Glucagon-like Peptide-1-based and Emerging Cardiometabolic Therapies in Heart Failure with Preserved Ejection Fraction: Linking Molecular Mechanisms to Clinical Outcomes.

Narrative review examining pathophysiology and clinical evidence of GLP-1RAs in HFpEF

“This review examines the pathophysiological basis of HFpEF within the cardio-renal-metabolic continuum, appraising the clinical evidence, benefits and limitations of GLP-1RAs in HFpEF and discussing future directions including phenotype-directed therapy, mechanism-based combination strategies and next-generation molecules.”

Patients with heart failure with preserved ejection fraction (HFpEF), often with comorbidities such as obesity, type 2 diabetes, and chronic kidney disease

“Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome driven by frequent coexistence of cardio-renal-metabolic comorbidities.”

Varies by cited trial; largest pooled analysis included 3,743 patients

“the largest pooled individual patient-level analysis of semaglutide in HFpEF to date, encompassing 3,743 patients from the SELECT, FLOW, STEP-HFpEF and STEP-HFpEF DM trials, showed that semaglutide reduced the composite of CV death or worsening HF events by 31% and worsening HF events alone by 41%.”

Varies by cited trial; some analyses noted short follow-up duration

“In addition, the relatively short follow-up duration of major RCTs investigating GLP-1RAs in HFpEF may be insufficient to fully capture the long-term impact of these therapies on hard outcomes, recurrent HF hospitalisation and HFpEF progression.”

GLP-1RAs improved HF symptoms, physical limitation, and exercise capacity in patients with HFpEF and obesity

“The STEP-HFpEF and STEP-HFpEF DM trials showed that 2.4 mg semaglutide once weekly significantly improved HF symptoms, physical limitation and exercise capacity compared with placebo in patients with HFpEF and obesity, including those with T2D.”

GLP-1RAs reduced the risk of cardiovascular death or worsening heart failure events

“the largest pooled individual patient-level analysis of semaglutide in HFpEF to date, encompassing 3,743 patients from the SELECT, FLOW, STEP-HFpEF and STEP-HFpEF DM trials, showed that semaglutide reduced the composite of CV death or worsening HF events by 31% and worsening HF events alone by 41%.”

Tirzepatide lowered the risk of a composite of death from cardiovascular causes or worsening heart failure

“the SUMMIT trial showing that tirzepatide lowered the risk of a composite of death from CV causes or worsening HF by 38% compared to placebo.”

Questions remain regarding long-term cardiovascular outcomes, consequences of treatment discontinuation, and potential loss of muscle mass

“Nevertheless, questions remain regarding the long-term impact on cardiovascular outcomes, consequences of discontinuing treatment and the potential loss of muscle mass.”