Insights into mechanism of action of SGLT2i in chronic HF using proteomics
Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program
Introduction and methods
SGLT2is reduce the risk of CV death, HF hospitalization, and major adverse renal events . However, their mechanism of action has not been fully elucidated.
Aim of the study
The authors aimed to gain insights into the potential mechanism of action of the SGLT2i empagliflozin in patients with chronic HF by collecting samples before and following short- or long-term treatment with empagliflozin or placebo.
Plasma samples of 1139 patients from the EMPEROR-Reduced (300 empagliflozin, 300 placebo) and EMPEROR-Preserved (270 empagliflozin, 269 placebo) trials were randomly selected. Eventually, 1134 patients with good-quality samples were included in the pooled analysis. In the plasma samples, expression levels of 1283 circulating proteins were measured at baseline and at week 12 or week 52 using the Olink® Explore 1536 platform.
Differences in the change in protein expression levels between the empagliflozin and placebo groups were assessed, while adjusting for prespecified baseline covariates (i.e., age, sex, geographical region, DM, LVEF, and eGFR). To identify the biological effects of the differentially-expressed proteins on the heart and kidneys, the authors also conducted a biomedical literature search.
Differentially-expressed proteins at week 12
- At week 12, 32 of 1283 proteins (2.49%) fulfilled the threshold for differential expression: From baseline to week 12, the levels of these proteins were increased by ≥10% for empagliflozin versus placebo, with a false discovery rate <1% (which is more stringent that the commonly used rate of <5%).
- Of these 32 differentially-expressed proteins, 9 showed the largest treatment effect of empagliflozin (>15% increase, with false discovery rate < 1%). These proteins were: insulin-like growth factor-binding protein 1 (IGFBP1), transferrin receptor protein 1 (TfR1), carbonic anhydrase 2 (CA2), erythropoietin, protein-glutamine gamma-glutamyltransferase 2 (TGM2), thymosin beta-10 (TSMB10), U-type mitochondrial creatine kinase (uMtCK), insulin-like growth factor-binding protein 4 (IGFBP4), and adipocyte fatty acid–binding protein 4.
- A post-hoc sensitivity analysis that included eGFR change from baseline to week 12 as additional covariate showed that 5 of the 32 proteins now fell below the threshold for differential expression. The false discovery rate of the remaining 27 proteins increased slightly but remained <5%.
Differentially-expressed proteins at week 52
- The changes in the protein levels from baseline to week 52 were generally in agreement with those from baseline to week 12, except for the change in the expression level of kidney injury molecule-1 (KIM-1).
- The KIM-1 level decreased by 12% (false discovery rate: 0.006%) in the empagliflozin group compared with the placebo group between baseline and week 52, but there was no significant change between baseline and week 12.
Biological effects of differentially-expressed proteins on the heart
- Of the 28 differentially-expressed proteins between baseline and week 12 or week 52, 14 had been shown in the literature to have cardiac effects.
- The most common cardiac effect was the promotion of autophagic flux (5 proteins). This was particularly typical of the 3 heart-acting proteins with the largest effect size (IGFBP1, TfR1, and erythropoietin).
- Other effects of the differentially-expressed proteins on the heart included reduction of oxidative stress or its consequences and improvement of mitochondrial health in the myocardium (TfR1, phospholipase A2, angiopoietin-related protein 4, IGFBP4, and uMtCK); inhibition of cardiac apoptosis, inflammation, and fibrosis (erythropoietin, and connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed family member 5); and enhancement of cardiac repair, regenerative capacity, and energy metabolism (retinol-binding protein 2 (RBP2), IGFBP4, TGM2, and uMtCK).
Biological effects of differentially-expressed proteins on the kidneys
- Of the 28 differentially-expressed proteins, 9 had established renal effects.
- The effects of the differentially-expressed proteins on the kidneys included promotion of renal autophagy, integrity, and regeneration (RBP2, TSMB10, and epithelial cell adhesion molecule); suppression of renal injury, inflammation, and fibrosis (uromodulin and KIM-1); and modulation of tubular sodium reabsorption (CA2, guanylin, and uromodulin).
Large-scale proteomic analysis of plasma samples of chronic HF patients showed that the change in the expression level of 28 proteins differed after 12- or 52-week treatment with empagliflozin versus placebo. These differentially-expressed proteins have been shown to promote autophagic flux, suppress inflammation and fibrosis, and stimulate repair and regeneration in both the heart and kidneys. In addition, 3 of the identified proteins are known to be involved in modulation of renal sodium reabsorption, which can limit the long-term natriuretic effects of SGLT2is. According to the authors, “the results of these experimental studies are likely to be highly relevant to the clinical setting.”
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