GLP-1-based therapeutics for cardiorenal protection in metabolic diseases

Abstract Over last decade, significant progress has been made in cardiorenal protection for metabolic diseases, such as type 2 diabetes (T2D) and obesity. With an expanding range of pharmacological options and continuously evolving guidelines, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have garnered substantial clinical and societal attention for their role in T2D and weight-management. GLP-1RAs have consistently demonstrated robust HbA1c- and bodyweight-reducing efficacy in clinical and real-world studies. In addition, mounting data established their cardiorenal benefits beyond glycemic control in select high-risk populations. In T2D, GLP-1RAs have been shown to improve both hard cardiovascular and, more recently, relevant kidney outcomes. Meanwhile, in individuals with obesity but without T2D, semaglutide (at a higher dose compared to T2D) reduces body-weight by up to 15%, and lowers the risk of major adverse cardiovascular-events by 20%. The success of GLP-1-based therapy fueled the development of new single-molecules, that combine GLP-1R agonism with activation of other entero-pancreatic hormone receptors (e.g. glucose-dependent insulinoptropic polypeptide [GIP], glucagon and amylin) aiming to achieve complementary and potentially synergistic effects. These next-generation GLP-1-based therapeutics for metabolic diseases, either already available or approaching clinical approval, appear to enhance the metabolic and weight-reducing efficacy compared to existing GLP-1RAs. An example is tirzepatide, a dual GLP-1/GIP receptor agonist, which has been approved for both T2D and obesity-management, demonstrating up to 22.5% weight-loss in phase-3 trials. This review explores the landscape of current and emerging GLP-1-based therapies, their efficacy in managing hyperglycemia and bodyweight, recent evidence supporting their cardiorenal benefits, and clinical implications of these advancements.