Type 2 diabetes mellitus (T2DM) is an important cardiovascular risk factor, and its global prevalence is estimated to reach 600 million by the year 2045 [1]. Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a new class of glucose-lowering agents. A large number of clinical trials have demonstrated that SGLT2 inhibitors improve the cardiovascular outcomes of T2DM patients [2, 3, 4, 5]. Structural changes (increased fibrosis and hypertrophy) and electrical remodeling (increased Ca²⁺ handling abnormalities) of the atria are among the myocardial changes induced by diabetes mellitus (DM) [6, 7]. Studies have shown that SGLT2 inhibitors reduce oxidative stress and improve mitochondrial function, thereby reducing atrial fibrosis and hypertrophy [8, 9, 10].

Echocardiographic assessment of total atrial conduction time (TACT) is a marker of the morphological (atrial size), electrical (ion channel alterations) and structural changes (e.g., fibrosis and hypertrophy) associated with atrial remodeling [11]. TACT increases in the presence of valvular disease, hypertension, a high body mass index (BMI), a history of atrial fibrillation (AF) and a large left atrial diameter. An increase in TACT is a predictor of AF [11, 12]. Additionally, TACT can be used to predict AF recurrence after radiofrequency catheter ablation (RFCA) [13]. Prolonged TACT in heart failure predicts poor cardiac prognosis (including mortality) [14]. It should be noted that there is limited evidence in the literature that TACT prolongation is reversible [15].

Considering the above, we aimed to explore whether SGLT2 inhibitors may reduce TACT in patients with T2DM, as a hypothesis-generating approach.

A total of 107 patients (57 female, 50 male) were included in the study; 57 patients were on dapagliflozin, and 50 were on empagliflozin. The mean age of the participants was 54 years (range: 49–62 years), and 42.1% had hypertension, while 15.9% had cardiovascular disease (CVD). The mean duration of SGLT2 inhibitor use was 183 days. The drugs administered prior to this study are shown in Table 4.

The clinical, anthropometric, laboratory and echocardiographic parameters at baseline and six months after starting treatment with SGLT2 inhibitors are shown in Table 1. BMI, systolic blood pressure, diastolic blood pressure, creatinine, total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and glycated hemoglobin (HbA1c) level statistically decreased after six months of treatment (p 0.001, p 0.001, p 0.001, p 0.001, p = 0.011, p = 0.034, p = 0.005 and p 0.001, respectively). With respect to the echocardiographic parameters, the PA-TDI septal, lateral, posterior, anterior, inferolateral, RA free wall and mean duration values as well as the lateral E/e^′ and septal E/e^′ ratios and RA max and min volumes statistically decreased (all p 0.001). Further, the hematocrit and high-density lipoprotein (HDL) cholesterol values and E/A ratio statistically increased (p 0.001, p = 0.007, p 0.001, respectively). In an exploratory subgroup analysis, no significant difference in $\mathrm{\Delta }$ TACT was observed between patients receiving dapagliflozin and empagliflozin (p $>$ 0.05).

The univariate correlation analysis of changes in the mean PA-TDI duration showed that the mean PA-TDI was correlated with $\mathrm{\Delta }$ BMI (r = 0.094, p = 0.044) and $\mathrm{\Delta }$ lateral E/e^′ ratio (r = 0.312, p = 0.001) (Table 2). Multiple regression analysis showed that $\mathrm{\Delta }$ BMI and $\mathrm{\Delta }$ lateral E/e^′ ratio (p = 0.026 and p = 0.001, respectively) were inversely related to mean PA-TDI duration. These findings remained after adjusting the $\mathrm{\Delta }$ mean PA-TDI value for age and sex (Table 3).

