To assess the potential role of tirzepatide on primary stroke prevention in patients with type 2 diabetes mellitus (T2DM).

T2DM is a major modifiable risk factor for stroke. Emerging antidiabetic agents, including tirzepatide and sodium-glucose cotransporter-2 (SGLT2) inhibitors, have demonstrated cardiovascular benefits. However, their potential role in mitigating incident stroke risk has not been comprehensively investigated through direct comparative effectiveness research.

We conducted a retrospective, active-comparator, target trial emulation (TTE) via TriNetX Global Collaborative Network, including adults with T2DM who initiated tirzepatide or SGLT2 inhibitors between June 1, 2022, and August 1, 2024. Patients with prior cerebrovascular disease or contraindications to study medications were excluded. Propensity score matching (PSM) (1:1) was implemented to balance cohorts based on demographic characteristics, comorbidities, concomitant medications, and socioeconomic variables. The primary outcome was incident ischemic stroke. Secondary outcomes included all stroke, transient ischemic attack (TIA), non-traumatic intracerebral hemorrhage (ICH), and major adverse cardiovascular events (MACE). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. All analyses were performed using the TriNetX platform’s built-in statistical capabilities.

Following PSM, 87,380 patients remained in each cohort, with comparable mean ages of 56.9 ± 11.8 years in the tirzepatide group and 56.7 ± 12.5 years in the SGLT2 inhibitors group. Tirzepatide was associated with a significantly reduced risk of incident ischemic stroke compared to SGLT2 inhibitors (HR:0.67; 95% CI:0.59-0.75). Among secondary outcomes, tirzepatide users demonstrated lower incidence rates of TIA (HR:0.84; 95% CI:0.72-0.99), all stroke (HR:0.66; 95% CI:0.59-0.74), ICH (HR:0.71; 95% CI:0.52-0.98), and MACE (HR:0.60; 95% CI:0.56-0.63) compared to SGLT2 inhibitor users.

In this TTE, initiation of tirzepatide was associated with significantly lower incidence of ischemic stroke and overall stroke compared to treatment with SGLT2 inhibitors among adults with T2DM. These findings suggest potential cerebrovascular protective effects of tirzepatide beyond glycemic control.