Effect of SGLT2 inhibition on coronary microvascular function in patients with type 2 diabetes

Background Treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitor reduces risk of cardiovascular death and heart failure but the underlying mechanisms remain poorly understood. It has been suggested that a shift in fuel source in the myocardium from glucose and free fatty acids to the more energy efficient ketogenesis reduces oxidative stress involved in coronary microvascular damage, leading to improved coronary microvascular function. Purpose To test the hypothesis that treatment with the SGLT2 inhibitor empagliflozin improves non-endothelial dependent coronary microvascular function. Methods We included 26 patients with type 2 diabetes in a double blinded, placebo-controlled cross-over study. Participants were treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was change in coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Secondary endpoints were change in echocardiographic parameters of cardiac systolic function and 184 cardiovascular protein biomarkers. Results Nineteen patients completed both study periods according to protocol. There was a significant weight loss and reduction in Hba1c after empagliflozin treatment (table). We found no improvement in CFVR and parameters of cardiac systolic function. We observed a general tendency of reduction in level of cardiovascular biomarkers after empagliflozin treatment (figure) with significant difference between empagliflozin and placebo for 27 proteins, including IL18, ST2, YKL40, ACE2 and leptin. Conclusions Despite a significant weight loss and reduction in Hba1c after empagliflozin treatment, we found no effect on non-endothelial dependent coronary microvascular function in patients with type 2 diabetes mellitus. Improvement in multiple biomarkers may indicate underlying mechanisms but need confirmation in larger studies. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Danish Council for Independent Research Table 1. Change in outcome parameters Figure 1. Change in biomarker levels