The main finding of this prospective pilot study is that 6 months of sodium-glucose cotransporter 2 inhibitors (SGLT2i) treatment significantly shortens echocardiography-derived TACT in patients with T2DM and preserved left ventricular ejection fraction (Pre SGLT2i: 121.1 (111.6–129.8) ms, Post SGLT2i: 110.5 (101.1–119.6) ms, p 0.001). The reduction in mean TACT values, as measured by PA-TDI time after six months of treatment, suggests that SGLT2 inhibitors may have potential positive effects on atrial structural and electrical remodeling. Although the reduction in TACT was statistically significant, the clinical relevance of an approximately 10 ms decrease remains uncertain. Since arrhythmic outcomes such as incident atrial fibrillation were not evaluated, no direct conclusions can be drawn regarding clinical benefit. Previous experimental and clinical studies have shown that DM causes atrial remodeling through atrial fibrosis, hypertrophy, and ion channel dysfunction [19, 20]. As a result of these processes, TACT is prolonged, and the risk of developing AF increases. TACT is a non-invasive and reproducible marker used to predict AF, reflecting atrial fibrosis and electrical heterogeneity [21]. In our study, the significant shortening of TACT after SGLT2 inhibitor treatment suggests that diabetes-related atrial remodeling may be at least partially reversible.

The cardiovascular benefits of SGLT2 inhibitors have been demonstrated in numerous large randomized clinical trials. Studies such as EMPA REG OUTCOME, CANVAS, and DECLARE TIMI 58 have shown that these agents reduce cardiovascular mortality and hospitalizations due to heart failure [2, 3, 5]. However, the underlying mechanisms of these benefits are not fully understood. Experimental studies have shown that SGLT2 inhibitors reduce oxidative stress, improve mitochondrial function, and suppress myocardial fibrosis [22]. This reduction in atrial fibrosis may be one of the possible mechanisms for the TACT shortening observed in our study. Supporting these events, a study by Soliman et al. [23] observed that the use of SGLT2i in diabetic patients undergoing catheter ablation for AF reduced the recurrence rate of AF. This observation suggests that SGLT2i treatment may have a significant effect on the electrophysiological balance of the atria [23].

Studies examining the effects of SGLT2 inhibitors on atrial arrhythmia burden are limited in the literature. Although no significant between-group difference was observed between dapagliflozin and empagliflozin in our study, the analysis was exploratory and the study was not specifically powered for a head-to-head comparison. A meta-analysis reported that SGLT2 inhibitors reduced the incidence of AF [24]. Similarly, an observational study reported a lower risk of new-onset AF in diabetic patients using empagliflozin [25]. However, these studies did not evaluate direct atrial electrical remodeling indicators such as atrial conduction times or TACT. In this respect, our study is one of the rare studies that demonstrates the effect of SGLT2 inhibitors on atrial conduction characteristics echocardiographically. It is noteworthy that in our study, the change in TACT was found to be independently and significantly associated with changes in BMI and lateral E/e^′ ratio. This suggests that improvements in metabolic status and diastolic performance may contribute to the shortening of atrial conduction time. Obesity contributes to atrial enlargement and fibrosis through increased atrial pressures and inflammation, and is associated with the prolongation of TACT [26]. Weijs et al. [27] showed that the duration of PA-TDI is increased in the presence of high BMI. In our current study, we observed a significant decrease (p 0.001) in BMI (kg/m²) with 6 months of SGLT2i treatment. In multiple regression analysis, we found that $\mathrm{\Delta }$ BMI (95% CI: 0.056–0.852, p: 0.026) was an independent prognostic factor of mean PA-TDI. The use of SGLT2 inhibitors reduced the mean duration of PA-TDI. This may be due to a regression in diastolic dysfunction. In diabetic patients, an increase in the E/e^′ ratio, an indicator of worsening diastolic function, is associated with the development of heart failure and increased mortality, independent of hypertension and coronary heart disease [28]. A study by Chao et al. [12] showed that the PA-TDI duration was significantly increased at different stages of diastolic dysfunction. The weight loss achieved by SGLT2 inhibitors may have contributed to the shortening of conduction time by reducing atrial load. Matsutani et al. [15] found that after three months of treatment with SGLT2i (canagliflozin), patients with T2DM could improve ventricular diastolic function (E/e^′). In parallel with this study, our research observed a decrease in septal [pre-SGLT2i: 8.3 (7.1–10), post-SGLT2i: 7.5 (6.2–8.8), p 0.001] and lateral [pre-SGLT2i: 7 (5.8–8.8), post-SGLT2i: 6 (5–7.5), p 0.001] E/e^′ ratios after approximately 183 days of SGLT2i treatment. This may reflect an improvement in diastolic function and a decrease in left atrial pressure. Diastolic dysfunction is known to be associated with atrial remodeling and AF development [29]. In conclusion, we believe that the hemodynamic and metabolic effects of SGLT2 inhibitors have positive indirect contributions to atrial conduction.

