Empagliflozin's Anti-Inflammatory Spectrum in Type 2 Diabetes Mellitus: Piecing Together the Puzzle

This article refers to ‘Unlocking the power of empagliflozin: Rescuing inflammation in hyperglycaemia-exposed human cardiomyocytes through comprehensive multi-level analysis’ by R. Benedetti et al., published in this issue on pages xx–xx. Originally developed for the treatment of type 2 diabetes mellitus (T2DM), sodium–glucose cotransporter 2 (SGLT2) inhibitors are currently part of guideline-directed medical therapy for the whole spectrum of heart failure. Irrespective of the diabetes status, the SGLT2 inhibitor empagliflozin decreases the risk of heart failure hospitalizations and cardiovascular death.1-4 Despite its clinical efficacy in heart failure, the exact molecular mechanisms underlying the beneficial effects of empagliflozin in heart failure remain unclear. Among its pleiotropic actions on the myocardium,5 anti-inflammatory effects, including reduction in NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activity6 and oxidative stress,7 have been reported. In this issue of the Journal, Benedetti et al.8 explored the anti-inflammatory properties of empagliflozin in T2DM via a three-step approach including meta-analyses of clinical trials, cellular data and in silico modelling. In detail, following a meta-analysis of clinical trials investigating the impact of empagliflozin on plasma biomarkers of systemic inflammation in T2DM patients, the impact of empagliflozin on human AC16 cardiomyocytes exposed to hyperglycaemia was investigated. Finally, the results were intersected with a published available dataset of T2DM patients with heart failure. Meta-analysis of clinical trials revealed reduced biomarkers of systemic inflammation (interleukin [IL]-6, tumour necrosis factor-α, C-reactive protein) in T2DM patients following empagliflozin treatment. In human AC16 cardiomyocytes cultured under hyperglycaemic conditions for 2 (acute) and 7 (chronic) days, empagliflozin decreased the hyperglycaemia-induced inflammatory pathways on transcriptional level, reduced cytokine release (IL-1ß and IL-6), expression levels of components of the NLRP3 inflammasome, intracellular Ca2+ levels and fatty acids. Empagliflozin alleviated the hyperglycaemia-induced oxidative stress phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) in cardiomyocytes, which was counteracted by inhibition of the anti-inflammatory NAD+-dependent deacetylase sirtuin 1 (SIRT1), highlighting a functional interrelationship between empagliflozin and SIRT1. Comparing differential gene expression from human AC16 cardiomyocytes with T2DM patients with heart failure and controls, the authors found that a substantial set of genes was highly expressed in hyperglycaemic cardiomyocytes treated with empagliflozin and cardiac biopsies of healthy controls. The study supports previously described anti-inflammatory properties of empagliflozin, including its capacity to reduce NLRP3 inflammasome activity6 be it here in cardiomyocytes under hyperglycaemic conditions. Whereas the authors can be praised for their multi-level study design, different aspects need to be considered. T2DM is an inflammatory disease in which the pancreatic islets and insulin-sensitive tissues such as adipose tissue, liver, muscle and the heart produce cytokines and chemokines, leading to the recruitment of immune cells into the tissues, and provoking systemic low-grade inflammation that further promotes inflammation in the heart. As such, cardiac inflammation in T2DM-associated diabetic cardiomyopathy can be explained by the combination of (1) the direct effect of hyperglycaemia on the cardiac cells, including cardiomyocytes, endothelial cells and (potentially) cardiac fibroblasts; (2) the subsequent infiltration of immune cells into the diabetic heart; and (3) the low-grade systemic inflammation, while (4) heart failure associated with diabetic cardiomyopathy can further trigger the inflammatory process.9 Given the complexity of diabetic cardiomyopathy and the diverse systemic and cardioprotective effects of empagliflozin, comparing differential gene expression from in vitro findings with cardiac biopsies, as done by the authors, warrants careful interpretation before drawing further conclusions. The authors compared the differential gene expression of hyperglycaemia-stressed cardiomyocytes with published transcriptome datasets from biopsies of T2DM patients with dilated hypokinetic post-ischaemic cardiomyopathy and healthy controls. They proposed that diabetic cardiomyopathy and T2DM-associated dilated hypokinetic post-ischaemic cardiomyopathy share key pathological features, such as inflammation, oxidative stress, and fibrosis. While these are indeed common factors in both conditions, as well as in many cardiac diseases, their specific contributions – such as duration, extent, and type – differ significantly. Dilated post-ischaemic cardiomyopathy in T2DM patients is primarily driven by an ischaemic trigger, leading to replacement fibrosis and eccentric remodelling with reduced ejection fraction. In contrast, diabetic