Growth Differentiation Factor-15 in Sodium–Glucose Cotransporter 2 Inhibition: Mechanistic Insights from the EMPEROR Program

This article refers to ‘Growth differentiation factor-15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program’ by J.P. Ferreira et al., published in this issue on pages 155–164. Sodium–glucose cotransporter-2 (SGLT2) inhibitors are an essential part of guideline-directed medical therapy in patients with chronic heart failure (HF).1, 2 Initially developed as glucose-lowering agents for the treatment of type 2 diabetes mellitus (T2DM), SGLT2 inhibitors have been demonstrated to substantially reduce the risk of cardiovascular death or hospitalization for HF, cardiovascular death, first hospitalization for HF and all-cause mortality across the whole spectrum of systolic left ventricular ejection fraction and irrespective of T2DM.3 In addition, clinical trials have shown that SGLT2 inhibitors significantly improve outcomes in patients with chronic kidney disease with or without T2DM.4, 5 The underlying mechanisms by which SGLT2 inhibitors exert their effects are still not completely elucidated and several theories have been put forward, involving (i) enhancement of cardiac energy metabolism, (ii) decrease of inflammation, (iii) attenuation of adverse cardiac remodelling and fibrosis, and (iv) improvement of vascular function.6 In this issue of the Journal, Ferreira and colleagues report an exploratory analysis from the EMPEROR (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure) program focusing on the prognostic implications of growth differentiation factor-15 (GDF-15) and the effect of empagliflozin on GDF-15 levels in patients with HF.7 The study cohort comprised 1124 patients recruited from the EMPEROR-Reduced and EMPEROR-Preserved trials who received either empagliflozin 10 mg once daily (n = 564) or placebo (n = 560) in addition to standard HF medication. Patients with the highest baseline levels of GDF-15 (3rd tertile) were significantly older, had longer duration of HF and a greater comorbidity burden including T2DM, hypertension, atrial fibrillation and chronic kidney disease. The study results demonstrated that GDF-15 was significantly associated with higher rates of cardiovascular death, HF hospitalization and a composite kidney endpoint (relative decrease of estimated glomerular filtrate rate [eGFR] ≥40%, absolute decrease of eGFR to <10–15 ml/min/1.73 m2 or renal replacement therapy) in patients with HF. These findings are in line with multiple previous studies identifying GDF-15 as a significant prognostic biomarker linked to outcomes in cardiovascular diseases, including HF, valvular heart disease, atherosclerosis and coronary artery disease.8-10 GDF-15 is a member of the transforming growth factor beta (TGF-β) superfamily and is secreted by different cell types including cardiomyocytes, hepatocytes, macrophages, endothelial cells and adipocytes.10, 11 While GDF-15 is only weakly expressed in most organs under physiological conditions, it is upregulated in response to pathological states such as ischaemia, inflammation, tissue injury and biomechanical stress.10-12 GDF-15 plays an important role in various cardioprotective pathways and exerts anti-inflammatory, anti-apoptotic and anti-hypertrophic effects.10-13 As a major finding of the current study, empagliflozin led to an 8% increase of GDF-15 levels after 52 weeks of treatment. This was primarily observed in patients not receiving metformin which is an established activator of adenosine monophosphate-activated protein kinase (AMPK) and a potent stimulator of GDF-15 expression. A similar effect was observed in the Empire HF Biomarker substudy which included 190 patients with HF with reduced ejection fraction.14 Notably, the Empire HF Biomarker study reported an inverse relationship of empagliflozin-induced GDF-15 elevation and adverse markers of left ventricular geometry as well as circulating high-sensitivity troponin T levels. These findings support the cardioprotective properties of increased GDF-15 levels upon SGLT2 inhibition which must be distinguished from GDF-15 elevations in treatment-naïve HF patients where GDF-15 serves as a surrogate parameter of disease severity and a marker of poor outcomes. Interestingly, no other standard HF therapy, including sacubitril/valsartan, has been shown to have a significant impact on GDF-15.15 This clearly underscores the unique properties of SGLT2 inhibitors as multi-system, cardiometabolic drugs. Overall, the authors should be congratulated on their study which supports the role of GDF-15 as a biomarker in HF and offers hypothesis-generating insights into the interplay of GDF-15 and SGLT2 inhibition. Their findings should be further explored, as this may pave the way towards more specific HF therapies in the future. Conflict of interest: none declared.