Type 2 diabetes and the cardio–renal–metabolic syndrome: The evolving roles of GLP-1 and dual GLP-1/GIP receptor agonists

Abstract

The impact of type 2 diabetes (T2D) extends beyond mere management of blood glucose; it also encompasses related cardiovascular, renal and metabolic issues. This interconnected framework, known as the cardio-renal-metabolic (CRM) syndrome, calls for a shift in therapeutic approach. While traditional treatments have made progress focusing on glucose management, a residual risk still exists for conditions such as atherosclerotic cardiovascular disease, chronic kidney disease, heart failure and obesity. The 2025 American Diabetes Association Standards of Care now emphasize treatment algorithms based on risk and complication management, prioritizing comorbidities associated with the CRM syndrome rather than solely focusing on glucose management. This article consolidates current evidence, mechanistic insights and clinical trial findings that support the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist to reduce CRM risk. We examine key cardiovascular and renal outcomes trials, as well as metabolic-related trials, such as weight loss and the management of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and their alignment with guideline-directed care. In addition to efficacy and safety, we also focus on addressing disparities in access and overcoming implementation challenges, such as low use among specific subpopulations. Lastly, we explore the future of incretin-based therapies, including new triple agonists and ongoing research. Prompt and equitable adoption of GLP-1-based therapeutic options could improve the standard of care for T2D by addressing the entire range of CRM syndrome.