Effectiveness of tirzepatide in patients with HFpEF using a target trial emulation retrospective cohort study

Abstract

Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown promise in improving metabolic and cardiovascular profiles in patients with obesity. However, its potential benefits in patients with heart failure with preserved ejection fraction (HFpEF) remain unclear. We conducted a real-world, retrospective cohort study using the TriNetX global database. A total of 14,154 patients with HFpEF were included after 1:1 propensity score matching. Tirzepatide use was associated with significantly lower risks of the primary composite outcome of heart failure exacerbation and all-cause mortality (HR 0.52), as well as reductions in major adverse cardiovascular events (HR 0.64) and major adverse kidney events (HR 0.44). Subgroup analyses demonstrated consistent benefits across different strata. Sensitivity analyses using alternative exposure definitions confirmed the robustness of the findings. These results support the potential clinical utility of tirzepatide in HFpEF management and warrant further investigation in randomized controlled trials.

Fig. 1. Study cohort process.

HCOs healthcare organizations, HFpEF Heart failure with preserved ejection fraction, T2D type 2 diabetes, y/o years old.

Fig. 2. Kaplan-Meier time-to-event free curves of the composite outcome including heart failure exacerbation and all-cause mortality comparison to tirzepatide and control groups.

Survival probabilities over 1 year are shown for the tirzepatide and control groups. Shaded areas represent 95% confidence intervals.

Fig. 3. Subgroup analysis for the risk of composite outcome of heart failure exacerbation and all-cause mortality comparison to tirzepatide and control groups.

BMI body mass index, CI confidence interval, eGFR estimated Glomerular filtration rate, MRA mineralocorticoid receptor antagonist, SGLT2i sodium-glucose co-transporter 2 inhibitors, T2D type 2 diabetes, y/o, years old. HRs and 95% CIs are presented, with the centre defined as the HR and error bars representing the CIs. The vertical line indicates an aHR of 1.0. The Cox proportional hazards analysis was used to assess the hazard ratios of outcomes between groups, with significance determined at a two-sided p-value < 0.05. No adjustment was made for multiple comparisons.