SGLT2 inhibition could potentially impact inflammation in acute myocardial infarction

This commentary refers to ‘Empagliflozin in acute myocardial infarction: the EMMY trial’, by D. von Lewinski et al., https://doi.org/10.1093/eurheartj/ehac494 and the discussion piece ‘Modulation of inflammatory response after myocardial infarction: one explanation for the cardiovascular benefit of empagliflozin in the EMMY trial?’, by A. Trimaille et al., https://doi.org/10.1093/eurheartj/ehad257.

We thank Trimaille and colleagues for their letter and thoughts on our EMMY trial investigating the impact of early empagliflozin treatment initiation (within 72 h) vs. placebo in people having an acute myocardial infarction.¹ In their letter, the authors raise the question about the mechanisms explaining the beneficial effects of empagliflozin on measurements of cardiac structure and function observed in the EMMY trial and specifically the role of inflammation and anti-inflammatory properties of empagliflozin in this patient population.² The authors highlight an important topic, since a plethora of potential mechanisms explaining the beneficial effects of sodium glucose-linked transporter-2 inhibitors (SGLT2i) have been proposed, including hemodynamic and volume regulation, decrease in oxidative and endoplasmatic reticulum stress, restoration of mitochondrial stress, ketogenesis, and suppression of proinflammatory pathways.³ A recent interaction network analysis highlighted autophagy, oxidative stress, aging, senescence, inflammation, and AMPK pathways as their key interactions to explain direct and indirect SGLT2i mechanisms of action.⁴ Furthermore, in vitro and in vivo inflammation models suggested a significant role of empagliflozin on AMPK activation-mediated energy repletion and reduced inflammation.⁵ However, assessing the impact of SGLT2i in human clinical trials is more challenging, as sequential myocardial biopsies would be required to elucidate local inflammatory processes and the impact of SGLT2i treatment. In EMMY, we did collect biomarker samples, allowing us to measure circulating biomarkers representing inflammation. Currently analyses on high sensitivity C-reactive protein, interleukin-6, neutrophil-to-lymphocyte ratio, and trimethylamine N-oxide are being performed to further elucidate the mediatory role of inflammation in the beneficial effects of empagliflozin after acute myocardial infarction. However, measuring systemic levels of biomarkers might not be best suited to capture local inflammatory processes taking place in the myocardium.

Declarations

Disclosure of Interest

H.S. is on the advisory board and speakers bureau of by Amarin, Boehringer Ingelheim, NovoNordisk, Eli Lilly, and Daiichi Sankyo and received research funding (to the Medical University of Graz) from Eli Lilly, Boehringer Ingelheim and Sanofi. D.v.L. is on the advisory board and speakers bureau of AstraZeneca and Boehringer Ingelheim and received research funding (to the Medical University of Graz) from Boehringer Ingelheim.

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