{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:07:14Z","timestamp":1788865634788,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"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. Pharmacol."],"abstract":"<jats:p>Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease (CKD) and kidney failure in addition to determining an elevated risk of cardiovascular (CV) disease. Traditional approaches to DKD management have focused primarily on slowing kidney disease progression through improved glycemic control. However, growing recognition of the complex interplay among metabolic, kidney, and CV dysfunction has led to the emergence of the cardio-kidney-metabolic (CKM) syndrome framework, emphasizing the interconnected pathophysiology and shared risk profiles of these conditions. This evolving paradigm has transformed the understanding and management of DKD from an isolated kidney disorder to a multisystem disease requiring integrated therapeutic strategies. Recent advances have significantly altered the landscape of DKD management. In addition to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, newer therapies including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists have demonstrated substantial kidney and CV protective effects. Emerging evidence suggests that combination therapy may potentially shift the treatment paradigm from slowing CKD progression toward preservation of kidney function. In this review, we discuss DKD within the broader framework of CKM syndrome, highlighting the epidemiologic, pathophysiologic, prognostic, and therapeutic intersections among diabetes, CKD, and CV disease. We summarize major therapeutic advances, review evidence supporting multidrug combination strategies, and examine current gaps between clinical evidence and real-world implementation. We further propose a phenotype-driven framework for sequencing combination therapy based on each patient\u2019s dominant pathophysiologic driver as a hypothesis-generating alternative to uniform add-on strategies. Finally, we discuss the future direction of DKD management and the need for integrated multidisciplinary approaches aimed at improving outcomes.<\/jats:p>","DOI":"10.3389\/fphar.2026.1907928","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:14:06Z","timestamp":1788862446000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Diabetic kidney disease within the framework of cardio-kidney-metabolic health: a paradigm shift"],"prefix":"10.3389","volume":"17","author":[{"given":"Juarez R.","family":"Braga","sequence":"first","affiliation":[{"name":"Division of Nephrology, Central Arkansas Veterans Health System","place":["Little Rock, AR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Ayub","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Central Arkansas Veterans Health System","place":["Little Rock, AR, United States"]},{"name":"Department of Nephrology, University of Arkansas for Medical Sciences","place":["Little Rock, AR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srikanth","family":"Vallurupalli","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Arkansas for Medical Sciences","place":["Little Rock, AR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nithin","family":"Karakala","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Arkansas for Medical Sciences","place":["Little Rock, AR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph H.","family":"Holthoff","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Central Arkansas Veterans Health System","place":["Little Rock, AR, United States"]},{"name":"Department of Nephrology, University of Arkansas for Medical Sciences","place":["Little Rock, AR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1681\/ASN.2012070718","article-title":"Kidney disease and increased mortality risk in type 2 diabetes","volume":"24","author":"Afkarian","year":"2013","journal-title":"J. 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