Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus

Abstract

Background: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 (sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms (“atrial fibrillation,” “atrial flutter”). Results: Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68–0.95]; P =0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFL: HR, 0.79 [95% CI, 0.58–1.09]; no AF/AFL: HR, 0.81 [95% CI, 0.67–0.98]; P for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 [95% CI, 0.66–1.04]) versus multiple risk factors (HR, 0.78 [95% CI, 0.62–0.99]; P for interaction 0.72) or a history of HF (HF: HR, 0.78 [95% CI, 0.55–1.11]; No HF: HR, 0.81 [95% CI, 0.68–0.97]; P for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A 1c , body mass index, blood pressure, or estimated glomerular filtration rate (all P for interaction >0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 [95% CI, 0.64–0.92]; P =0.005). Conclusions: Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient’s previous history of AF, atherosclerotic cardiovascular disease, or HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

“…The main mechanisms of their cardioprotective effects are improvements in cardiac cell metabolism and ventricular loading conditions, inhibition of Na + /H + exchange in myocardial cells, alterations in adipokine and cytokine production, and reductions in cardiac cell necrosis and cardiac fibrosis [ 34 , 35 ]. SGLT2i has also been shown to reduce sympathetic overdrive, which plays an important role in the development of AF [ 18 ].…”

“…The CVD-REAL Nordic study also indicated that dapagliflozin was associated with lower risks of cardiovascular events and all-cause mortality but a neutral risk of AF (HR: 0.92; [95% CI 0.76–1.12]; P = 0.414) compared with DPP-4is in a real-world clinical setting [ 19 , 20 ]. Conversely, post-hoc analysis of the DECLARE-TIMI 58 trial indicated that dapagliflozin reduced the risk of AF/AFL by 19% (HR: 0.81; [95% CI 0.68–0.95]; P = 0.009) and the number of total AF/AFL events by 23% compared to placebo in 17,160 T2DM patients, regardless of the presence or absence of AF/AFL, established cardiovascular disease, or heart failure at baseline [ 18 ]. To the best of our knowledge, only the CVD‐REAL Nordic study has directly compared the risk of AF between SGLT2i and DPP4i treatment among T2DM patients in a real-world setting [ 19 ].…”

“…Although these randomized controlled trials have shown firm evidence of the benefits of SGLT2i with regards to ischemic cardiovascular diseases and mortality, all-cause mortality, and heart failure hospitalizations in patients with a high cardiovascular risk, whether SGLT2i themselves reduce the risk of atrial arrhythmia or AF is unclear. Recently, the post-hoc analysis of the DECLARE-TIMI 58 trial indicated that dapagliflozin significantly reduced the risk of AF/atrial flutter (AFL) in T2DM patients [ 18 ]. However, the CVD-REAL Nordic showed no significant difference of the new-onset AF associated with the use of dapagliflozin compared with dipeptidyl peptidase-4 inhibitor (DPP4i) or other glucose-lowering agents in T2DM patients in real-world practice [ 19 , 20 ].…”

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

“…[20] SGLT2i has also been shown to reduce sympathetic overdrive, which plays an important role in the development of AF. [21] Other diabetes medications including metformin, thiazolidinedione (TZD), and DPP4i, may also be associated with a lower risk of AF. A previous study of a nationwide, population-based dynamic cohort indicated that the use of metformin was associated with a decreased risk of AF in T2DM patients who were not using other antidiabetic drugs, probably by attenuating atrial cell tachycardia-induced myolysis and oxidative stress.…”

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

“…Recently, the post-hoc analysis of the DECLARE-TIMI 58 trial indicated that dapagli ozin signi cantly reduced the risk of AF/atrial utter (AFL) in T2DM patients. [18] However, the CVD-REAL Nordic showed no signi cant difference of the new-onset AF associated with the use of dapagli ozin compared with dipeptidyl peptidase-4 inhibitor (DPP4i) or other glucose-lowering agents in T2DM patients in real-world practice. [19,20] Therefore, the primary aim of the present study was to investigate whether SGLT2i is associated with a decreased risk of incident AF compared with DPP4i, speci cally focused on Asian population with T2DM, in a large real-world setting.…”