Metformin and beyond: glucose-lowering therapy as a potential modulator of abdominal aortic aneurysm growth and stability- systematic review with narrative synthesis.

backgroundAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease with rupture mortality exceeding 80%. Although diabetes mellitus (DM) is a major risk factor for atherosclerotic cardiovascular disease, a growing body of epidemiological and experimental evidence suggests an inverse association between DM and AAA development, progression, and rupture. Increasing attention has focused on glucose-lowering therapies—particularly metformin—as potential modulators of aortic wall remodeling.

methodsWe conducted a systematic literature search followed by a narrative synthesis of evidence from observational studies, randomised controlled trials (RCTs), and experimental research evaluating the association between diabetes mellitus, antidiabetic therapies, and abdominal aortic aneurysm. PubMed, Scopus, and the Cochrane Library were searched through February 2025 to identify relevant primary human studies assessing the impact of DM and glucose-lowering therapies on AAA incidence, growth, rupture, and related outcomes. Experimental animal models and mechanistic studies were reviewed separately to explore biological plausibility and underlying pathways.

resultsAcross more than 30 population-based cohorts and registry studies, DM was consistently associated with a lower likelihood of AAA development, slower aneurysm growth, and reduced rupture risk. Longitudinal studies reported attenuated aneurysm expansion among diabetic individuals, with reductions in growth rates ranging approximately from 0.3 to 0.8 mm/year. Experimental and mechanistic studies were broadly consistent with these associations and are summarized separately. Among glucose-lowering therapies, metformin emerged as the most extensively studied agent, with observational data suggesting slower AAA progression independent of glycaemic control. Early RCTs confirm feasibility and safety but remain underpowered for definitive clinical outcomes. Evidence for newer drug classes, including SGLT2 inhibitors and GLP-1 receptor agonists, is currently limited to preclinical models.

conclusionsCurrent evidence supports a biologically plausible and epidemiologically consistent inverse association between diabetes mellitus and AAA development and progression. Metformin appears to exert stabilising effects on aneurysm biology through pleiotropic vascular mechanisms beyond glucose lowering. Definitive confirmation from adequately powered, event-driven randomised trials is still required. Glucose-lowering therapy—particularly metformin—may represent a promising future pharmacologic adjunct for delaying AAA progression and improving long-term outcomes.