Metformin for AAA Growth Inhibition: A randomized controlled trial

Abdominal aortic aneurysm (AAA) is a major health issue and ruptured AAA a
common cause of death in Europe and North America. Worldwide 200.000 annual
deaths are attributed to AAA. To prevent rupture, early detection and
preventive surgical repair in selected individuals is recommended. AAA
screening programs are already implemented in the UK, Sweden and the USA. Most
screening detected AAAs are, however, small (diameter 30-54 mm) and are under
surveillance until expansion to the threshold for elective surgical repair;
i.e. diameter >=55 mm for men and >=50 mm for women. 70% of the men and women who
are being monitored for small AAAs, eventually will require surgical repair. In
2015, ~1200 AAA repairs were performed in Sweden at a cost of ~30 million
Euros. In the Netherlands even more AAA repairs are performed, 3300 a year. AAA
repair is associated with significant mortality (1-5%), perioperative
complications (up to 20%), cost (~25,000 Euros/patient) and need for life-long
post-operative follow-up, imaging and repeat surgery (in~20% of cases).

A key limitation of contemporary treatment strategies of AAA is the lack of
therapy directed at small AAA. Although surgical repair is an effective
treatment for large AAA, several large trials have shown that early surgery of
small AAA does not reduce mortality. Given that AAA diameter is the strongest
predictor for rupture and the natural course for AAA is continued expansion, a
mean to reduce AAA growth rate would be highly beneficial. Commonly used
cardiovascular drugs, such as anti-platelet drugs, statins, angiotensin
converting enzyme inhibitors and beta-blockers have not been shown to slow AAA
growth in cohort studies. Previous interventional trials with therapy directed
at AAA growth reduction include antibiotics, mast cell inhibitors,
beta-blockers, platelet inhibitors, and angiotensin converting enzyme blockers,
with trials of stem cells and cyclosporine under way. These trials have all
been either small, with negative results or had unacceptable side effects.

Risk factors for AAA often mimic those of arteriosclerosis, with the notable
exception of diabetes mellitus. Several large trials have shown that people
with diabetes are less likely to develop AAA and when they do; the AAA expands
slower and is less likely to rupture. However, in 2016 a study of 58 patients
with diabetes reported that the drug metformin, the world*s most widely used
drug for type II diabetes, was associated with reduced AAA growth. Following
this, a cohort study of 1.2 million patients with diabetes, reported that
metformin prescription was associated with a 36% reduced risk of developing an
AAA and in a cohort of 1755 AAA patients a 36-76% slower AAA growth rate were
reported in patients with diabetes and metformin prescription, but not those
without. A similar finding was made in a cohort of 13,834 American veterans
with AAA and diabetes where metformin was independently associated with reduced
growth rates of AAA of different sizes.

Metformin may reduce AAA growth by inhibiting key pathological mechanisms
implicated in AAA, including inflammation and extracellular matrix remodeling.
Two different rodent models of AAA have found that metformin may reduce AAA
growth in euglycemic animals. These studies suggest that metformin may reduce
AAA growth by reducing aortic inflammation, elastin degradation, smooth muscle
cell depletion and monocyte infiltration independent of glucose levels.

In Sweden, data from a cohort of 526 patents under surveillance for small AAA
support these findings with a reduced AAA growth rate and altered cytokine
expression in patients prescribed metformin. In a connected experimental animal
study, metformin was also shown to inhibit AAA formation, improve endothelial
vasomotor function and reduce pro- inflammatory gene expression in euglycemic
mice.

Metformin is a well-established first-line treatment of type II diabetes. It
acts primarily by reducing blood glucose levels by inhibiting hepatic glucose
production and increase insulin sensitivity. It is cheap, safe and able to
reduce micro- and macrovascular complications and overall death (UKPDS 1998,
Holman 2008, Griffin 2017). This has prompted several large trials of metformin
given to persons without diabetes showing that metformin is safe and highly
tolerable in variable patient groups.

Metformin is available as a generic drug at low cost. It is generally well
tolerated, with few serious side effects. Gastrointestinal problems may occur
primarily in the run-in phase. This is usually mitigated by taking metformin
with a meal and increasing the dose stepwise over a course of several weeks to
the desired level.

