Role of Dapagliflozin in Ischemic Preconditioning in Patients With Symptomatic Coronary Artery Disease – DAPA-IP study protocol

Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5′-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate whether the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, documented ischemia by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo 4 exercise tests, the first two, with a time interval of 30 minutes between them, after the washout period of cardiovascular or hypoglycemic medications and, the last two, after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 minutes between them. Patients with stable multivessel CAD, preserved left ventricular ejection fraction (LVEF), and documented ischemia will be included. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischaemia-reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD.