CHF patients are divided into two main groups: those with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF), as defined by the measurement of left ventricular ejection fraction, the central measure of left ventricular systolic function. The LVEF cut-off has varied over time, but AHA/ACC/HFSA and ESC guidelines now utilize ≤40% for HFrEF and ≥50% for HFpEF, with a third group in the middle having mildly reduced EF (HFmrEF). Despite similar symptoms and disabilities, HFrEF and HFpEF appear to have features of distinct syndromes, with differing epidemiology, LV morphology and cellular changes, though some have challenged this view. 

Owing to the links between obesity and more serious HFpEF, the prescription weight loss agents semaglutide and tirzepatide could be a boon in this patient population. The STEP-HFpEF trials (one in diabetics and one in non-diabetics) showed that semaglutide was associated with improvements in symptoms, physical limitations, exercise function and weight loss. Consistent improvements were observed irrespective of weight loss in the trial in diabetics, and across the two trials, benefits were found to be consistent across a number of prespecified subgroups, indicating that the mechanism of benefit extends beyond weight loss. Tirzepatide’s SUMMIT trial in obese HFpEF met its primary endpoint and demonstrated a 38% reduction in the primary composite endpoint, which may relate to Mounjaro’s greater weight loss efficacy. Success could additionally help reimbursement in obese HFpEF patients, since coverage for the treatment of obesity itself is not universal.