GLP-1 Receptor Agonists Reduce Heart Failure Hospitalization Risk Compared to DPP-4 Inhibitors
New target trial emulation study finds GLP-1 receptor agonists associated with lower heart failure hospitalization risk versus DPP-4 inhibitors and similar risk to SGLT-2 inhibitors in type 2 diabetes patients.
GLP-1 receptor agonists are associated with a lower risk of hospitalization for heart failure compared with DPP-4 inhibitors and similar risks compared with SGLT-2 inhibitors in routine clinical care for patients with type 2 diabetes, according to a target trial emulation study published in Circulation in February 2026.
Two target trials were emulated using population-based health care data from Stockholm, Sweden (2010-2021). Target trial 1 included 32,979 patients (42% GLP-1RA and 58% DPP-4i) with a mean age of 64 years and 40% female, while target trial 2 included 30,104 patients (49% GLP-1RA and 51% SGLT-2i) with a mean age of 63 years and 38% female. Cox regression was used to estimate intention-to-treat hazard ratios, with inverse probability of treatment weighting used to balance 72 confounders.
Starting a GLP-1RA was associated with a lower 3-year absolute risk of hospitalization for heart failure than starting a DPP-4i (3.4% versus 4.3%), corresponding to a weighted hazard ratio of 0.77 (95% CI, 0.66-0.91). Absolute 3-year risks for GLP-1RA compared with SGLT-2i on hospitalization for heart failure were 3.6% and 3.3% with a weighted hazard ratio of 1.02 (95% CI, 0.85-1.18). The absolute risk difference was largest for patients with higher predicted risk of heart failure at baseline.
Results were consistent for single agents, including liraglutide and semaglutide, in per-protocol analyses, and in the majority of subgroups. In positive control outcome analyses, GLP-1RA use was associated with a lower rate of major adverse cardiovascular events than DPP-4i use (weighted hazard ratio, 0.85 [95% CI, 0.74-0.99]), consistent with trial findings.
Across large cardiovascular outcome trials, glucagon-like peptide 1 receptor agonists consistently reduce three-point major adverse cardiovascular events in patients with overweight, obesity and established CVD with and without diabetes. In obesity-related heart failure of preserved ejection fraction, semaglutide and tirzepatide improve symptoms and functional capacity and reduce worsening heart failure events, while effects on cardiovascular mortality remain uncertain.
Data support that sustained weight loss of at least 10% is more likely to translate into CVD event reduction, alongside other organ specific mechanisms that impact cardiovascular health independent from weight reduction. The only randomized cardiovascular outcome data in patients with obesity without diabetes are from SELECT trial with semaglutide showing marked reduction in cardiovascular complications compared to placebo.