Empagliflozin alters 10 protein pathways in non-diabetic, non-heart failure patients, impacting fibrosis and inflammation.

While Sodium-glucose cotransporter 2 (SGLT2) inhibitors like empagliflozin are established for reducing cardiovascular and cardiorenal events in patients with existing heart failure or diabetes, their potential benefits in primary prevention for individuals without overt disease remain less understood. This study addresses the gap in understanding the molecular mechanisms by which SGLT2 inhibitors might exert cardioprotective effects at a protein level in a non-diabetic and non-heart failure population, focusing on early markers of cardiac remodeling.

This investigation was a sub-study of the EMPA-HEART 2 CardioLink-7 randomized clinical trial. Participants without diabetes or clinically overt heart failure, but with risk factors for adverse cardiac remodeling, were randomized to receive either empagliflozin 10 mg/day or placebo for 6 months. Blood samples were collected at baseline and at the 6-month follow-up. Proteomics analysis, involving both discovery and verification phases, was performed on samples from n=21 empagliflozin-treated individuals and n=22 placebo recipients.

In the discovery phase, 28 out of 1622 proteins met the threshold for differential expression at 6 months. A subsequent verification phase confirmed 10 specific proteins. These included calmodulin-like protein 5, desmoplakin, hornerin, peroxiredoxin-2, macrophage colony-stimulating factor 1 receptor (M-CSFR1), 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 all 10 verified proteins from baseline to 6 months was significantly decreased in the empagliflozin group. Their identified functions span critical biological processes such as ion channel signaling, fibrosis, oxidative stress, inflammation, apoptosis, immune response, proteolysis, and neuromodulation, indicating broad mechanistic modulation. > The expression of 10 verified proteins, including desmoplakin and peroxiredoxin-2, was significantly decreased in the empagliflozin group compared to placebo from baseline to 6 months, suggesting broad pathway modulation.