Protective Effects of ACF210, a Dual GLP-1/APJ Receptor Agonist, against Cardiovascular-Kidney-Metabolic Syndrome Induced by T2D

Current therapies cannot simultaneously address the interconnected metabolic, cardiac, and renal damage in Cardiovascular-Kidney-Metabolic (CKM) syndrome. This study investigated ACF210, a novel long-acting dual agonist targeting both GLP-1 and APJ receptors, as a potential treatment for type 2 diabetes (T2D)-induced CKM syndrome. ACF210 was synthesized by fusing the human IgG4 Fc fragment to the C-terminus of GLP-1 and the N-terminus of Elabela-21 (ELA). In vitro receptor activation assays confirmed that ACF210 effectively activated the GLP-1 receptor while inhibiting APJ-related cAMP signaling. db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced T2D were treated with dulaglutide, Fc-ELA, or ACF210 for 12 weeks. Observation of organizational structure, functional assessment and serum analyses were conducted. ACF210 outperformed other treatments, showing superior improvements in blood glucose control, β-cell function, and reduction of hepatic steatosis. Crucially, it provided significant multi-organ protection: enhancing cardiac diastolic function, reducing biomarkers of heart failure (NT-proBNP), and lessening mitochondrial damage and fibrosis, and inducing the microangiogenesisl in the heart. In the kidneys, it improved function, indicated by lower cystatin C levels, and mitigated podocyte damage. In conclusion, ACF210 not only effectively alleviates dysglycemia by enhancing β-cell function but also significantly protects against diabetes-associated hepatic, cardiac, and renal damage, supporting its further exploration for the clinical management of CKM syndrome.