Correspondence Section
RESEARCH LETTER
The Metformin for Abdominal Aortic Aneurysm Growth
Inhibition (MAAAGI) Trial
Worldwide about 20 million people have an abdominal
aortic aneurysm (AAA) and rupture leads to approximately
200 000 deaths annually. To prevent rupture, early detec-
tion and preventive surgical repair of large AAAs is recom-
mended, and several countries have AAA screening
programmes.1 However, most detected AAAs are small at
the time of detection, and are monitored by regular repeat
imaging, usually over many years, until they reach the
threshold diameter that justifies surgical treatment.
Thus, a growth inhibitory treatment could be employed
to reduce the later risk of surgery and rupture, and such a
treatment option is most warranted. However, previous
attempts with antiplatelet drugs, statins, angiotensin con-
verting enzyme inhibitors, beta blockers, antibiotics, and
mast cell inhibitors have all failed to stop AAA growth,2 and
currently there is no drug therapy for small AAAs.
Observational studies have repeatedly shown that dia-
betes is associated with lower development of AAAs, and
recent experimental and observational studies suggest that
metformin, the most commonly used antidiabetic drug for
type 2 diabetes, slows AAA growth by inhibiting key path-
ological mechanisms implicated in AAA: inflammation and
extracellular matrix remodelling (Fig. 1).3e5
The MAAAGI trial (NCT0422405) is an investigator driven
population based multicentre, prospective, parallel group,
randomised, open label trial with blinded outcome assess-
ment to assess whether metformin up to 2 g daily over a
five year period (vs. standard of care) reduces AAA growth
in non-diabetic patients. Primary efficacy will be assessed
by difference in AAA diameter determined by computed
tomography after five years vs. at baseline, with a pre-
planned interim stop/go analysis at two years. Secondary
outcomes include AAA volume and ultrasound diameter
growth, AAA events (rupture or elective repair), quality of
life, and health economic assessment. A total of 500 pa-
tients with small AAA (maximum aortic diameter of 30e
49 mm for men and 30e44 mm for women) are recruited
from six Swedish sites and randomised in a 1 : 1 ratio, giving
an 80% power to detect a 30% reduced growth rate at two
and five years, or a 30% reduced need for elective surgical
repair at five years, assuming a 30% dropout rate. Obser-
vational data suggest this is a conservative estimate of the
effect size.
As AAA diameter is the strongest predictor of rupture and
the main indication for prophylactic surgical repair, growth
rate is often used as the primary outcome measure of AAA
drug randomised controlled trials (RCTs), allowing for
smaller randomised cohorts with limited follow up. Given
that AAA growth rate is expected to be the main driver of
repair or rupture, it is probably futile to continue a study for
Eur J Vasc Endovasc Surg (2021) 61, 710e711
the full length of time required to achieve sufficient power
for such hard clinical endpoints if there is no effect on
growth within the first few years of treatment. A double
blind RCT design would require either a shorter phase II trial
to prove an effect on growth followed by a phase III trial to
show clinical endpoints or a larger long term study directly.
The current open label design with blinded primary
outcome assessment (growth) provides a pragmatic solu-
tion allowing for an interim analysis of growth at two years
with full power. If no effect is seen after two years, it is
unlikely that the drug will have a long term clinically sig-
nificant effect and the study will be terminated prema-
turely. If there is a positive trend at two years a great
amount of time is saved by allowing the same subjects to
continue for the full five years rather than starting a new
RCT to assess clinically relevant endpoints. Although an
interim analysis is theoretically possible with a double blind
design, it is not feasible in an academically driven trial. Thus,
although the lack of double blinding is a natural short-
coming, it also provides an opportunity, and we believe this
may be a useful model for future drug trials with patients
with small AAAs.
The current strategy for the management of small
AAAs, with regular surveillance imaging and prophylactic
surgical repair when the aneurysm reaches  5.5 cm for
men and  5.0 cm for women, is safe. Therefore, to
become an option in a real world setting, any medical
option with the intention to replace or delay AAA surgery
needs to be cost effective and highly tolerable for the
patient in the long term. Metformin is an established
drug, is generally well tolerated with few serious side
effects and fulfils these criteria. A Markov cohort model
suggests limited effect on life years gained by slowing
AAA growth but a major shift in events with fewer repairs
and more patients under longer surveillance. This results
in a major cost difference in favour of medical treatment,
if the cost of the drug is low and the growth inhibitory
effect is large enough. For metformin, which is extremely
cheap (0.1 Euro/day), the required growth inhibitory ef-
fect for it to become cost effective is low, starting
at > 10% growth reduction. The low cost required for a
drug to be a realistic treatment alternative for this
particular disease reduces the economic incentive for
pharmaceutical companies to develop new drugs against
AAA expansion and prompts academically driven research
on already available pharmaceuticals.
The first MAAAGI patient was randomised on 14
February 2020. Shortly thereafter the COVID-19 pandemic
hit the world. The target group for the MAAAGI trial is all
elderly people who are at higher risk if infected with SARS-
CoV-2. In order not to expose patients with AAAs to a risk
of infection during study visits, inclusion was temporarily
paused. As soon as circumstances allow, recruitment will
resume.
Correspondence Section: Research Letter 711

