Semaglutide or tirzepatide in heart failure across ejection fraction phenotypes: a new-user, active-comparator target trial emulation
E Rawish, F Lemmer, J F Cleland, I EitelAbstract
Background
GLP-1–based therapies improve symptoms in obesity-related HFpEF, but their impact on hard clinical outcomes in heart failure across the left ventricular ejection fraction (LVEF) spectrum remains uncertain, particularly for HFrEF.
Purpose
To evaluate the effectiveness and safety of semaglutide and tirzepatide versus cardiovascular-neutral DPP-4 inhibitors (placebo-proxy comparators) in patients with heart failure (HF) and type 2 diabetes (T2D), overall and stratified by LVEF phenotype.
Methods
We conducted new-user, active-comparator target trial emulations within a large, international, federated, electronic health record network. Adults with HF, T2D and a documented LVEF were included. Initiators of semaglutide (from Jan 2020) or tirzepatide (from May 2022) were 1:1 propensity-score matched to contemporaneous DPP-4 inhibitor initiators (sitagliptin/linagliptin). A head-to-head emulation compared tirzepatide versus semaglutide (from May 2022). The primary endpoint was 12-month time-to-first acute HF event or all-cause mortality. Prespecified LVEF strata included HFrEF (≤40%), HFmrEF (41–49%), and HFpEF (≥50%).
Results
For LVEF matched cohorts, semaglutide (n=3,135 per group) was associated with lower risk of the primary endpoint versus placebo-proxy comparators (19.3% vs 25.0%; HR 0.72, 95% CI 0.64–0.80; p<0.001). Tirzepatide (n=1,523 per group) was also associated with lower risk (14.7% vs 25.3%; HR 0.53, 0.44–0.63; p<0.001). Associations were consistent across all three LVEF phenotypes. Both agents were associated with lower risks of broader MACE composites and progression to end-stage kidney disease. Severe ventricular arrhythmias were not increased. In head-to-head comparison (n=4,394 per group), tirzepatide did not differ significantly from semaglutide (HR 0.89, 0.78–1.02; p=0.094).
Conclusions
In patients with HF and T2D, Initiation of semaglutide and tirzepatide was associated with a substantially lower 12-month risk of acute HF events or death without an arrhythmic safety signal. These findings support prioritising dedicated randomised outcome trials in HF regardless of LV phenotype and comparative trials of GLP-1-based strategies.Figure 1 - Kaplan-Meier EstimatesFigure 2 - Forrest Plot LVEF subgroups