Dapagliflozin and ventricular repolarization across heart failure phenotypes.

BACKGROUND

Type 2 diabetes mellitus (T2DM) is associated with abnormal ventricular repolarization and increased arrhythmic risk. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors may exert electrophysiological effects beyond glycemic control. We investigated changes in electrocardiographic (ECG) markers of ventricular repolarization after dapagliflozin initiation in SGLT-2 inhibitor-naïve patients with T2DM according to heart failure (HF) phenotype.

METHODS

In this prospective, non-randomized, controlled observational study, 700 patients with T2DM were enrolled between June 2023 and February 2026. Patients initiating dapagliflozin (n = 350) were classified as HFrEF (LVEF <50%, n = 87), HFpEF (LVEF ≥50% with HF, n = 93), or no HF (LVEF ≥50% without HF, n = 170); 350 controls continued pre-existing antidiabetic therapy. Twelve-lead ECG and echocardiography were performed at baseline and 3 months. Prespecified endpoints included QT, QTc, QT dispersion, Tp-e, Tp-e/QT, and Tp-e/QTc. Inverse probability of treatment weighting and Holm-Bonferroni correction were applied.

RESULTS

Dapagliflozin was associated with greater reductions in all prespecified ECG parameters than controls (all between-group p <0.001; Cohen's d = 0.48-1.08), with consistent findings after IPTW. Reductions were greatest in HFrEF (QTc = -14.3 ms; Tp-e = -9.1 ms), followed by HFpEF (-11.2 and -7.4 ms) and no HF (-7.6 and -3.8 ms); all between-subgroup comparisons p <0.001. HFrEF independently predicted greater QTc reduction (β = -4.8 ms vs no HF, p < 0.001). Change in Tp-e correlated weakly with HbA1c change (r = -0.145, p = 0.037). LVEF increased in HFrEF (+3.2%) and HFpEF (+0.9%).

CONCLUSIONS

Dapagliflozin initiation was associated with reductions in multiple ECG markers of ventricular repolarization, with the greatest changes observed in HFrEF. These findings concern surrogate ECG measures and do not establish a reduction in clinical arrhythmic events. Confirmation in prospective randomized trials is warranted.