The antifibrotic effect of empagliflozin: Insights from the EMPIRE trial programme

Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors are foundational in treating patients with heart failure (HF), type 2 diabetes (T2D), and chronic kidney disease (CKD). One proposed mechanism behind the clinical effect is attenuation of fibrotic pathways. However, clinical data to support this mechanism are lacking. Purpose To investigate the antifibrotic effect of empagliflozin. Methods Pooled analysis of the investigator-initiated Empire trial programme, consisting of two separate double-blind, randomised, placebo-controlled trials; the Empire HF trial including patients with chronic HF with reduced ejection fraction (HFrEF) on optimal guideline-directed medical therapy and the Empire Prevent trial including patients with obesity at risk of HF. Patients were treated for 12 or 24 weeks, respectively, with empagliflozin 10 mg once daily or matching placebo. The allocation sequence was computer-generated, and treatment allocation was masked. The endpoints of interest were the between-group difference in change of circulating fragments of the N-terminal pro-peptide of type III collagen (PRO-C3) and the C-terminal pro-peptide of type VIa3 collagen (PRO-C6) from baseline to end of follow-up. All analyses were performed in the intention-to-treat population in an analysis of covariance model with baseline adjustment for PRO-C3 or PRO-C6, respectively, as well as age, sex, and study site, and with the allocated group as a fixed factor. Results Overall, 380 patients (N=188 in empagliflozin and N=192 in placebo) were included in the analyses. Baseline characteristics were well balanced (Table 1). Mineralocorticoid-receptor antagonist treatment was established in 35% (66% in patients with HFrEF). The adjusted ratio of change from baseline to end of follow up for empagliflozin versus placebo for PRO-C3 was 0.90 [95% confidence interval 0.85-0.95; P<0.0001], corresponding to a 10% relative reduction with empagliflozin. For PRO-C6, the adjusted ratio of change was 0.99 [0.95-1.03; P=0.54] (Figure 1). No significant treatment interactions were observed across subgroups defined by baseline PRO-C3 or PRO-C6, HF, CKD, or BMI (all P interaction > 0.05). Conclusions Treatment with empagliflozin significantly decreased levels of circulating PRO-C3, reflecting attenuated systemic fibroblast activation. This effect did not differ in important clinical subgroups. To what extent this indicated antifibrotic effect may underpin the clinical effects of empagliflozin remains to be elucidated.