Dapagliflozin, inflammation and left ventricular remodelling in patients with type 2 diabetes and left ventricular hypertrophy

Abstract

Background and aims: Sodium-glucose co-transporter 2 (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 are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack 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 its 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 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess 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 were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months.

Conclusions: Dapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin.

Trial registration: Clinicaltrials.gov NCT02956811 (06/11/2016).

Keywords: Cytokines; Global longitudinal strain; Heart failure; Inflammation; Left ventricle hypertrophy; Sodium-glucose co-transporter 2 inhibitors.

Fig. 1

Treatment and 12 months change in left ventricular mass stratified by above and below the median of baseline CRP of 1.07 mg/L, baseline IL-1β of 0.49 pg/ml, baseline IL-6 of 1.26 pg/ml, and baseline NLR of 2.06 in DAPA-LVH trial. Data are presented as mean [95% confidence interval (CI)]. Change in LV mass in grams in the placebo group (black) and the dapagliflozin group (blue)

Fig. 2

Treatment and 12 months change in global longitudinal strain (GLS) stratified by above and below the median of baseline CRP of 1.07 mg/L, baseline IL-1β of 0.49 pg/ml, baseline IL-6 of 1.26 pg/ml, and baseline NLR of 2.06 in DAPA-LVH trial. Data are presented as mean [95% confidence interval (CI)]. Change in GLS in percentage in the placebo group (black) and the dapagliflozin group (blue)