Project Summary Abdominal aortic aneurysm (AAA) disease is a common cause of premature death in adult Americans. To date, no medical (e.g., non-surgical) therapies have proven effective at limiting AAA disease progression, or reducing the risk of AAA rupture or aneurysm-related sudden death. The recognition that diabetic individuals are less likely to develop AAAs and when present in diabetics, AAAs enlarge less rapidly and rupture less frequently, introduces new possibilities for medical AAA disease management. Recent retrospective studies suggest that metformin, the world’s most commonly prescribed oral hypoglycemic agent, may be associated with reduced rates of AAA enlargement. To date, however, the ability of metformin to suppress AAA disease has not been evaluated in a scientifically rigorous, prospective fashion. Building off existing observational evidence and novel preliminary data, generated to support this proposal, it is our fundamental hypothesis that metformin therapy will safely suppress AAA disease progression in non- diabetic patients. To test this hypothesis, two Specific Aims are proposed. The First Aim will evaluate the tolerability and safety of metformin in nondiabetic patients with AAA disease. Tolerance will be assessed by the serial administration of quality of life surveys and tracking participant compliance and retention. Safety will be assessed by semi-annual examinations, review of the source medical record, supplementary hematologic and metabolic panel surveys as needed. The Second Aim will test the ability of metformin XR (extended release) to reduce the average annual rate of enlargement of existing small to intermediate size AAAs by ≥ 30% compared to placebo. For this Aim, 480 participants will be randomized 1:1 to metformin or placebo. The primary endpoint will be the increase in mean maximal orthogonal AAA diameter through 24 months, as determined by computed tomographic aortography (CTA). Successful completion of these Aims will advance the understanding of AAA disease as well as the translational utility of metformin therapy to treat cardiovascular diseases in nondiabetic patients. These Aims specifically address the NIH Strategic Vision Goals of 1) understanding human biology, 2) reducing human disease, and 3) advancing translational research, as well as Objectives of 1) understanding normal biologic function and resilience, 2) investigating newly discovered pathobiological mechanisms, and 3) developing and optimizing novel therapeutic strategies to prevent, treat and cure HLBS diseases.