GLP-1-based therapeutics for cardiorenal protection in metabolic diseases
Ellen M. Apperloo, Hiddo J.L. Heerspink, Daniël H. van Raalte, Marcel H.A. Muskiet
Abstract
Over the 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 body weight-reducing efficacy in clinical and real-world studies. In addition, mounting data established their cardiorenal benefits beyond glycaemic 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 than in 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 fuelled the development of new single molecules that combine GLP-1R agonism with activation of other entero-pancreatic hormone receptors [e.g. glucose-dependent insulinotropic 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 metabolic and weight-reducing efficacy compared with 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 hyperglycaemia and body weight, recent evidence supporting their cardiorenal benefits and clinical implications of these advancements.