Metformin treatment status and abdominal aortic aneurysm disease progression.
In population-based studies performed on multiple continents during the past two decades, diabetes mellitus has been negatively associated with the prevalence and progression of abdominal aortic aneurysm (AAA) disease. We investigated the possibility that metformin, the primary oral hypoglycemic agent in use worldwide, may influence the progression of AAA disease.



Preoperative AAA patients with diabetes were identified from an institutional database. After tabulation of individual cardiovascular and demographic risk factors and prescription drug regimens, odds ratios for categorical influences on annual AAA enlargement were calculated through nominal logistical regression. Experimental AAA modeling experiments were subsequently performed in normoglycemic mice to validate the database-derived observations as well as to suggest potential mechanisms of metformin-mediated aneurysm suppression.



Fifty-eight patients met criteria for study inclusion. Of 11 distinct classes of medication considered, only metformin use was negatively associated with AAA enlargement. This association remained significant after controlling for gender, age, cigarette smoking status, and obesity. The median enlargement rate in AAA patients not taking oral diabetic medication was 1.5 mm/y; by nominal logistic regression, metformin, hyperlipidemia, and age ≥70 years were associated with below-median enlargement, whereas sulfonylurea therapy, initial aortic diameter ≥40 mm, and statin use were associated with above-median enlargement. In experimental modeling, metformin dramatically suppressed the formation and progression, with medial elastin and smooth muscle preservation and reduced aortic mural macrophage, CD8 T cell, and neovessel density.



Epidemiologic evidence of AAA suppression in diabetes may be attributable to concurrent therapy with the oral hypoglycemic agent metformin.
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif.
Naoki
N
Fujimura
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif.
Jiang
J
Xiong
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif.
Ellen B
EB
Kettler
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif.
Haojun
H
Xuan
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif.
Keith J
KJ
Glover
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif.
Matthew W
MW
Mell
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif. Electronic address: baohuixu@stanford.edu.
Baohui
B
Xu
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif. Electronic address: rld@stanford.edu.
Ronald L
RL
Dalman
D000284:Administration, Oral; D000368:Aged; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000517:prevention & control*; D002140:California / Q000453:epidemiology; D057225:Data Mining; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D016015:Logistic Models; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016017:Odds Ratio; D065840:Protective Factors; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors
D007004:Hypoglycemic Agents; D008687:Metformin