Coronary flow reserve increase after 4-year dapagliflozin treatment in patients with type 2 diabetes: the DAPAHEART follow-up study

Background: Cardiovascular (CV) outcome trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce CV mortality in type 2 diabetes (T2DM). We previously found that 4 weeks of SGLT2i treatment increased coronary flow reserve (CFR) by 30% and reduced epicardial adipose tissue (EAT) thickness by 19% in T2DM patients with stable coronary artery disease (CAD). However, long-term effects remain unclear. This pilot study aimed to assess the long-term impact of dapagliflozin on CFR and EAT thickness in T2DM patients with CAD. Methods: Patients with T2DM and stable CAD were enrolled in the DAPAHEART trial, a single-center, 4-week, randomized (1:1 dapagliflozin 10 mg vs. placebo), double-blind, controlled study. At the end of the trial, placebo group patients also transitioned to dapagliflozin. CFR and EAT thickness were measured at baseline, after 4 weeks, and after 4 years using 13N-ammonia PET/CT. Results: CFR increased 34.4% after 4 years (from 2.15 ± 0.19 at baseline to 2.85 ± 0.26, p = 0.001) with 29.18% reduction in EAT thickness (p = 0.03). BMI decreased in all patients (p = 0.001), but changes in BMI and EAT thickness were not significantly correlated (R2 = 0.0662; p = 0.5), suggesting a weight-independent effect of dapagliflozin on EAT. Conclusion: The 30% CFR improvement seen after 4 weeks of dapagliflozin persisted at 4 years, together with a significant reduction in EAT thickness, possibly explaining CFR improvement. Similar results in the placebo group after treatment strongly support a causal relationship and underscore the long-term CV benefits of dapagliflozin and its role in reducing CV risk in T2DM patients.