The effect of GLP-1RAs and co-agonists on body composition across obesity and type 2 diabetes

Obesity has become a major global public health concern. The excessive accumulation of abdominal adipose tissue represents a major risk factor for metabolic syndrome, cardiovascular disease, type 2 diabetes mellitus (T2DM), certain malignancies, hepatic steatosis, and cerebrovascular accidents. Visceral adipose tissue (VAT) deposition exhibits significantly greater pathogenic potential than subcutaneous adipose tissue (SAT). When conventional lifestyle modifications (including caloric restriction and increased physical activity) prove insufficient for achieving clinically meaningful weight reduction, pharmacological interventions or metabolic bariatric surgery may be considered to improve quality of life and mitigate obesity-related complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert their therapeutic effects through several mechanisms, including stimulating glucose-dependent insulin secretion, suppressing glucagon release, reducing appetite, delaying gastric emptying, and promoting weight loss. Currently, several of these agents are approved for the management of both T2DM and obesity. Moreover, emerging therapeutic strategies have expanded beyond single GLP-1 receptor activation to encompass dual and triple agonists that concurrently target glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptors. These co-agonists, such as tirzepatide (a dual GIP/GLP-1 receptor agonist) and retatrutide (a triple GIP/GLP-1/glucagon receptor agonist), demonstrate enhanced efficacy in glycemic control and weight reduction compared to selective GLP-1RAs alone, offering promising avenues for comprehensive metabolic management in patients with obesity and T2DM. Recent advances have deepened our understanding of GLP-1RA mechanisms in weight regulation, with a particular emphasis on their effects on body composition. Contemporary therapeutic strategies have evolved from focusing solely on weight reduction to prioritizing the maintenance of lean muscle mass during weight loss. This review systematically examines how GLP-1RAs and novel GLP-1 co-agonists contribute to the optimization of body composition in patients with obesity, highlighting their potential to achieve superior metabolic outcomes beyond simple weight reduction.