Risk of Heart Failure Hospitalization for GLP-1 Receptor Agonists Versus DPP-4 Inhibitors or SGLT-2 Inhibitors in Patients With Type 2 Diabetes: A Target Trial Emulation

Feb 24, 2026Circulation

Risk of Heart Failure Hospitalization with GLP-1 Receptor Agonists Compared to DPP-4 or SGLT-2 Inhibitors in People with Type 2 Diabetes

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Abstract

Starting a GLP-1 receptor agonist (GLP-1RA) is associated with a 3.4% absolute risk of hospitalization for heart failure (HHF) over three years, compared to 4.3% for dipeptidyl peptidase-4 inhibitors (DPP-4is).

GLP-1RA initiation shows a weighted hazard ratio of 0.77 for HHF compared to DPP-4is, indicating a reduced risk.
The absolute risk of HHF for GLP-1RA compared to sodium-glucose cotransporter-2 inhibitors (SGLT-2is) was 3.6% versus 3.3%, with a weighted hazard ratio of 1.02, suggesting similar risks.
Higher baseline predicted risk of heart failure correlates with larger absolute risk differences for HHF between GLP-1RA and DPP-4is.
Results are consistent across individual agents and various patient subgroups.
GLP-1RA use is also linked to a lower rate of major adverse cardiovascular events compared to DPP-4is, with a weighted hazard ratio of 0.85.

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BACKGROUND: Novel treatments are needed for the primary and secondary prevention of heart failure in patients with type 2 diabetes, including individuals with and those without a history of heart failure. Conflicting trial evidence exists on whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of hospitalization for heart failure (HHF) in this broad population and whether this is a class effect or varies by specific agent. Furthermore, their comparative effectiveness against sodium-glucose cotransporter-2 inhibitors (SGLT-2is) is unknown.

METHODS: We emulated 2 target trials using population-based health care data from Stockholm, Sweden (2010-2021). Target trial 1 included adult patients with type 2 diabetes who newly initiated GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP-4is), and target trial 2 compared GLP-1RA with SGLT-2i. The primary outcome was HHF. Cox regression was used to estimate intention-to-treat hazard ratios, with inverse probability of treatment weighting used to balance 72 confounders. Major adverse cardiovascular events were used as the positive control outcome. Analyses were conducted for the GLP-1RA class overall and for individual agents, including liraglutide and semaglutide.

RESULTS: Target trial 1 included 32 979 patients (42% GLP-1RA and 58% DPP-4i) with a mean age of 64 years and 40% female; and target trial 2 included 30 104 patients (49% GLP-1RA and 51% SGLT-2i) with a mean age of 63 years and 38% female. Starting a GLP-1RA was associated with a lower 3-year absolute risk of HHF 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 HHF 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, 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.

CONCLUSIONS: GLP-1RA use is associated with a lower risk of HHF compared with DPP-4i and similar risks compared with SGLT-2i in routine clinical care for patients with type 2 diabetes.

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Risk of Heart Failure Hospitalization for GLP-1 Receptor Agonists Versus DPP-4 Inhibitors or SGLT-2 Inhibitors in Patients With Type 2 Diabetes: A Target Trial Emulation

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