Proteomics analysis of empagliflozin in patients without diabetes or overt heart failure from empagliflozin and cardiac remodeling in people without diabetes CardioLink-7 randomized clinical trial.

BACKGROUND

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular and cardiorenal events in people across the spectrum of heart failure. Using proteomics analysis, this study investigated the potential benefits of SGLT2 inhibitors in primary prevention at a protein level in patients without diabetes or heart failure.

METHODS

This is a sub-study of the EMPA-HEART 2 CardioLink-7 trial, which randomized people without diabetes or clinically overt heart failure but with risk factors for adverse cardiac remodeling to empagliflozin (10 mg/day) or placebo for 6 months. Blood samples were collected during the randomization visit and at the 6-month follow-up visit for proteomics analysis. Our investigation involved two phases of approach: discovery and verification.

RESULTS

Samples from individuals assigned to empagliflozin (n = 21) and placebo (n = 22) (median baseline N-terminal pro-B-type natriuretic peptide levels: 33.9 and 78.4 pg/ml, respectively) were analyzed. In the discovery phase, 28 of 1622 proteins fulfilled our threshold for being differentially expressed at 6 months. Ten proteins were verified, including calmodulin-like protein 5, desmoplakin, hornerin, peroxiredoxin-2, macrophage colony-stimulating factor 1 receptor, endosialin, high-temperature requirement serine protease A1, immunoglobulin epsilon heavy chain, proteasome subunit beta type-5, and cerebellin-4. Compared to the placebo group, the expression of these proteins from baseline to 6 months was all significantly decreased in the empagliflozin group. Their functions involved ion channel signaling, fibrosis, oxidative stress, inflammation, apoptosis, immune response, proteolysis, and neuromodulation.

CONCLUSION

Empagliflozin modified multiple biologically relevant pathways in the nondiabetes and non-heart failure setting. These findings should be considered hypothesis-generating and warrant validation in larger, adequately powered studies.