Metformin mechanism:
ECM remodeling
MMPs
SMC apoptosis
Proteolysis
Neoangiogenesis
Inflammation
Inflammatory cells
Proinflammatory
cytokines

Figure 1. Suggested mechanisms of action of metformin in abdominal aortic aneurysm pathology. By reducing
extracellular matrix (ECM) remodelling (inhibiting matrix metalloproteinase [MMP] activity, preserving
smooth mucle cells [SMC], and reducing proteolysis of mainly elastin and collagen), angiogenesis, and
inflammation (inhibiting T cell and macrophage infiltration and activation, and reducing the expression of pro-
inflammatory cytokines) aneurysm development and growth may be reduced.

CONFLICTS OF INTEREST Anders Wanhainen*

None.
FUNDING
The Swedish Heart-Lung Foundation, King Gustaf V and
Queen Victorias Frimurarestiftelse, and the Uppsala Örebro
Regional Research Council.
REFERENCES
1 Wanhainen A, Hultgren R, Linné A, Holst J, Gottsäter A,
Langenskiöld M, et al. Outcome of the Swedish nationwide
abdominal aortic aneurysm screening program. Circulation
2016;134:1141e8.
2 Golledge J, Moxon JV, Singh TP, Bown MJ, Mani K, Wanhainen A.
Lack of an effective drug therapy for abdominal aortic aneurysm.
J Intern Med 2020;288:6e22.
3 Itoga NK, Rothenberg KA, Suarez P, Ho T-V, Mell M, Xu B, et al.
Metformin prescription status and abdominal aortic aneurysm
disease progression in the U.S. veteran population. J Vasc Surg
2019;69:710e6.
4 Dalman RL, Wanhainen A, Mani K, Modarai B. Top 10 candidate
aortic disease trials. J Intern Med 2020;288:23e37.
5 Raffort J, Hassen-Khodja R, Jean-Baptiste E, Lareyre F. Relation-
ship between metformin and abdominal aortic aneurysm. J Vasc
Surg 2020;71:1056e62.
Department of Surgical Sciences, Vascular Surgery, Uppsala University,
Uppsala, Sweden
Department of Surgical and Peri-operative Sciences, Umeå University,
Umeå, Sweden
Jon Unosson, Kevin Mani
Department of Surgical Sciences, Vascular Surgery, Uppsala University,
Uppsala, Sweden
Anders Gottsäter
Department of Vascular Diseases, Skåne University Hospital and Lund
University, Malmö, Sweden
on behalf of the MAAAGI Trial Investigators
*Corresponding author. Department of Surgical Sciences, Vascular Surgery,
Uppsala University, SE-75185 Uppsala, Sweden.
Email-address: anders.wanhainen@surgsci.uu.se (Anders Wanhainen)
Available online 27 January 2021
Ó 2020 European Society for Vascular Surgery. Published by Elsevier B.V. All
rights reserved.
https://doi.org/10.1016/j.ejvs.2020.11.048