New-onset syncope in diabetic patients treated with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors: A Chinese population-based cohort study

Background and Aims Syncope and post-syncopal adverse events lead to a heavy burden in the healthcare systems with negative impact on the economy globally. However, no effective treatments have been identified to prevent the risk of new-onset syncope. This study compared the preventive effect of incident syncope between sodium-glucose cotransporter-2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i). Methods This was a retrospective, territory-wide cohort study enrolling type 2 diabetes mellitus (T2DM) patients treated with SGLT2i or DPP4i between January 1st, 2016, and December 31st, 2020, in Hong Kong, China. The outcomes were new-onset syncope, cardiovascular mortality, and all-cause mortality. Multivariable Cox regression and different approaches using the propensity score were used to evaluate the association between SGLT2i vs. DPP4i with incident syncope and mortality. Results After matching, a total of 37502 patients with T2DM were included (18751 SGLT2i users, 18751 DPP4i users). During a median follow-up of 5.56 years, compared to DPP4i users, SGLT2i therapy was associated with a 51% lower risk of new-onset syncope (HR, 0.49; 95%CI [0.41-0.57], P<0.001), 65% lower risk of cardiovascular mortality (HR, 0.35; 95%CI [0.26-0.46], P<0.001), and a 70% lower risk of all-cause mortality (HR, 0.30; 95%CI [0.26-0.34], P<0.001) in the fully adjusted model. Similar association with syncope was observed for dapagliflozin (HR, 0.70; 95%CI [0.58-0.85], P<0.001), canagliflozin (HR, 0.48; 95%CI [0.36-0.63], P<0.001) and ertuglifolzin (HR, 0.45; 95%CI [0.30-0.68], P<0.001), but was attenuated for empagliflozin (HR, 0.79; 95%CI [0.59-1.05], P=0.100) after adjusting for potential confounders. Subgroup analyses suggested that, compared to DPP4i, SGLT2i showed a significantly protective effect in incident syncope among T2DM patients, regardless of gender, age, comorbidities burden and other medication history, as well as among patients with different levels of fasting glucose, HbA1c, and glycemic variability. Conclusions Compared to DPP4i, SGLT2i could significantly reduce the risk of new-onset syncope in patients with T2DM, regardless of gender, age, comorbidities, other medication history, and degree of glycemic control. Our findings suggest a promising future of SGLT2i in preventing incident syncope. Abstract Figure Structured graphical abstract CI: confidence interval; DPP4i: dipeptidyl peptidase-4 inhibitor; HR: hazard ratio; SGLT2i: sodium-glucose cotransporter-2 inhibitor.