Heart Failure with Preserved Ejection Fraction — A Metabolic Disease?

This NEJM editorial explores whether heart failure with preserved ejection fraction (HFpEF) is primarily a metabolic condition rather than a myocardial one. Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF has resisted treatments targeting cardiac load. Patients with HFpEF often present with metabolic comorbidities (e.g., obesity, diabetes), prompting investigation into upstream therapies. The editorial focuses on the STEP-HFpEF trial, which showed that semaglutide—a GLP-1 receptor agonist—yielded significant benefits in obese HFpEF patients: 13% body weight reduction, improved 6-minute walk distance, and enhanced Kansas City Cardiomyopathy Questionnaire scores. NT-proBNP levels fell more than expected despite weight loss, suggesting reduced intracardiac pressures. GLP-1 agonists may work via anti-inflammatory and metabolic pathways, though direct myocardial receptor expression is unclear. The piece contrasts semaglutide’s effects with prior findings on SGLT2 inhibitors and posits HFpEF as a syndrome driven by systemic metabolic and inflammatory disruption, lacking the load–capacity mismatch seen in HFrEF.

This NEJM editorial explores whether heart failure with preserved ejection fraction (HFpEF) is primarily a metabolic condition rather than a myocardial one. Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF has resisted treatments targeting cardiac load. Patients with HFpEF often present with metabolic comorbidities (e.g., obesity, diabetes), prompting investigation into upstream therapies. The editorial focuses on the STEP-HFpEF trial, which showed that semaglutide—a GLP-1 receptor agonist—yielded significant benefits in obese HFpEF patients: 13% body weight reduction, improved 6-minute walk distance, and enhanced Kansas City Cardiomyopathy Questionnaire scores. NT-proBNP levels fell more than expected despite weight loss, suggesting reduced intracardiac pressures. GLP-1 agonists may work via anti-inflammatory and metabolic pathways, though direct myocardial receptor expression is unclear. The piece contrasts semaglutide’s effects with prior findings on SGLT2 inhibitors and posits HFpEF as a syndrome driven by systemic metabolic and inflammatory disruption, lacking the load–capacity mismatch seen in HFrEF.