Heart failure and peptides — what the literature actually supports for HFrEF and HFpEF

Why this dossier exists

Heart failure is the condition where peptide pharmacology has produced its biggest positive clinical-trial signal of the 2020s — and also where it has produced one of its cleanest Phase 2 failures. The two readings sit on opposite sides of the same ejection-fraction divide. In heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%), the GLP-1 class has now read out three positive randomized trials in obese populations: Kosiborod et al., NEJM 2023, 389:1069–1084 (STEP-HFpEF), Kosiborod et al., NEJM 2024, 390:1394–1407 (STEP-HFpEF-DM), and Packer et al., NEJM 2025 (epub Nov 2024), SUMMIT trial — the last of which reported a 38% reduction in cardiovascular death or worsening heart-failure events on tirzepatide. In heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%), the same class has produced a neutral-to-concerning signal: the Margulies et al., JAMA 2016, 316:500–508 (FIGHT) liraglutide trial missed its primary endpoint and post-hoc analyses surfaced worsening HF and arrhythmia signals. The cardiolipin-stabilising tetrapeptide elamipretide (SS-31) produced an acute hemodynamic signal in Daubert et al. 2017 that did not survive chronic dosing in the PROGRESS-HF Phase 2.

This dossier walks the peptide and peptide-adjacent evidence base for heart failure across the HFrEF / HFpEF axis, separates the trial-supported signals from mechanism extrapolation, and frames the entire conversation against the small-molecule SGLT2-inhibitor backbone that defines modern heart-failure pharmacology. The honest read across the corpus: tirzepatide's SUMMIT result is the most clinically rigorous positive peptide-class signal in heart failure as of late 2024, and it is restricted to HFpEF in patients with obesity. Almost every other peptide in this conversation sits in mechanism-extrapolation or failed-primary-endpoint territory.