cardiomyopathy is defined by abnormal myocardial structure and function in the absence of coronary artery disease, hypertension, or significant valvular disease. Its hallmark features include interstitial and perivascular fibrosis, hypertrophy, and diastolic dysfunction, with progression to systolic dysfunction and clinical heart failure. Thus, the pathogenesis of these conditions differs fundamentally, and they cannot be equated. Additionally, the authors concluded that the similar trends in gene expression between healthy controls and the hyperglycaemia+empagliflozin group suggest that their experimental model replicates the diabetic condition predisposing to heart failure or diabetic cardiomyopathy. While this is an intriguing hypothesis, the connection warrants further clarification and supporting evidence to strengthen the interpretation. The complexity of T2DM and diabetic cardiomyopathy also further accentuates the need for the use of a more translational in vitro model than the immortalized, proliferating human cardiomyocyte cell line AC16 under hyperglycaemic conditions. Human AC16 is a well known cell line and a recognized model system with the charm of its simplicity and reproducibility and ease of transfection and transduction. Though, the diversity of T2DM and its impact on the heart calls for a more complex model system taking besides hyperglycaemia, also hyperlipidaemia, hyperinsulinaemia, low-grade inflammation, immune cell infiltration and the multi-cellularity of the heart into account, with the latter supporting the use of human engineered heart tissue, cardiac organoids and cardiac living slices. In fact, using an organomimetic model of living myocardial slices derived from myocardial tissue of heart failure patients in a miniaturized manner, molecular events elicited by SGLT2 inhibitors in the diseased human myocardium in its in vivo three-dimensional composition could recently be shown.10 The less pronounced benefit of SGLT2 inhibitors in female compared to male heart failure patients11 and the potentially greater effect in Black and Asian patients12 further accentuates the need to unravel sex- and ethnicity-related differences in SGLT2 inhibitor responsiveness among others via the use of patient-derived cells/model systems,13 that is overcoming the use of one cell line of one sex and race, of which as for the human AC16 cell line in many cases information about biological sex and race is even not given. The authors also reveal that empagliflozin tempers the endoplasmic reticulum (ER) stress response by modulating key cellular pathways, a process significantly enhanced by the activation of the nutrient-sensitive metabolic regulator, SIRT1. Specifically, hyperglycaemic conditions markedly increased phosphorylation of eIF2α, a pivotal stress-response protein, indicating elevated ER stress. Treatment with empagliflozin reversed this effect, restoring phosphorylation levels to near-control conditions. However, inhibition of SIRT1 using EX-527 negated empagliflozin's protective effects, highlighting the synergistic relationship between empagliflozin and SIRT1 in alleviating ER stress. Stress granules (SGs), typically formed under translational stress, were monitored using G3BP1 and TIAR as markers. Interestingly, SG accumulation was not observed under hyperglycaemic conditions, but empagliflozin's ability to restore metabolic activity and reduce oxidative stress was observed. Conversely, SIRT1 inhibition reinstated oxidative stress markers, including eIF2α phosphorylation, reinforcing the critical role of SIRT1 in nutrient-stress adaptation. This underscores the potential of targeting SIRT1 to optimize empagliflozin's benefits, paving the way for improved strategies in managing hyperglycaemia-induced cellular dysfunction. In conclusion, despite some limitations and potential overinterpretations, the study by Benedetti et al.8 provides valuable insights into the complex interplay between diabetes, inflammation, and heart failure while highlighting the anti-inflammatory properties of empagliflozin. The anti-inflammatory effects of SGLT2 inhibitors on the diabetic heart can be attributed to several mechanisms: (1) their glucose-lowering effects, which reduce hyperglycaemia-induced cardiac inflammation, immune cell infiltration, and systemic low-grade inflammation; (2) their direct protective effects on hyperglycaemia-induced stress in cardiomyocytes, as supported by this study, in endothelial cells14 and potentially in cardiac fibroblasts; and (3) their contribution to improving heart failure outcomes (Figure 1). S.V.L. is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, SFB-1470-A07 and Project 536819681) and by the Deutsche Krebshilfe (Project 70115119). S.V. is supported by CIHR and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Conflict of interest: S.V. has received speaking and/or research honoraria from Novo Nordisk, Lilly, Amgen, Boehringer Ingelheim, AstraZeneca, Novartis, Amarin, HLS Therapeutics and Merck. All other authors have nothing to disclose.

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