Metformin prescription status and abdominal aortic aneurysm disease progression in the US veteran population

Background: Identification of a safe and effective medical therapy for abdominal aortic aneurysm (AAA) disease remains a significant unmet medical need. Recent small cohort studies indicate that metformin, the world's most commonly prescribed oral hypoglycemic agent, may limit AAA enlargement. We sought to validate these preliminary observations in a larger cohort. Methods: All patients with asymptomatic AAA disease managed in the Veterans Affairs Health Care System between 2003 and 2013 were identified by International Classification of Diseases, Ninth Revision codes. Those with a concomitant diagnosis of diabetes mellitus who also received two or more abdominal imaging studies (computed tomography, magnetic resonance imaging, or ultrasound) documenting the presence and size of an AAA, separated by at least 1 year, were included for review. Maximal AAA diameters were determined from radiologic reports. Further data acquisition was censored after surgical AAA repair, when performed. Comorbidities, active smoking status, and outpatient medication records (within 6 months of AAA diagnosis) were also queried. Yearly AAA enlargement rates, as a function of metformin treatment status, were compared using two statistical models expressed in millimeters per year: a multivariate linear regression (model 1) and a multivariate mixed-effects model with random intercept and random slope (model 2). Results: A total of 13,834 patients with 58,833 radiographic records were included in the analysis, with radiology imaging follow-up of 4.2 +/- 2.6 years (mean +/- standard deviation). The average age of the patients at AAA diagnosis was 69.8 +/- 7.8 years, and 39.7% had ametformin prescription within +/- 6 months of AAA. The mean growth rate for AAAs in the entire cohort was 1.4 +/- 2.0 mm/y by model 1 analysis and 1.3 +/- 1.6 mm/y by model 2 analysis. The unadjusted mean rate of AAA growth was 1.2 +/- 1.9 mm/y for patients prescribed metformin compared with 1.5 +/- 2.2 mm/y for those without (P<.001), a 20% decrease. This effect remained significant when adjusted for variables relevant on AAA progression: metformin prescription was associated with a reduction in yearly AAA growth rate of -0.23 mm (95% confidence interval, -0.35 to -0.16; P<.001) by model 1 analysis and 0.20 mm/y (95% confidence interval, -0.26 to -0.14; P<.001) by model 2 analysis. A subset analysis of 7462 patients with baseline AAA size of 35 to 49 mm showed a similar inhibitory effect (1.4 6 2.0 mm/y to 1.7 +/- 2.2 mm/y; P<.001). Patients' factors associated with an increased yearly AAA growth rate were baseline AAA size, metastatic solid tumors, active smoking, chronic obstructive pulmonary disease, and chronic renal disease. Factors associated with decreased yearly AAA growth rates included prescriptions for angiotensin II type 1 receptor blockers or sulfonylureas and the presence of diabetes-related complications. Conclusions: In a nationwide analysis of diabetic Veterans Affairs patients, prescription for metformin was associated with decreased AAA enlargement. These findings provide further support for the conduct of prospective clinical trials to test the ability of metformin to limit progression of early AAA disease.