From metabolism to microcirculation: the multifaceted vascular benefits of SGLT2 inhibitors in chronic heart failure

Heart failure (HF) progression is critically linked to microvascular dysfunction and metabolic disturbances. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) exert their known cardioprotective effects through mechanisms extending beyond glycemic control, notably by influencing cellular metabolism and potentially enhancing microvascular integrity (Tarnawska et al., 2025). We previously found that dapagliflozin, an SGLT2i, improved endothelial cell energy metabolism by enhancing mitochondrial respiration in cell cultures and mouse models (Walczak et al., 2025).

This study was designed to assess the impact of SGLT2i therapy on L-arginine metabolism and nitric oxide (NO) production, and to correlate these changes with improvements in microvascular function in patients with chronic HF and ejection fraction above 40%.

We prospectively analyzed plasma amino acids, NO metabolites and microvascular function in 16 HF patients (Table 1) before and after the initiation of dapagliflozin or empagliflozin (10 mg/day) treatment. Levels of L-arginine and related metabolites (L-ornithine, L-citrulline, ADMA, and SDMA) were precisely quantified using liquid chromatography coupled to mass spectrometry. NO metabolites were measured via colorimetric assay. Peripheral microvascular function was non-invasively assessed using flow-mediated skin fluorescence (FMSF), which reflects overall microcirculatory and metabolic conditions by measuring the skin fluorescence of reduced nicotinamide adenine dinucleotide (NADH) following brachial artery occlusion (Parzuchowska et al., 2025).

Following three months of SGLT2i treatment, a significant reduction in plasma L-arginine concentration was observed, alongside favorable trends toward increased L-citrulline, NO metabolites, and L-ornithine levels. Peripheral microvascular function, assessed using the FMSF technique, showed a significant improvement in the Normoxia Oscillatory Index (NOI) parameter as early as 1 month, with sustained improvement at 3 months compared with baseline. Crucially, the NOI parameter, which reflects resting microcirculation efficiency, showed significant inverse correlations with the endogenous NO synthase inhibitors: ADMA (r=-0.52, p<0.05) and SDMA (r=-0.59, p<0.05).

SGLT2i have the potential to enhance microcirculation in HF patients probably by improving NO metabolism and ammonia detoxification, reinforcing endothelium-targeted therapeutic strategies.

Patient characteristics.