426-P: Semaglutide, Empagliflozin, and Cagrilintide Reduce Levels of Serum Endotrophin in Type 2 Diabetic Rats

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) demonstrated cardiovascular (CV) and kidney outcomes benefit in persons with type 2 diabetes (T2D). The long-acting amylin analogue, cagrilintide, is under investigation for the treatment of obesity and T2D. Endotrophin, a pro-fibrotic fragment derived from collagen type VI, is an independent risk marker of mortality, CV and kidney outcomes, and dulaglutide treatment decreased levels of this biomarker compared with insulin glargine in persons with T2D. We investigated for the first time the effect of semaglutide, empagliflozin, and cagrilintide on endotrophin in type 2 diabetic rats. Method: We measured endotrophin (by the rodent PRO-C6 ELISA) in serum collected at baseline and study end from diabetic ZDF rats treated with either vehicle (n = 10), semaglutide (n = 7), empagliflozin (n = 4), or cagrilintide (n = 10). The dose chosen for semaglutide (50 nmol/kg), empagliflozin (30 mg/kg), and cagrilintide (10 nmol/kg) was based on previous research. Results: Levels of endotrophin increased significantly during the study in vehicle-treated rats, reflecting the disease progression (median [95% CI] for increase: 182.5 [55.87-298.0], P < 0.01). Interestingly, treatment with semaglutide, empagliflozin, and cagrilintide each attenuated this increase, resulting in significantly lower levels of endotrophin compared to vehicle at study end (P < 0.01), (P < 0.05), and (P < 0.01), respectively. Conclusion: We developed a novel, robust assay to detect the clinically relevant endotrophin biomarker in rodents. Levels of serum endotrophin increased over time in vehicle-treated rats, which is in line with endotrophin predicting disease progression in persons with T2D. In addition to the beneficial effects on metabolic factors, semaglutide, empagliflozin, and cagrilintide each reduced levels of endotrophin, suggesting a potential effect to reduce fibrosis.