The effect of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP-4 inhibitors on stroke risk in type 2 diabetes: a nationwide longitudinal cohort study in Sweden with contextualisation analysis.

Abstract

The impact of SGLT2 inhibitors (SGLT2i), GLP-1 receptor agonists (GLP-1RA), and DPP-4 inhibitors (DPP-4i) on stroke risk in individuals with type 2 diabetes remains uncertain. Meta-analyses of randomised controlled trials (RCTs) show a protective effect for GLP-1RA but neutral findings for SGLT2i and DPP-4i, whereas observational studies often suggest broader stroke risk reductions. This study aimed to estimate the associations of SGLT2i, GLP-1RA, and DPP-4i with stroke risk in nationwide longitudinal data, and to contextualize these results within existing meta-analyses of RCTs and observational studies. This was a nationwide longitudinal study including individuals with type 2 diabetes first registered in the Swedish National Diabetes Register between January 1, 2013, and December 31, 2019. Individuals with a prior stroke or insufficient data for multiple imputation were excluded. The primary outcome was ischemic stroke. Treatments, comorbidities, and laboratory values were updated over time. Marginal structural models with inverse probability of treatment weighting and weighted Cox regression were used to estimate hazard ratios (HRs) for ischemic, hemorrhagic and total stroke pooled across five multiply imputed datasets. To contextualise the findings, PubMed was searched from inception to June 23, 2026, for meta-analyses of randomised controlled trials and observational studies reporting stroke outcomes for the three drug classes. We included 171,917 individuals with type 2 diabetes [59.2% males, baseline mean (SD) age 62.7 (11.6), mean (SD) follow-up 3.0 (1.9) years] contributing 1,617,462 clinical registrations. During follow-up, 2734 (1.59%) ischemic and 428 (0.25%) hemorrhagic strokes occurred. GLP-1RA use was associated with a lower risk of ischemic (HR 0.46, 95% CI 0.29-0.72) and total stroke (HR 0.51, 95% CI 0.33-0.79), whereas no clear associations were observed for hemorrhagic stroke. SGLT2i and DPP-4i showed no clear associations with any stroke outcome. The contextualisation identified 91 meta-analyses. RCT meta-analyses generally showed a protective effect for GLP-1RA and neutral effects for SGLT2i and DPP-4i, while observational meta-analyses suggested protective associations for GLP-1RA and SGLT2i. In this nationwide study, GLP-1RA were associated with reduced stroke risk, while SGLT2i and DPP-4i showed neutral effects. The overall direction of findings was consistent with evidence from RCT meta-analyses. Future research should investigate how these therapies can be optimally incorporated into treatment strategies for stroke prevention in individuals with type 2 diabetes. Sahlgrenska University Hospital's funds, the Swedish National Stroke Association, the Swedish Brain Foundation, the Swedish Heart Lung Foundation, the Bygg-Göta Foundation for scientific research, the Winberg foundation, and the Swedish state under the ALF agreement between the Swedish government and the county councils.