Metformin May Limit AAA Disease Progression

By Megan Mayerle, PhD

March 21, 2019

The aorta is the major blood vessel that supplies blood to the body. An abdominal aortic aneurysm (AAA) is an enlarged area in the lower part of the aorta; over time, AAAs enlarge to the point of eventual rupture and (if left untreated) exsanguination. AAA rupture and related aortic emergencies are a leading cause of sudden death in adults worldwide.

Based on evidence that ultrasound screening for AAA reduces AAA-related mortality by more than 40%, ultrasound screening examinations for individuals at risk for AAA are provided by European healthcare systems and the Medicare system in the United States. Importantly, AAA ultrasound in the only screening benefit (analogous to mammography for breast cancer) provided by Medicare for any cardiovascular-related disease. Once identified, and having enlarged to nearly twice the normal aortic diameter, AAAs are currently managed exclusively by surgical repair or endoluminal exclusion.

The focus of AAA management is to prevent premature death from rupture. Unfortunately, even though most AAAs are identified at an early stage of the disease, no medical intervention, has proved effective in limiting progressive aorta enlargement, reducing the eventual risk for rupture or surgical repair. Risk factors for developing AAA, aside from advanced age, include smoking and other atherosclerotic risk factors. However, though diabetes is a strong risk factor for atherosclerosis, it is negatively associated with the development of AAA.

In 2016, a CVI team led by Naoki Fujimura MD, Baohui Xu PhD, and Ronald L. Dalman MD, suggested that metformin, the world’s most commonly prescribed oral hypoglycemic agent, may also be effective in limiting progression of AAA disease. In a recent follow-up study published in the Journal of Vascular Surgery, the team, now including lead author Nathan Itoga MD, sought to validate these preliminary observations in population-wide study through the US Department of Veterans Affairs VINCI database query process.

The researchers found that while the rate of aneurysm enlargement was reduced as expected by about 50% in diabetic as compared to non-diabetic AAA veteran patients nationwide, metformin use (as compared to other oral and parenteral hypoglycemic agents) was associated with an additional 20% reduction in the aneurysm enlargement rate.  

Since the original report by Fuijmura et al, the suppressive effect of metformin has been confirmed in additional cohorts of diabetic AAA patients worldwide. What remains to be determined now, according to Itoga and colleagues, is whether metformin will have similar or even greater efficacy in non-diabetic AAA patients, a much larger population of patients at greater risk of aneurysm rupture and rupture-related sudden death. An application for funding for a clinical trial testing this hypothesis has been submitted to the Heart, Lung and Blood Institute.

Regardless of the ultimate utility of using metformin to suppress aneurysm progression in the clinic, investigation of the mechanisms responsible for aneurysm inhibition by metformin, if proven effective, will greatly accelerate the search for practical and cost-effective alternatives to surgical therapy to prevent aneurysm-related sudden death.  

Ronald L. Dalman, MD

Nathan Itoga, MD

Baohui Xu, PhD