Introduction and objective: Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality for heart failure. We demonstrated that 4-weeks-treatment with SGLT-2i leads to a 30% increase in coronary flow reserve (CFR) in T2D people with stable coronary artery disease (CAD) (DAPAHEART trial). The aim of this study is to evaluate the long-term effects of treatment with dapagliflozin on CFR in patients with T2D. Methods: T2D patients with CAD already enrolled for a single-center, 4 weeks, prospective, randomized (1:1 dapagliflozin 10 mg or placebo), double-blind, controlled study have been followed up for 4 years. At the end of the trial all the patients in placebo group started therapy with dapagliflozin. After 4 years of treatment the CFR has been evaluated using 13N-ammonia PET-CT. Results: During the follow-up, the antidiabetic treatment remained stable. The 2 groups were metabolically well balanced. In DAPA group (n=5), the increase of 30% in CFR was sustained over 4 years (p=ns). A comparison between pre and post-4-years follow-up in DAPA group showed a 35% increase in CFR (p=0.09). The placebo group (n=4), after 4 years of dapagliflozin treatment, exhibited a 28.6% increase in CFR (p=0.07). Overall, a 25% increase in CFR was observed across all patients after 4 years (p=0.008, n=9), along with a reduction in myocardial resting blood flow (p=0.002, n=9) as observed in the DAPAHEART trial. Conclusions: This 4-years follow-up trial demonstrates that the 30% increase of CFR obtained after 4 weeks treatment is maintained after 4 years, confirming the previous published results in a new population. This improvement in CFR may have important implications on the management and prognosis of patients with T2D and CAD.