{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:53:28Z","timestamp":1791928408508,"version":"4.3.4"},"reference-count":185,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Type 2 diabetes (T2D) has been treated as an underlying disease\u2014hyperglycemia, but is instead a systemic disease\u2014mediating the network of neural, endocrine, and immune signaling. In recent years, the concept of the cardio\u2013renal\u2013cerebral\u2013metabolic axis has provided an integrative pathophysiological framework for understanding the multisystem complications of diabetes. From this perspective, the present review systematically elucidates the substantial evolution in modern T2D therapeutic strategies from simple glycemic control to comprehensive multi-organ protection. The primary pathology is that high insulin resistance and chronic metabolic disturbances trigger oxidative stress and inflammation, which in turn drive a vicious cycle in the heart, kidneys, and brain. In this review, we demonstrate that new drugs based on sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and mineralocorticoid receptor antagonists, which are capable of lowering glucose to promote efficient glycemic control, decrease cardiovascular events, lower the risk of renal disease, and demonstrate neuroprotective properties as the key to organ protection. Additionally, non-pharmacological interventions and new treatments can be combined as a multi-targeting, multilayer management system. Furthermore, greater knowledge and integration of the cardio-renal-cerebral-metabolic axis could signal a shift toward precision medicine to stabilize the network's homeostasis and improve long-term patient outcomes.<\/jats:p>","DOI":"10.3389\/fmed.2026.1746457","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T14:50:27Z","timestamp":1774363827000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Systemic effects of type 2 diabetes therapies: an integrated perspective on the cardio\u2013renal\u2013 cerebral\u2013metabolic axis"],"prefix":"10.3389","volume":"13","author":[{"given":"Lin","family":"Zhu","sequence":"first","affiliation":[{"name":"University Town Hospital, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Department of Endocrinology","place":["Jinan, 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