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Review
. 2025 Jul;16(7):1341-1365.
doi: 10.1007/s13300-025-01743-6. Epub 2025 May 9.

Role of Residual Inflammation as a Risk Factor Across Cardiovascular-Kidney-Metabolic (CKM) Syndrome: Unpacking the Burden in People with Type 2 Diabetes

Roya Ghafoury  1 , Mojtaba Malek  2 , Faramarz Ismail-Beigi  3 , Mohammad E Khamseh  4
Affiliations
Review

Role of Residual Inflammation as a Risk Factor Across Cardiovascular-Kidney-Metabolic (CKM) Syndrome: Unpacking the Burden in People with Type 2 Diabetes

Roya Ghafoury et al. Diabetes Ther. 2025 Jul.

Abstract

Type 2 diabetes mellitus (T2DM) is a global health crisis, with cardiovascular disease (CVD) accounting for 75% of mortality in this population. Despite advances in managing traditional risk factors, such as low-density lipoprotein cholesterol (LDL) cholesterol reduction (IMPROVE-IT, FOURIER), antithrombotic therapies (PEGASUS, COMPASS), and triglyceride-lowering agents (REDUCE-IT), a substantial residual cardiovascular risk persists, driven in part by chronic low-grade systemic inflammation. Chronic low-grade inflammation is a central driver of cardiovascular-kidney-metabolic (CKM) syndrome in T2DM, perpetuating residual cardiovascular risk despite optimal management of traditional risk factors. This narrative review synthesizes evidence on how inflammation accelerates coronary heart disease (CHD), heart failure (HF), stroke, diabetic kidney disease (DKD), and peripheral artery disease (PAD). We evaluate the anti-inflammatory mechanisms of current therapies such as statins, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, as well as emerging agents like colchicine and interleukin (IL)-1β/IL-6 inhibitors, emphasizing their differential efficacy across CKM traits. By integrating pathophysiological insights with clinical trial data, we propose biomarker-guided strategies to target inflammation as a modifiable risk factor, offering a roadmap to bridge the gap in diabetes-related cardiovascular care.

Keywords: Atherosclerosis; Cardiovascular-kidney-metabolic syndrome; Chronic inflammation; Inflammatory biomarkers; Residual cardiovascular risk; Type 2 diabetes mellitus.

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Conflict of interest statement

Declarations. Conflict of Interest: Mohammad E. Khamseh is an Editorial Board member of Diabetes Therapy. Mohammad E. Khamseh was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Roya Ghafoury, Mojtaba Malek, and Faramarz Ismail-Beigi declare no conflicts of interest. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Figures

Fig. 1
Fig. 1
Residual inflammation as a risk factor in CKM syndrome. Residual inflammation in CKM syndrome drives the progression of cardiovascular, kidney, and metabolic disorders in T2DM through diverse mechanisms. This leads to elevated inflammatory biomarkers in the circulation. The inflammation contributes to clinical outcomes, including coronary heart disease (CHD), heart failure (HF), stroke, diabetic kidney disease (DKD), and peripheral artery disease (PAD). Targeted anti-inflammatory therapies address the residual risk by reducing systemic inflammation. These therapies are listed in decreasing font size based on the strength of supporting evidence, with first-line therapies appearing in larger fonts and emerging treatments in smaller fonts
See this image and copyright information in PMC

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