The reversibility of TACT has been addressed to a limited extent in the literature. There are few studies reporting a reduction in TACT after hypertension treatment or weight loss [29, 30]. The results of our study are important because they show that TACT can be significantly reduced with a pharmacological agent, moreover, with a class of drugs used primarily for glycemic control. Considering all factors, the reduction in TACT observed in our study should not be interpreted as a direct pharmacological effect of SGLT2 inhibition alone. Given the concurrent improvements in BMI, glycemic control, blood pressure, lipid profile, and diastolic parameters, the shortening of atrial conduction time may predominantly reflect improved hemodynamic loading conditions and metabolic status rather than a direct anti-arrhythmic effect or reduction in atrial fibrillation risk.

This prospective pilot study demonstrated that SGLT2 inhibitor therapy significantly reduced total atrial conduction time in patients with T2DM. This finding suggests that the cardiovascular benefits of SGLT2 inhibitors may not be limited to ventricular function but may also encompass atrial electrical and structural remodeling. Randomized controlled trials with long-term follow-up in larger patient populations are necessary to confirm these effects and demonstrate their clinical significance.

In this study, SGLT2 inhibitor therapy was associated with a decrease in TACT in patients with type 2 diabetes. This finding should be considered hypothesis-generating and may reflect improvements in diastolic parameters, atrial electromechanical properties, and cardiometabolic status.

SGLT2i, sodium-glucose cotransporter 2 inhibitors; T2DM, type 2 diabetes mellitus; TACT, total atrial conduction time; PA-TDI, the onset of the P wave in lead II and the peak A^′ wave on tissue Doppler imaging; HbA1c, glycated hemoglobin; BMI, body mass index; AF, atrial fibrillation; EFs, ejection fractions; MDRD, Modification of Diet in Renal Disease; MINOCA, myocardial infarction with nonobstructive coronary arteries; PCI, percutaneous coronary intervention; ECGs, electrocardiograms; SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, glomerular filtration rate; eGFR, estimated glomerular filtration rate; LA, left atrial; RA, right atrial; ASE, American Society of Echocardiography; EACVI, European Association of Cardiovascular Imaging; IQR, interquartile range; CVD, cardiovascular disease; Ch, chamber; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

The paper is listed as, “Impact of Sodium-glucose Cotransporter 2 Inhibitors on Echocardiography-derived Total Atrial Conduction Time” as a preprint on Research Square at: https://www.researchsquare.com/article/rs-3053464/v1.

The datasets used and analyzed during the current study are available from the corresponding authors upon reasonable request.

Conceptualization, ET, FK, SB; Methodology, ET, FK, SB; Software, ET, FK; Validation, ET, FK; Formal analysis, ET, FK, SB; Investigation, ET, SB; Resources, ET, SB; Data curation, ET, FK, SB; Writing—original draft, ET, FK, SB; Writing—review & editing, ET, FK; Visualization, ET, FK, SB; Supervision, ET, FK, SB; Project administration, ET, SB, FK; Funding acquisition, ET, FK. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study protocol conformed to the Declaration of Helsinki and was approved by the ethics committee of Gazi Yaşargil Training and Research Hospital (approval number: 2022-50; date: March 11, 2022). Written informed consent was obtained from all participants.

Not applicable.

This research received no external funding.

The authors declare no conflicts of interest.