Physicians' Academy for Cardiovascular Education

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

Literature - Zannad F, Ferreira JP, Butler J, et al. - Eur Heart J. 2022 Aug 26;ehac495 [Online ahead of print]. doi: 10.1093/eurheartj/ehac495

Introduction and methods


SGLT2is reduce the risk of CV death, HF hospitalization, and major adverse renal events [1]. 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.

Main results

Differentially-expressed proteins at week 12

Differentially-expressed proteins at week 52

Biological effects of differentially-expressed proteins on the heart

Biological effects of differentially-expressed proteins on the kidneys


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.”


Show references

Find this article online at Eur Heart J.

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