Can Metformin Be Repurposed to Shrink Aneurysms?

A small number of potentially game-changing trials in Europe and around the world could be on the verge of identifying, for the first time, a medical treatment to prevent the progression of abdominal aortic aneurysms.

Globally, around 20 million people have abdominal aortic aneurysms. They are extremely dangerous if they rupture and lead to the deaths of around 200,000 people every year worldwide.

The Metformin for Abdominal Aortic Aneurysm Growth Inhibition (MAAAGI) trial has been testing whether the world’s most common antidiabetic drug, metformin, can stop aneurysm growth or even shrink them. The trial is based at Scandinavia’s largest aortic center at Uppsala University Hospital, Uppsala, Sweden, and is testing the drug in patients in Sweden, Denmark, and the Netherlands.

Two other randomized controlled trials , based in the United States and Australia, are also testing the same premise in patients in other parts of the world.

The Holy Grail

“The unmet need is big, so everybody really wants this to work to give us something we can offer patients,” said Jes Sanddal Lindholt, MD, DMSci, PhD, clinical professor at the Odense University Hospital in Odense, Denmark, who has researched and treated patients with these aneurysms for decades.

Today, he explained, small abdominal aortic aneurysms —

Once the aneurysm hits the threshold for intervention, classic open surgery can remove it for good, but it is expensive and risky because people with abdominal aortic aneurysms are often elderly with comorbidities, including cardiovascular ones. “The results have improved tremendously since the 1990s, but it still comes with the risk of simply dying of the procedure,” Lindholt told Medscape Medical News.

Endovascular procedures are a less invasive alternative, with less risk for infection and other complications associated with open surgery. But don’t always remove the aneurysm completely, and so require further monitoring. “There is a chance that it regrows, leaks, and needs further repair in the future,” said Lindholt.

That is why medical management is seen as a holy grail for many in the vascular community who have searched for years for an option among antiplatelet drugs, statins, beta-blockers, antibiotics, and mast cell inhibitors.

Anders Wanhainen, MD, PhD, professor of vascular surgery at Uppsala University, is running the Swedish branch of the MAAAGI trial. He said that demonstrating that metformin has an inhibitory effect on aneurysm growth in nondiabetic patients could mean a paradigm shift in the management of the condition. “I think, ideally, very few will require surgery in the future because most could be treated with medical options that slow the growth until they die of old age,” he told Medscape Medical News.

Wanhainen’s team has been running the open-label trial in nondiabetic patients with abdominal aortic aneurysms since 2020. He said metformin is an extremely attractive medication because it is already off-patent and its safety profile has been established. “Metformin costs about a euro cent per day, so we don’t require a very large effect for this to be cost-effective for society,” he said.

International Interest

So eager are researchers to determine if metformin works that, in 2022, a group at Stanford University in Stanford, California, launched the Limiting Abdominal Aortic Aneurysm with Metformin Trial (LIMIT) in the United States.

Wanhainen explained that, although LIMIT is a blinded, randomized, controlled trial, there are deliberate similarities with MAAAGI regarding study design and outcomes. The aim was to make the trials as similar as possible so the researchers can combine them in the future, he explained.

MAAAGI is not the only trial in Europe. The Metformin Aneurysm Trial (MAT) started with patients in Australia and New Zealand but is now recruiting 1000 patients in the United Kingdom.

Other trials have not been so lucky.

Slow COVID-19 recruitment stopped the Austrian Metformin Therapy in Non-diabetic Abdominal Aortic Aneurysm Patients trial last year after randomizing only 54 of the planned 170 participants, according to a paper co-authored last month by Wanhainen and the head of LIMIT, Ronald L. Dalman, MD, professor of surgery at Stanford School of Medicine, Stanford, California.

Yet the need for answers is spurring researchers on, despite obstacles.

Medical Treatment Could Mean Cost-Effective Screening

One hope is that more screening programs will eventually begin. Today, only a few national programs exist to routinely screen those at most risk for abdominal aortic aneurysms. In the United Kingdom, men aged over 65 years are eligible for such screening.

But, despite the lives that might be saved, other countries have resisted setting up screening programs largely because of the expense, especially if the only treatment is surgery.

“So another effect of having medical treatment available is that screening might be even more valuable than today,” said Wanhainen.

Though signals from previous smaller studies in animals and humans have been positive, there is no guarantee trials will find a metformin inhibitory effect on aneurysm growth when they report back in the next few years.

Many researchers had already noticed that people with diabetes tended to see slower growth of their aneurysms, said Lindholt, who conducted major studies in Denmark for several decades to establish the case for a screening program. “What wasn’t understood was whether the effect was because of something to do with blood glucose levels in the aorta or to do with the drugs patients were taking,” he explained.

Researchers like Lindholt continue to look for other drugs that could shrink abdominal aortic aneurysms. But even this will not prevent the rupture of undetected, asymptomatic aneurysms. “The dangerous thing about an aneurysm is not knowing you have it,” said Lindholt.

MAAGI is sponsored by Uppsala University Hospital and LIMIT by Stanford University.

MAT receives its funding from the National Health and Medical Research Council of Australia, the Royal Australasian College of Surgeons, the Australian and New Zealand Society for Vascular Surgery, the Townsville Hospital and Health Service, and the Health Research Council of New Zealand. The British Heart Foundation is providing funding of £1,290,726 over 5 years to the UK arm.

Tatum Anderson is a global health and medical journalist. For more than 20 years, she has placed articles in publications like the Bulletin of the World Health Organization, The Lancet, BMJ, BBC News, and The Economist.