Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been suggested to have beneficial effects against infection. However, the comparative risks of new onset infective endocarditis between SGLT2Is, dipeptidyl peptidase-4 inhibitors (DPP4Is) and glucagon-like peptide-1 receptor agonist (GLP1a) remain unknown. Objective: This real-world study aims to compare the risks of infective endocarditis upon exposure to SGLT2I and dipeptidyl peptidase-4 inhibitors (DPP4I). Methods: This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus (T2DM) on either SGLT2I or DPP4I between 1st January 2015 and 31st December 2020 using a territory-wide registry in Hong Kong. The primary outcome was new-onset infective endocarditis. The secondary outcome was cardiovascular-related mortality. Propensity score matching (1:1 ratio) using the nearest neighbour search was performed. Multivariable Cox regression was applied to identify significant associations. A three-arm sensitivity analysis including the GLP1a cohort was conducted. Results: This cohort included 75638 T2DM patients (median age: 62.3 years old [SD: 12.8]; 55.79 % males). The SGLT2I and DPP4I groups consisted of 28774 patients and 46864 patients, respectively. After matching, 104 and 161 infective endocarditis in the SGLT2I and DPP4I groups occurred over a follow-up of 5.6 years. SGLT2I use was associated with lower risks of infective endocarditis (Hazard ratio [HR]: 0.58; 95% Confidence Interval [CI]: 0.41-0.81) and cardiovascular mortality (HR: 0.49; 95% CI: 0.33-0.72) compared to DPP4I use after adjustments for demographics, comorbidities, medications, renal function, and HbA1c levels. Similar associations were observed in subgroup analyses regardless of gender, hypertension, prior valvular disease, renal disease, or immunodeficiency. In the sensitivity analysis, SGLT2I was not associated with lower risks of infective endocarditis compared to GLP1a. The results remained consistent in the competing risk and the other sensitivity analyses. Conclusions: SGLT2I use was associated with lower risks of new-onset infective endocarditis compared to DPP4I after adjustments.

The authors have declared no competing interest.

The authors received no funding for the research, authorship, and/or publication of this article.

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This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKWC IRB) (UW-20-250) and complied with the Declaration of Helsinki.

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