SGLT2 inhibitor reduces epicardial adipose tissue in nondiabetic patients with HFrEF
Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study
Introduction and methods
The mechanisms of action of SGLT2 inhibitors in HFrEF remain largely unknown. The EMPA-TROPISM study previously showed that empagliflozin significantly improved LV volumes, LV mass, LV systolic function, functional capacity, and quality of life in nondiabetic patients with HFrEF, compared with placebo [1]. The current pre-specified secondary analysis of this study analyzed the effects of empagliflozin on epicardial adipose tissue (EAT), Subcutaneous adipose tissue (SAT), myocardial extracellular volume (ECV), aortic stiffness and inflammatory biomarkers.
A total of 84 nondiabetic adults with HFrEF were randomized in a 1:1 ratio to receive empagliflozin 10 mg daily or matching placebo in addition to optimal medical treatment. Patients underwent CMR scans at baseline and at 6 months post-randomization. Blood was taken from all participants at baseline after 6 months of treatment for the evaluation of plasma biomarkers using proteomics.
Main results
- EAT was quantified from the cine images in the end-diastolic short-axis. At 6 months, EAT was significantly reduced in the empagliflozin group, compared to the placebo group (-5.14 ml, 95%CI -8.24 to -2.04, vs. -0.75 ml, 95%CI -3.44 to 1.94, P<0.05).
- Empagliflozin also significantly reduced SAT between baseline and 6 months post-randomization, compared to placebo (-5.33 cm², 95%CI -12.21 to 1.55, vs. an increase of 9.13 cm², 95%CI -2.05 to 20.31, P<0.05).
- Myocardial ECV was significantly reduced in the empagliflozin group at 6 months follow-up, compared to the placebo group (-1.25%, 95%CI -1.81 to -0.69, vs. an increase of 0.24%, 95%CI -0.33 to 0.81, P<0.01). Empagliflozin also significantly reduced matrix volume (-4.85 ml, 95%CI -6.84 to -2.86, vs. an increase of 0.70, 95%CI -0.8 to 2.2 in the placebo group, P<0.01) and cardiomyocyte volume (-6.95 ml, 95%CI -9.47 to -4.43 vs. an increase of 0.80 ml, 95%CI -1.8 to 3.4 in the placebo group).
- Aortic stiffness was estimated using pulsed wave velocity (PWV). At 6 months follow-up, aortic PWV was significantly decreased in the empagliflozin group (-0.58 cm/s, 95%CI -0.91 to -0.25), compared to an increase of 0.60 cm/s (95%CI 0.16 to 1.04, P<0.01) in the placebo group.
- Targeted proteomic profiling was used to assess the effects of treatments on 92 proteins. Significant differences between the empagliflozin group and placebo group were found were found in the expression of 17 proteins. These proteins were mostly involved inflammatory pathways. After adjustment with the Benjamini-Hochberg method, tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) and E-selectin remained significant (P=0.0045 and P=0.0134, respectively).
Conclusion
In nondiabetic patients with HFrEF, EAT, SAT, myocardial ECV, matrix volume and cardiomyocyte volume were significantly reduced after 6 months treatment with empagliflozin compared to 6 months placebo. Treatment with empagliflozin also normalized aortic stiffness and reduced several inflammatory biomarkers.
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