Dapagliflozin, Inflammation and Left Ventricular Remodelling in Patients with Type 2 Diabetes and Left Ventricular Hypertrophy

Abstract Background and Aims SGLT2 inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there is some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a paucity of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with effects on inflammation. Methods We measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10mg daily or placebo for 12 months and underwent cardiac MRI at baseline and end of treatment. The primary analysis was to investigate treatment effect on the 12 months in inflammatory markers. We assessed the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation. Results Following 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p=0.026). There were no significant statistical changes in other inflammatory markers. There was no significant relationship between changes in inflammatory markers at 12 months and changes in LV mass (r=0.124) but there were modest correlations between changes in GLS and NLR (r=0.311), IL-1β (r=0.246), TNF-α (r=0.230) at 12 months. Overall dapagliflozin reduced LV mass and improved GLS. The effect of dapagliflozin on LV mass and GLS was not significantly different regardless of baseline levels of inflammation, although individuals with higher baseline IL-1β had a larger GLS improvement. Conclusions Although dapagliflozin caused a significant reduction in CRP compared to placebo, our study did not strongly suggest that the beneficial left ventricular remodelling caused by dapagliflozin was the result of any potential anti-inflammatory activity. Trial registration ISRCTN15573532