Glucagon-like peptide-1 receptor agonists in lupus

Project Summary/Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with excess morbidity and premature mortality. Up to half of all patients with SLE will develop lupus nephritis, which also contributes to heightened risks of cardiovascular (CV) events and end-stage kidney disease (ESKD). These adverse outcomes are driven by a combination of uncontrolled lupus disease activity, chronic tissue damage including proteinuric nephropathy, and glucocorticoid toxicity, which exacerbates conventional CV risk factors. A major unmet need in lupus care is to improve kidney and CV outcomes, and novel treatment approaches are needed. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of anti-obesity and hypoglycemic agents with pleiotropic cardioprotective, nephroprotective, and anti-inflammatory effects. These medications have been found to prevent major adverse cardiac events (MACE) and reduce kidney disease progression in non- SLE populations, including those with overweight/obesity and/or type 2 diabetes. Our central hypothesis is that GLP-1RA medications will have similar to greater benefits in patients with SLE. The goal of this proposal is to investigate the potential role for GLP-1RA to improve outcomes for patients with SLE and lupus nephritis. In Aim 1, we will leverage a large SLE cohort in an administrative healthcare database to emulate target trials to test the hypothesis that GLP-1RA use versus no GLP-1RA use will reduce the risk of MACE and kidney disease progression, including new-onset ESKD, among patients with SLE and overweight/obesity. We will also utilize an electronic health record (EHR)-based SLE cohort from multiple academic and community hospitals to test the hypothesis that GLP-1RA use among patients with SLE will be associated with improvements in conventional CV risk factors (including blood pressure, cholesterol, and body weight/body mass index) and a reduction in proteinuria in the subgroup of patients with lupus nephritis. In Aim 2, we will use the same EHR-based SLE cohort to test the hypothesis that GLP-1RA use will be associated with a lower risk of lupus flares and reduced biomarkers of disease activity. The anticipated findings will provide critical evidence for the potential benefits of GLP-1RAs in treatment of patients with lupus. If successful, the anticipated findings will lead to a new treatment paradigm and improvements in SLE care.