Empagliflozin to prevent worsening of left ventricular volumes and systolic function after myocardial infarction

Carberry, Jaclyn Elizabeth (2025) Empagliflozin to prevent worsening of left ventricular volumes and systolic function after myocardial infarction. PhD thesis, University of Glasgow.

Abstract

Background

Heart failure following an acute myocardial infarction (MI) is associated with significant morbidity and mortality, making its prevention a key therapeutic goal. Progressive adverse ventricular remodelling, characterised by ventricular dilation and declining systolic function, is a key precursor to the development of heart failure after MI. Early reperfusion therapy and medications that reduce mortality and heart failure post-MI, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers, also prevent adverse remodelling. The mineralocorticoid receptor antagonist (MRA) eplerenone improved outcomes post-MI but showed a significant anti-remodelling effect only after adjusting for baseline covariates. Sacubitril/valsartan did not reduce the risk of developing heart failure or cardiovascular mortality in high-risk post-MI patients and had minimal impact on remodelling. Sodium-glucose co-transporter 2 (SGLT2) inhibitors lower the risk of heart failure progression and mortality in patients with chronic heart failure across all ranges of left ventricular ejection fraction (LVEF). One of their key mechanisms of benefit in heart failure with reduced ejection fraction (HFrEF) is a positive effect on ventricular remodelling. Empagliflozin did not significantly reduce the primary outcome of heart failure hospitalisation or all-cause mortality in high-risk post-MI patients, but did lower the incidence of first and total heart failure hospitalisations and other adverse heart failure events. Whether this is related to a remodelling effect remains uncertain. In lower-risk post-MI patients, dapagliflozin improved cardiometabolic outcomes but did not significantly impact the composite outcome of cardiovascular death or heart failure hospitalisation. I conducted the EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS-MI) randomised, placebo-controlled trial, which was designed to test the hypothesis that empagliflozin, when added to standard care, would mitigate adverse left 3 ventricular remodelling in high-risk post-MI patients, as assessed using cardiovascular magnetic resonance (CMR) imaging.

Aims and methods

The aim of the EMPRESS-MI trial was to examine the effect of empagliflozin on left ventricular remodelling in patients with left ventricular systolic dysfunction after an acute MI using the gold-standard method, CMR. I performed a randomised, placebo-controlled trial comparing empagliflozin 10mg once daily with placebo, in addition to standard care, in patients within 12 hours and 14 days of an acute type 1 MI and an LVEF<45% by CMR. Key exclusion criteria were a history of HFrEF or contraindications to SGLT2 inhibitors. Patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 (measured using the modification of diet in renal disease formula) were excluded. Patients with permanent or persistent atrial fibrillation or an implanted cardiac device were excluded to avoid potential CMR image degradation. The primary outcome was the change in left ventricular end-systolic volume index (LVESVI) from baseline to 24 weeks as measured by CMR. The secondary outcomes, measured as change from baseline to 24 weeks, were: left ventricular end-diastolic volume index (LVEDVI), LVEF, left atrial volume index (LAVI), left ventricular mass index (LVMI), N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I (hs-TnI), and infarct size measured using CMR. Exploratory outcomes included the change in biomarkers relevant to the actions of empagliflozin (uric acid, glycated haemoglobin, and haematocrit), kidney function, and body weight. I also examined the relationship between intramyocardial haemorrhage (IMH) and left ventricular remodelling and the effect of empagliflozin.

Results

In 104 patients included in the final analysis set, mean±standard deviation age was 63.0±11.2 years and 90 (86.5%) patients were male. The median time from MI to randomisation was 3.0 days (interquartile range 2.0-5.0). 92 (88.5%) patients had an ST-elevation MI (STEMI) and 12 (11.5%) had a non-STEMI (NSTEMI). 83 (79.8%) MIs were in the anterior location. Nearly all patients (103 4 [99.0%]) had percutaneous coronary intervention (PCI) or thrombolysis. At randomisation, 97 (93.2%) patients were taking an ACE inhibitor or an ARB, 89 (85.6%) a beta blocker, 66 (63.5%) an MRA, and 30 (28.8%) were on a loop diuretic. 46 (44.2%) patients received a loop diuretic at any point during the index admission before randomisation. The mean LVEF by echocardiography was 35.0±4.9% and by CMR was 34.8±6.0%. In the placebo group, LVESVI decreased by 7.8±16.3 mL/m2, LVEDVI did not change (-0.3±18.7 mL/m2) and LVEF increased by 8.5±7.4% from baseline to 24 weeks. Empagliflozin had no effect compared with placebo on the change in LVESVI from baseline to 24 weeks; adjusted between-group difference 0.3 mL/m2 (95% confidence interval [CI] -5.2 to 5.8); P=0.92. Empagliflozin had no effect on the change in LVEDVI, LVEF, LAVI, LVMI, NT-proBNP, hs-TnI or infarct size but did increase haematocrit (P=0.006) and reduced uric acid (P=0.006) and body weight (P=0.006). At baseline, of 93 patients with complete data, 45 (48.4%) patients had IMH and 48 (51.6%) did not. In patients with IMH, LVESVI did not change between baseline and 24 weeks whereas in patients without IMH LVESVI decreased (-0.9±11.4 mL/m2 vs. 14.7±14.7 mL/m2; P<0.001). In patients with IMH, LVEDVI increased whereas in patients without IMH LVEDVI decreased (9.1±12.7 mL/m2 vs. - 7.8±16.8 mL/m2; P<0.001). LVEF improved in patients with and without IMH but to a lesser degree in those with IMH (7.4±7.1% vs. 10.7±7.7%; P=0.004). Empagliflozin had no effect on remodelling in patients with and without IMH at baseline.

Conclusion

In patients with left ventricular systolic dysfunction after an acute MI treated with contemporary reperfusion and medical therapy, the addition of empagliflozin to standard care did not have any effect on improving left ventricular volumes or function compared with placebo, and did not reduce biomarkers of left ventricular wall stress (NT-proBNP) or myocardial injury (hs- TnI). Progressive adverse cardiac remodelling did not occur in the majority of patients.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: Docherty, Dr. Kieran, Petrie, Professor Mark and Berry, Professor Colin
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85590
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 13 Nov 2025 15:32
• Last Modified: 13 Nov 2025 15:32
• Thesis DOI: 10.5525/gla.thesis.85590
• URI: https://theses.gla.ac.uk/id/eprint/85590

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