To the best of our knowledge, this is the largest observational study to specifically evaluate the risk of new-onset AF in T2DM patients 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 heart failure or cardiovascular disease, obesity, 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 is an important risk factor for ischemic stroke and the development of new-onset AF. 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 hypertension, chronic kidney disease, and heart failure, all of which further increase the risk of incident AF.
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. 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. 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.[25-27]
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.[9-11] 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.[30, 31] Conversely, post-hoc analysis of the DECLARE-TIMI 58 trial indicated that dapagliflozin reduced the risk of AF/atrial flutter (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, no previous studies have compared the risk of AF between SGLT2i and DPP4i treatment or other oral hypoglycemic agents among T2DM patients. Further prospective and randomized studies are necessary to clarify our results.
In this study, dapagliflozin seemed to result in a greater reduction in new-onset AF events than empagliflozin when compared with DPP4i (P interaction < 0.001) (Figure 4). Several possible mechanisms may explain this difference between these two SGLT2is. Empagliflozin has greater SGLT2 to SGLT1 selectivity (2500-fold) than dapagliflozin (1200-fold). Previous studies have shown that SGLT1 receptors are predominantly found in the human intestine, and that higher SGLT1 receptor selectivity can lower variations in postprandial blood glucose.[33, 34] In addition, other studies have suggested an association between higher blood glucose variability and a higher risk of new-onset AF in T2DM patients.[35, 36] In addition, dapagliflozin has longer lasting pharmacological effects such as sodium excretion and osmotic diuresis, and this may reduce blood pressure variability.[34, 37] Higher blood pressure variability has been associated with a higher risk of developing AF in the general population, especially in high-risk subjects including those with an old age and the presence of concomitant T2DM or chronic kidney disease. Finally, although both SGLT2is seemed to reduce the risk of heart failure, a previous study indicated that dapagliflozin may have greater effects on reducing heart failure compared to empagliflozin. Future studies are required to investigate the differences in risk reduction of new-onset AF between different SGLT2i.