To the best of our knowledge, this is the largest observational study to specifically evaluate the risk of new-onset AF focused on Asian population with T2DM treated with SGLT2i versus DPP4i. Our results showed that the use of SGLT2i was associated with a significantly lower risk of new-onset AF compared to DPP4i among T2DM patients. The benefits in reducing the risk of new-onset AF with SGLT2i over DPP4i persisted in several important subgroups including old age, presence of cardiovascular disease, impaired renal function, and elevated HbA1c levels. In addition, the advantages of SGLT2i over DPP4i in lowering the risk of new-onset AF persisted with different SGLT2i drugs (dapagliflozin or empagliflozin) and both low and standard doses of SGLT2i.
T2DM or insulin resistance is an important risk factor for ischemic stroke and the development of new-onset AF.[25, 26] An animal study demonstrated that diabetic rat atria had greater interstitial fibrosis, lower connexin 40 expression, and decreased conduction velocity. In addition, the diabetic atria showed electrical remodeling with prolongation of action potential duration (APD), an increase in spatial dispersion and frequency-dependent shortening of APD, and increased incidence of APD alternans. All of these factors facilitated the formation of re-entry associated atrial arrhythmia. Other studies have also reported adrenergic activation and heterogeneous sympathetic innervation in diabetic hearts, suggesting that neural remodeling may play a crucial role in diabetes-related atrial arrhythmia. Furthermore, T2DM itself is associated with several chronic diseases including obesity, hypertension, chronic kidney disease, and heart failure, all of which further increase the risk of incident AF.[6, 7, 29, 30]
SGLT2i is a new class of anti-hyperglycemic agents that inhibit glucose absorption by the proximal tubules of the kidney, resulting in glycosuria. SGTL2i has been shown to reduce blood sugar levels, blood pressure, body weight, albuminuria, lipid profile, arterial stiffness, and endothelial function via an insulin-independent mechanism in T2DM patients. Recent study indicated that SGLT2i had more favorable pleiotropic effects on body weight, liver function and eGFR changes when compared to DPP4i, potentially modifying the cardio-metabolic disease risks in T2DM patients. Moreover, SGLT2i has been shown to have impressive cardioprotective and renoprotective effects. 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.
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. Another study indicated that the use of DPP4i as second-line antidiabetic drugs was associated with a lower risk of AF compared with other second-line antidiabetic drugs among T2DM patients treated with metformin in real-world practice. TZD is an insulin sensitizer that also have anti-inflammatory and anti-oxidative effects, and they might decrease the risk of AF compared with other antidiabetic drugs. Pallisgaard et al. reported that the use of TZD was associated with a 24% reduction in the risk of incident AF compared with other antidiabetic drugs as second-line treatment among T2DM patients. However, no significant differences in the risk of incident AF with use of TZD were reported in the PROactive, RECORD, and BARI 2D trials.[39-41]
Three large randomized controlled trials, EMPA-REG OUTCOME (empagliflozin), CANVAS Program (canagliflozin), and DECLARE–TIMI 58 (dapagliflozin) demonstrated that three SGLT2i significantly reduced the risk of heart failure hospitalization in T2DM patients with/without established cardiovascular diseases compared with the current standard-of-care diabetes management.[13-15] Furthermore, the DAPA-HF trial indicated that dapagliflozin treatment reduced the risk of worsening heart failure or cardiovascular death by 26% compared to placebo among patients with heart failure and a reduced ejection fraction of < 40%, regardless of the presence or absence of T2DM. However, despite the potential improvements in atrial remodeling mediated by SGLT2i, few clinical studies have investigated the relationship between the use of SGLT2i and the risk of AF, and the results have been inconsistent. A meta-analysis of 35 eligible randomized controlled trials (canagliflozin, nine; empagliflozin, eight; dapagliflozin, 18), showed that SGLT2i significantly reduced all-cause mortality, major adverse cardiac events, non-fatal myocardial infarction, and heart failure hospitalization in T2DM patients compared to placebo. However, no significant difference was noted in the occurrence of stroke, unstable angina, or AF (odd ratio: 0.61; [95% CI 0.31-1.19]; P = 0.15). 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. 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. In contrast to the CVD‐REAL Nordic study, reporting a comparable risk of new-onset AF, we report a lower risk associated with SGLT2i compared with DPP4i treatment. This finding is of particular interest because it is more in line with the results of post-hoc analysis of the DECLARE-TIMI 58 trial. The seemingly discrepant findings between our results and those of the CVD‐REAL Nordic study could be attributable to chance and/or the presence of different baseline characteristics including ethnicity, the prevalence of underlying chronic kidney disease or AF (9% patients already have AF at baseline in the CVD‐REAL Nordic study), and a different drug prescription including the use of insulin, glitazone, and glucagon-like peptide-1 receptor agonist. The CVD-REAL Nordic study used a large National claim database but with a lacking of several important data including laboratory data and vital sign, which was also different from our study using a large multicenter hospital-based electronic medical record database with those important data available. Nevertheless, whether the study outcomes in our present study were confounded by those factors cannot not be excluded and need further elucidation. Further prospective and randomized studies are necessary to clarify our results.