Should SGLT2 inhibitors be prescribed after myocardial infarction with left ventricular dysfunction?

Therapeutic

Published on 21 jan 2025Lecture 6 min

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study evaluated the effect of dapagliflozin in 4,744 patients with heart failure with reduced ejection fraction, with or without type 2 diabetes, and showed that dapagliflozin in addition to standard treatment reduced the occurrence of heart failure and/or cardiovascular death by 26% (HR: 0.74; 95% CI 0.65 to 0.85; p < 0.001)(1). These results were found similarly in diabetic and non-diabetic patients (HR: 0.75, 95% CI 0.63-0.90 and HR: 0.73, 95% CI 0.60-0.88, respectively )(2). The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPERORReduced) study evaluated the effect of empagliflozin in 3,730 patients with chronic heart failure with reduced ejection fraction, with or without type 2 diabetes, and showed that empagliflozin reduced the risk of heart failure and/or cardiovascular death by 25% (HR: 0.75; 95% CI 0.65 to 0.86; p < 0.001)(3). The effect of empagliflozin on the primary endpoint was consistent, regardless of subgroup (including diabetic/non-diabetic). Several distinct mechanisms help explain the cardioprotective effects of iSGLT2(4-7): 1) the improvement of ventricular loading conditions secondary to the reduction of preload (mediated by osmotic diuresis and natriuresis) and afterload ( potentially produced by lowering arterial pressure and stiffness); 2) the use of more efficient energy substrates (cardiac ketones, in particular β-hydroxybutyrate); 3) direct inhibition of the sodium/hydrogen (Na+/H+) exchanger in the myocardium, resulting in reduction (or reversal) of cardiac damage, hypertrophy, fibrosis, remodeling and systolic dysfunction ; 4) reduction of left ventricular mass and improvement of diastolic function through inhibition of cardiac fibrosis; 5) improvement of endothelial function; and, 6) stimulation of increased glucagon secretion, which potentially improves cardiac performance by increasing cardiac index and “fuel” availability or decreasing peripheral vascular resistance(7). Finally, the renal protection conferred by iSGLT2 is also relevant for all patients with heart failure(7). Surprisingly, iSGLT2 did not demonstrate any benefit in the occurrence of major cardiovascular events in patients treated for myocardial infarction with left ventricular dysfunction. The DAPA-MI study evaluated the efficacy and safety of dapagliflozin (versus placebo) in 4,017 non-diabetic patients without known chronic heart failure (including 72% with ST segment elevation)(8). A win ratio analysis was used taking into consideration the following events: death, hospitalization for heart failure, non-fatal myocardial infarction, atrial fibrillation/flutter, onset of type 2 diabetes, evolution of the functional classification of the New York Heart Association (NYHA), body weight decreased by 5% (or more). The results of this study are in favor of dapagliflozin, but only on cardiometabolic criteria (win ratio: 1.34; 95% CI, 1.20 to 1.50; p < 0.001). Cardiovascular event rates were low and differences between groups were not statistically significant. The EMPAgliflozin on Hospitalization for Heart Failure and Mortality in Patients with aCuTe Myocardial Infarction (EMPACT-MI) study evaluated the efficacy and safety of empagliflozin compared to placebo in 3,260 patients with myocardial infarction in Previous 14 days (75% ST-segment elevation) with left ventricular ejection fraction (LVEF) of less than 45% and at risk of developing heart failure (with predefined enrichment criteria)(9). Treatment with empagliflozin did not show a reduction in the risk of occurrence of the primary endpoint (first hospitalization for heart failure and/or death from all causes) compared to placebo (5.9% versus 6.6%; HR: 0.90; 95% CI, 0.76 to 1.06). Similarly, rates of major secondary events did not differ significantly between the two groups. No safety issues were identified in either trial. All this therefore suggests that iSGLT2 can be prescribed without fear after myocardial infarction with left ventricular dysfunction, even if the clinical benefit in this specific context is not clearly established. Recovery of left ventricular function during the first weeks in the majority of these patients could explain the lack of clinical benefit. Previously, the EMMY (Impact of Empagliflozin on Cardiac Function and Biomarkers of Heart Failure in Patients with Acute Myocardial Infarction) trial demonstrated that patients who received empagliflozin after a myocardial infarction had reduced concentrations of natriuretic peptides, a discreet improvement in LVEF and a modest reduction in cardiac volumes(10). However, this trial was not designed to evaluate clinical events. However, these data suggest that iSGLT2 could improve cardiac function and thus reduce the risk of major long-term cardiovascular events. Patients with reduced LVEF following myocardial infarction are at risk of negative cardiac remodeling that may lead to the development of heart failure and death. Early addition of an iSGLT2 to standard therapy could delay or prevent this adverse remodeling in these patients. The EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS-MI) trial evaluated the effect of empagliflozin on cardiac remodeling by MRI in 105 patients with myocardial infarction with impaired LVEF (11). The primary endpoint, defined by the change in the left ventricular endosystole volume index at 24 weeks, did not show a significant difference between the two groups (empagliflozin: -8.3 ± 13.5 mL/ m2; placebo: -7.8 ± 16.3 mL/m2; difference: 0.3 mL/m2; 95% CI -5.2 to 5.8; 0.92). Furthermore, no significant differences were observed between empagliflozin and placebo in secondary outcomes, including left ventricular end-diastolic volume index and LVEF. Finally, the DAPA PROTECTOR study is currently evaluating the effectiveness of dapagliflozin (versus placebo) on systolic function and left ventricular remodeling in echocardiography at 6 months in 450 patients with myocardial infarction with an LVEF < 45% (figure 1 ; NCT05764057). Two criteria will make it possible to evaluate independent and powerful predictors of mortality after a heart attack: 1) systolic function, measured by the change in LVEF between the start of the study and the sixth month (± 1 month) and 2) left ventricular remodeling, assessed by the change in atrial volume (LAV) between the start of the study and the sixth month (± 1 month). Figure 1. DAPA PROTECTOR study. To the question “should iSGLT2 be prescribed after a myocardial infarction with left ventricular dysfunction?” », no clinical trial has to date demonstrated obvious clinical benefits. The benefit of early introduction of iSGLT2 post-infarction in these patients is therefore questionable, especially since a large proportion of them will regain almost normalized left ventricular function at three months. The introduction of an iSGLT2 for patients still presenting left ventricular dysfunction at this 3-month re-evaluation is then justified (level IA recommendation). It does not seem harmful to wait this time to introduce an iSGLT2. On the other hand, for patients in whom an iSGLT2 was introduced during hospitalization (due to left ventricular dysfunction), but who have since normalized their LVEF, the continuation of this long-term treatment must be reconsidered, in particular in the absence of diabetes, renal failure or heart failure. Links of interest (expertise, advice and training activities): Abbott, Amgen, AstraZeneca, BMS, Bayer, Biotronik, Boehringer Ingelheim, MSD, Novartis, Pfizer, Sanofi, Saint Jude Medical, Servier, Vifor Pharma.