The Diabetes Paradox in Aortic Aneurysms: An Unexpected Inverse Association

Aortic aneurysms are associated with substantial morbidity and mortalitbecause of the risk of progressive dilation, rupture, and related acute aortic complications. Although diabetes mellitus (DM) is a major cardiovascular risk factor, epidemiological studies have consistently reported an inverse association between DM and the prevalence and progression of abdominal aortic aneurysm (AAA). More limited evidence suggests an inverse association between diabetes and thoracic aortic aneurysm. Accordingly, this review focuses primarily on AAA; where available, evidence concerning TAA and aortic dissection is discussed separately. This review examines the pathophysiological mechanisms underlying the inverse association between DM and aortic aneurysm development. Key mechanisms include the effects of hyperglycemia on extracellular matrix remodeling, particularly through modulation of matrix metalloproteinase (MMP-2 and MMP-9) activity, increased formation of advanced glycation end products (AGEs), and enhanced collagen cross-linking. Experimental and translational evidence suggests that diabetes may influence inflammatory cell states and mural neoangiogenesis, although these effects appear to be context- and model-dependent. Antidiabetic therapies, including metformin, DPP-4 inhibitors, GLP-1 receptor agonists, thiazolidinediones, sulfonylureas, and SGLT2 inhibitors, may also contribute to the observed association through glucose-lowering and/or pleiotropic vascular effects. Furthermore, diabetes-related changes in aortic wall biomechanics, including increased wall thickness and potentially altered wall stress, may contribute to aneurysm stabilization. Overall, DM is associated with a lower prevalence and slower progression of AAA, potentially through a combination of metabolic, inflammatory, structural, and treatment-related mechanisms. These observations should not be interpreted as evidence that diabetes or chronic hyperglycemia is clinically beneficial; rather, they may help identify biological pathways relevant to aneurysm development and progression.