Key result
Semaglutide linked to ~28% lower risk of 12-month acute HF events or death vs DPP-4 inhibitors.
Why the study?
GLP-1-based therapies improve symptoms in obesity-related HFpEF, but their impact on hard clinical outcomes across the LVEF spectrum, particularly in HFrEF, remained uncertain.
Does initiation of semaglutide or tirzepatide reduce the 12-month risk of acute heart failure events or all-cause mortality compared to DPP-4 inhibitors in adults with heart failure and type 2 diabetes across LVEF phenotypes?
Observational
Yes
Does initiation of semaglutide or tirzepatide reduce the 12-month risk of acute heart failure events or all-cause mortality compared to DPP-4 inhibitors in adults with heart failure and type 2 diabetes across LVEF phenotypes?
In an international target trial emulation of patients with heart failure and type 2 diabetes, both semaglutide and tirzepatide were associated with substantially lower 12-month risks of acute heart failure events or death across all LVEF phenotypes without increasing arrhythmic risk.
May inform prescribing choices in HF with T2D; extends observational data across LVEF phenotypes but leaves causal effects open.
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.
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Rawish et al. (2026) conducted an observational in Heart failure and type 2 diabetes. Semaglutide or tirzepatide vs. DPP-4 inhibitors (sitagliptin/linagliptin) was evaluated on 12-month time-to-first acute HF event or all-cause mortality (HR 0.72, 95% CI 0.64-0.80, p=<0.001). Semaglutide (HR 0.72, 95% CI 0.64-0.80) and tirzepatide (HR 0.53, 95% CI 0.44-0.63) were associated with lower 12-month acute HF events or death vs DPP-4 inhibitors.
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