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

Abstract

Background and Aims Syncope is a symptom posing an important diagnostic and therapeutic challenge, and generate significant cost for the healthcare system. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) have demonstrated beneficial cardiovascular effects, but their possible effects on incident syncope have not been fully investigated. This study compared the effects between SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) on new-onset syncope. Methods This was a retrospective, territory-wide cohort study enrolling type 2 diabetes mellitus (T2DM) patients treated with SGLT2i or DPP4i between January 1st, 2015, and December 31st, 2020, in Hong Kong, China. The outcomes were hospitalization of new-onset syncope, cardiovascular mortality, and all-cause mortality. Multivariable Cox regression and different approaches using the propensity score were applied to evaluate the association between SGLT2i and DPP4i with incident syncope and mortality. Results After matching, a total of 37 502 patients with T2DM were included (18 751 SGLT2i users versus 18 751 DPP4i users). During a median follow-up of 5.56 years, 907 patients were hospitalized for new-onset syncope (2.41%), and 2346 patients died from any cause (6.26%), among which 471 deaths (1.26%) were associated with cardiovascular causes. 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 associations with syncope were 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 ertugliflozin (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. The subgroup analyses suggested that, compared to DPP4i, SGLT2i was associated with a significantly decreased risk of incident syncope among T2DM patients, regardless of gender, age, glucose control status, Charlson comorbidity index, and the association remained constant amongst those with common cardiovascular drugs and most antidiabetic drugs at baseline. Conclusions Compared to DPP4i, SGLT2i was associated with a significantly lower risk of new-onset syncope in patients with T2DM, regardless of gender, age, degree of glycaemic control, and comorbidity burden.

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