Risk of stroke in patients with type 2 diabetes receiving semaglutide or a dipeptidyl peptidase-4 inhibitor: a real-world US claims database analysis
Authors: Husain M , Evans M , Frenkel O , Mangla K K , Srivastava A , Lingvay I 
Published: October 2022

Abstract

Introduction
People with type 2 diabetes (T2D) have a higher risk of stroke than those without, are likely to experience stroke at a younger age, and have worse outcomes. The cardiovascular benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in T2D have been demonstrated in randomized controlled trials. A meta-analysis of these data has shown that GLP-1 RAs are associated with a significant reduction in the risk of stroke; however, there remains an evidence gap for the real-world effect of semaglutide specifically on stroke risk.

Purpose
To compare real-world risk of stroke in patients with T2D or T2D + atherosclerotic cardiovascular disease (ASCVD) initiating either semaglutide or a dipeptidyl peptidase-4 inhibitor (DPP-4i).

Methods
For inclusion, adults (≥18 years) in a US claims database required a claim indicating initiation of either semaglutide or a DPP-4i (index date) during the index period (1/1/18–30/9/20), a diagnosis code for T2D on or before the index date, and 12 months' continuous enrolment pre-index. Exclusion criteria were a claim for semaglutide, DPP-4i or injectable glucose-lowering medication, or diagnosis code for type 1 or secondary diabetes in the 12 months pre-index; or a claim associated with pregnancy or gestational diabetes any time during the study period. Patients were propensity score matched 1:1 on 27 baseline demographic and clinical characteristics. Patients who also had a diagnosis code for ASCVD pre-index were matched separately on 26 variables. Primary outcome was time to first stroke event during follow-up, defined as a medical claim with stroke as primary diagnosis during inpatient or emergency room visit. Patients with no event were censored at end of enrolment or end of study period (30/9/20), whichever was earliest.

Results
Post-matching, there were 17,920 pairs with T2D and 4234 pairs with T2D+ASCVD. The groups were well matched on baseline characteristics (Table). For T2D, patients initiating semaglutide had a lower risk of stroke than those initiating a DPP-4i (hazard ratio [HR], 0.63; 95% confidence interval [CI]: 0.41–0.95; p=0.029). This trend was more pronounced for T2D+ASCVD (HR, 0.45 [0.24–0.86]; p=0.015). Overall, 34 patients with T2D receiving semaglutide (0.2%) experienced a stroke event (incidence rate [IR] per 100 person-years, 0.25), compared with 60 patients receiving a DPP-4i (0.3%; IR, 0.40; IR ratio [IRR], 0.62; 95% CI: 0.40–0.95). For the groups with T2D+ASCVD, 13 patients receiving semaglutide (0.3%; IR, 0.40) and 32 receiving a DPP-4i (0.8%; IR, 0.90) experienced a stroke event (IRR, 0.44 [0.23–0.85]). The Figure shows cumulative incidence of stroke over follow-up (median 237–258 days).

Conclusion
This analysis provides initial insights into the potential of semaglutide to reduce real-world stroke risk in patients with T2D. Analyses with additional comparison groups and longer follow-up are needed to determine the broader clinical and economic implications.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was funded by Novo Nordisk A/S. Medical writing support was provided by Oxford PharmaGenesis, Oxford, UK with funding from Novo Nordisk A/S.