Giuliana G. Repetti, E. Dale Abel, Peter Tontonoz, Tamer Sallam
Obesity and its cardiometabolic sequelae remain a public health challenge. GLP-1R (glucagon-like peptide-1 receptor) agonists have emerged as a transformative therapy to combat obesity. Although weight loss is a key part of how these drugs work, growing evidence suggests their cardioprotective effects may transcend the reduction in adiposity. In this review, we examine the weight-dependent and weight-independent mechanisms by which the GLP-1 axis affects cardiovascular risk, with a particular focus on lipoprotein metabolism and adipose tissue plasticity. We explore how GLP-1R agonists exert favorable effects on postprandial lipoprotein metabolism and examine potential mechanisms by which they influence adipose tissue function to enhance metabolic health. Finally, we discuss outstanding questions regarding incretin-based therapies and present a potential framework for expanding the use of GLP-1R agonists from weight loss agents into components of cardiovascular risk reduction strategies. Looking ahead, it is clear that the GLP-1 axis is a pleiotropic regulator of cardiometabolic health whose full therapeutic potential has not yet been realized.