of SGLT2 inhibitors may offer limited benefits in addressing these specific risk factors. This is in contrast with renin angiotensin aldosterone system inhibitors such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, which have been shown to significantly reduce mortality and HF risk when initiated shortly after MI in patients with reduced ejection fraction or HF.4,5 These benefits were observed on top of standard post-MI therapies at the time these trials were conducted. However, it is important to acknowledge that these studies preceded the introduction of SGLT2 inhibitors and other contemporary cardioprotective agents.
The component of primary composite endpoint, apart from HF, was all-cause mortality. Patients with a history of MI are at an increased risk of experiencing a wide range of CV and non-CV events, such as malignancies, cardiac arrhythmias, stent thrombosis, recurrent MI, and infections. The results of the EMPACT-MI trial further emphasize that SGLT2 inhibitors do not provide clear benefits in preventing these consequences. Notably, the secondary composite endpoint, which consisted of HF hospitalization and CV death and accounted for the competing risk of HF, also yielded neutral results. Although proponents of SGLT2 inhibitor therapy might emphasize the observed reduction in HF events, consistent with findings from previous trials, this subanalysis should be interpreted cautiously, considering the null outcome in the primary trial and the relatively small contribution of HF events to the primary endpoint.
While the DAPA-MI and the EMPACT-MI have demonstrated the safety of initiating SGLT2 inhibitor therapy within 10 days of MI onset, the lack of additional efficacy suggests that the timing of SGLT2 inhibitor initiation in the acute phase of ACS may not confer significant benefits beyond the established treatment regimen. However, the safety profile of early SGLT2 inhibitor administration in AMI patients is reassuring and may support its use in this population, particularly in those with comorbidities such as diabetes, and/or HF, and/or CKD, where SGLT2 inhibitors have consistently proven cardiorenal benefits (Figure 1). Further research is warranted to explore the potential long-term effects of early SGLT2 inhibitor initiation in AMI patients and to identify subgroups that may derive greater benefit from this approach.
Sodium–glucose cotransporter 2 inhibitors should be continued or initiated in patients with heart failure, chronic kidney disease, or diabetes.
Finding the optimal timing for initiating any drug in an acute setting can be challenging, as it depends on various factors, including the patient's recovery status and individual characteristics. The DAPA-MI and EMPACT-MI trials have provided valuable insights; these trials have demonstrated that there is no urgent need to rush the initiation of SGLT2 inhibitors immediately following an MI, despite some therapies being most effective when initiated within a specific timeframe in acute settings. Instead, healthcare providers should adopt a more measured approach, carefully considering each patient's unique clinical profile, risk factors, and comorbidities when deciding on the optimal timing for SGLT2 inhibitor initiation post-MI.
Conclusion
In the era of widespread PCI, the complex nature of post-MI HF risk presents significant challenges for novel therapies aiming to provide incremental benefits. The EMPACT-MI trial showed that the established benefits of SGLT2 inhibitors in other CV populations did not extend to the post-MI setting. While safe to initiate post-MI, the lack of clear benefit suggests a need for a more individualized approach to SGLT2 inhibitor use, considering patient-specific risk factors and comorbidities.
Conflict of interest: E.T.K. reports receiving lecture fees from Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly Japan KK, Ono Pharmaceutical, Tanabe-Mitsubishi, research fund from Ono Pharmaceutical, and Tanabe-Mitsubishi, outside of the current work.
