To evaluate the neuroprotective potential of empagliflozin using the Olink Neurodegeneration Panel: A post-hoc analysis of the EMPEROR Program

Heart failure is a long-term condition in which the heart cannot pump blood as well as it should. It affects tens of millions of people worldwide and is a leading cause of hospital admission and early death. Many people with heart failure also experience problems with memory and thinking over time. This suggests that heart disease and brain health are closely connected, sometimes called the “heart–brain connection.” Reduced blood flow, long-term inflammation, and changes in body metabolism may slowly damage brain cells, but this process is still poorly understood.

Empagliflozin is a medicine currently used to treat heart failure, kidney disease and diabetes (uncontrolled blood sugar). It belongs to a group of drugs called sodium–glucose co-transporter 2 (SGLT2) inhibitors, which lower blood sugar and protect the heart and kidneys. Large clinical trials have already shown that empagliflozin reduces the risk of death and hospitalisation in people with heart failure. However, it is not yet known whether this treatment can also protect the brain from ongoing damage.

In this study, we will investigate whether empagliflozin may help reduce injury to brain cells in people with heart failure. We will do this by analyzing measurements of substances in the blood that are released when brain cells are damaged. These substances, often called biomarkers, include proteins linked to nerve injury and diseases such as Alzheimer’s disease. Higher levels of these proteins may reflect ongoing damage to the brain.

We will use the blood sample data from two large heart failure trials, EMPEROR-Reduced and EMPEROR-Preserved. We will analyze 41 different brain-related proteins in the blood samples taken at the start of the trial and again after one year of treatment. We will compare people who received empagliflozin with those who received a placebo, which is an inactive treatment, to see whether empagliflozin slows the rise of these brain injury markers over time.

We also aim to understand whether these brain-related proteins can help predict future health outcomes. Specifically, we will test whether people with higher levels of these proteins at the start of the study are more likely to die from cardiovascular causes or be hospitalised for worsening heart failure.

This research is important because it may show that a treatment already used for heart failure also helps protect the brain. If successful, these blood markers could help doctors identify patients at higher risk of both heart and brain complications and guide future clinical trials toward more personalised treatment strategies.