Diabetes-Driven Atherosclerosis: Updated Mechanistic Insights and Novel Therapeutic Strategies

Abstract

The global rise in diabetes prevalence has significantly contributed to the increasing burden of atherosclerotic cardiovascular disease (ASCVD), a leading cause of morbidity and mortality in this population. Diabetes accelerates atherosclerosis through mechanisms such as hyperglycemia, oxidative stress, chronic inflammation, and epigenetic dysregulation, leading to unstable plaques and an elevated risk of cardiovascular events. Despite advancements in controlling traditional risk factors like dyslipidemia and hypertension, a considerable residual cardiovascular risk persists, highlighting the need for innovative therapeutic approaches. Emerging treatments, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, epigenetic modulators, and RNA-based therapies, are showing promise in addressing the unique challenges of diabetes-associated ASCVD. Precision medicine strategies, such as nanoparticle-based drug delivery and cell-specific therapies, offer further potential for mitigating cardiovascular complications. Advances in multiomics and systems biology continue to deepen our understanding of the molecular mechanisms driving diabetes-associated atherosclerosis. This review synthesizes recent advances in understanding the pathophysiology and treatment of diabetes-related atherosclerosis, offering a roadmap for future research and precision medicine approaches to mitigate cardiovascular risk in this growing population.

Keywords: atherosclerosis; diabetes; epigenetic regulation; hyperglycemia; inflammation; oxidative stress; precision medicine.

Figure 1

Mechanisms driving atherosclerosis development and progression in diabetes. Diabetes mellitus is closely linked to pathogenic mechanisms that are integral to the development of atherosclerosis. Turbulent blood flow sensitizes endothelial cells at specific vascular sites, enabling them to exhibit distinct responses to systemic risk factors such as hypercholesterolemia and hyperglycemia. While the progression of atherosclerotic plaque formation follows a similar trajectory in individuals with and without diabetes, the process of atherogenesis is significantly accelerated in the context of diabetes. Key mechanisms contributing to plaque formation include endothelial dysfunction, endothelial-to-mesenchymal transition, the transmigration of monocytes across the endothelium followed by their differentiation into macrophages, the formation of foam cells, and the proliferation and migration of vascular smooth muscle cells toward the fibrous cap of the plaque. Abbreviations: COX2 (cyclooxygenase-2), H3K14ac (histone 3 lysine 14 acetylation), H3K9ac (histone 3 lysine 9 acetylation), H4K12ac (histone 4 lysine 12 acetylation), H4K5ac (histone 4 lysine 5 acetylation), HDAC (histone deacetylase), ICAM1 (intercellular adhesion molecule 1), NOX (NADPH oxidase), oxLDL (oxidized LDL), ROS (reactive oxygen species), ShmC (5-hydroxymethylcytosine), SmC (5-methylcytosine), SOD (superoxide dismutase), TET2 (methylcytosine dioxygenase TET2), TNF (tumor necrosis factor), and VCAM1 (vascular cell adhesion protein 1).

Figure 2

Emerging mechanism-based therapeutic strategies for diabetes-associated atherosclerosis are gaining attention due to limitations in current treatments for atherosclerotic cardiovascular disease. Existing therapies primarily address conventional risk factors, such as hyperglycemia, hyperlipidemia, and hypertension, but fail to adequately target the unique pathophysiological mechanisms underlying atherosclerosis in diabetes mellitus. Novel approaches focus on anti-inflammatory therapies, epigenome-targeted therapies, oxidative stress modulators, cell-specific therapies, endothelial dysfunction therapies, plaque stability, trained immunity modulators, and targeted molecular therapies. The dash at the end of the line indicates inhibition. Abbreviations: ApoC3 (apolipoprotein C-III), BET (bromodomain and extra-terminal protein), DNMT (DNA methyltransferase), EndMT (endothelial-to-mesenchymal transition), GLP-1 (glucagon-like peptide-1), ICAM-1 (intercellular adhesion molecule-1), KLF (Kruppel-like factor), MCC950 (specific NLRP3 inflammasome inhibitor), Nrf2 (nuclear factor erythroid 2-related factor 2), NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), NOX (NADPH oxidase), PCSK9 (proprotein convertase subtilisin/kexin type 9), ROS (reactive oxygen species), RUNX1 (runt-related transcription factor 1), SGLT2 (sodium–glucose cotransporter 2), TGF-β (transforming growth factor-beta), VCAM-1 (vascular cell adhesion molecule-1).