Sodium-glucose cotransporter 2 inhibitor enhances mitochondrial stress resistance without altering ATP production in patients with ST-elevation myocardial infarction
N Apaijai, P Suwannasom, K Leemasawat, N Noparatkailas, A Phrommintikul, N Pagowong, S C Chattipakorn, N ChattipakornAbstract
Background
Previous clinical trials have demonstrated the cardioprotective effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure and acute coronary syndrome beyond glycemic control. Improvement in mitochondrial function has been proposed as a key mechanism underlying these cardioprotective effects in preclinical studies. However, the effects of SGLT2i on circulating mitochondrial function in patients with ST-segment elevation myocardial infarction (STEMI) have not been investigated.
Purpose
To determine whether SGLT2i improves circulating mitochondrial function in patients with STEMI.
Methods
This prospective, double-blind, randomized trial enrolled 45 patients with STEMI who were randomized in a 1:1 ratio to receive either SGLT2i (dapagliflozin 20 mg loading dose followed by 10 mg daily for 12 weeks) or placebo. Cardiac function was assessed by left ventricular ejection fraction (LVEF) using cardiac magnetic resonance imaging. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, and at 2 days, 2 weeks, 6 weeks, and 12 weeks following primary percutaneous coronary intervention (PCI) to evaluate mitochondrial function. The primary endpoint was ATP production in PBMCs. Secondary endpoints included LVEF and additional mitochondrial respiratory parameters.
Results
At baseline, ATP levels and LVEF were comparable between groups (Fig.1A,B). In the placebo group, ATP levels increased at 2- and 12-weeks post-PCI compared with their baseline (p< 0.05), whereas ATP levels remained unchanged in the SGLT2i group (Fig.1B). LVEF did not differ between groups at 12 weeks post-PCI (Fig.1A). Temporal improvement in mitochondrial function was observed in the placebo group, including increased basal respiration at 2 weeks post-PCI and enhanced spare respiratory capacity and maximal respiration at 2- and 6- weeks post-PCI; these parameters returned to baseline levels by 12 weeks (Fig.1C-E). Notably, at 12 weeks post-PCI, patients receiving SGLT2i exhibited significantly higher spare respiratory capacity compared with placebo (mean difference= −46.01; 95% CI= −90.71 to −1.41; p= 0.04, Fig.1E).
Conclusion
Although SGLT2i did not improve LVEF or ATP production within 12 weeks in STEMI patients, it enhanced mitochondrial stress resistance, as reflected by increased spare respiratory capacity. Longer treatment duration may be required to fully elucidate the mitochondrial and cardioprotective benefits of SGLT2i in STEMI.