As metformin is a generic drug there is no commercial interest in exploring its
potential as a drug to reduce AAA growth, necessitating an academically driven
trial. The rationale for this randomized controlled trial is to investigate
whether treatment with Metformin inhibits growth of small AAAs.

This study has been transitioned to CTIS with ID 2024-517387-37-00 check the CTIS register for the current data.

The proposed multi-center population-based open-label randomized controlled
trial with blinded outcome assessment will examine if metformin slows AAA
growth in patients with small AAAs who do not have diabetes.

Primary objective
To examine if up to 2g metformin administered daily over a five-year period
reduces AAA growth as measured by computed tomography (CT) imaging of AAA
diameter in patients with small AAAs who do not have diabetes. An interim
STOP/GO analysis will be performed after two-years of treatment.

Secondary objectives
To examine if metformin limits increase in; a) CT-assessed AAA volume; b)
ultrasound assessed AAA diameter; c) improves health-related quality of life;
d) reduces the need for surgery (diameter >=55mm) or rupture; and e) represents
a cost-effective treatment to reduce the need for AAA surgery.

Exploratory objectives
To examine; a) if there is a dose or time related response of metformin
regarding the primary or secondary endpoints; and b) if metformin favorably
modifies circulating inflammation and matrix remodeling biomarkers; or c)
affects perivascular adipose tissue.

Safety objective
To determine adverse events; primarily related to known side effects of
metformin and possible unexpected effects on AAA, related to metformin
treatment after two and five years.

The MAAAGI-trial is a population-based multi-center, prospective, parallel
group, randomized, open label trial with blinded outcome assessment to assess
if metformin up to 2g daily over a five-year period will reduce AAA growth in
patients who do not have diabetes.

Patients will be recruited from a cohort of patients with diagnosed AAA at one
Dutch side e.g., Amsterdam UMC, Amsterdam and seven Swedish sides.
The patients should have a maximum aortic diameter of 30-49 mm for men and
30-44 mm for women, who do not have diabetes and be expected to tolerate
metformin. A total of 500 patients with AAA will be included in the study, 250
in each study arm. Patients will be randomized to metformin or standard care in
a 1:1 ratio. At the Amsterdam UMC, 100 patients will be randomized in a 1:1
ratio to each arm.

The patients are scheduled for one enrolment visit, eight study visits and ten
phone contacts for those randomized to metformin (three to support titration of
study drug) and seven phone contacts for those randomized to standard care. The
study visits will take place at the vascular laboratory at the respective
surgical departments for clinical examination and blood sampling and at the CT
units at the radiology departments where CT-imaging will be performed. The
study visits and 7 telephone conversations are also part of standard care.

After a run in phase to support titration of metformin, visits and phone
contacts are scheduled to alternate every three months until 24 months and
twice yearly thereafter. CT imaging and AAA US will be performed at baseline,
24 months and end of study, as well as if necessary according to clinical
routine. Study drug will start at baseline and continue through completion.

End of study is defined as 1) study completion at 60 months, or 2)
discontinuation from study before that for any reason, for example due to AAA
repair or patients will.

When all patients have completed the 24-month follow-up (including imaging) an
interim analysis will be performed to assess for efficacy and safety; if there
is no trend towards a positive effect or signs of a harmful effect of
metformin, the study will be stopped at this phase. If there is a significant
beneficial or harmful effect of metformin, the study will also be stopped at
this phase.

The treatment allocation in this study will consist of:

Study Arm 1: Metformin tablets taken orally with target dose of 2g daily

Study Arm 2: Standard care as described in current AAA guidelines (Wanhainen
2019)

Standard care includes help with smoking cessation if applicable; encouragement
of physical activity and a healthy diet; blood pressure control; statin and
anti-platelet therapy treatment if the patient have clinical manifestations of
atherosclerotic disease. Local guidelines dictate which classes of drugs are
recommended and who is responsible for treatment and follow up. The study
participants allocated to metformin receive standard care plus metformin
treatment.

Patients will be encouraged to take metformin every day at similar times,
preferably with a meal to minimize side effects. Metformin is titrated stepwise
to avoid gastrointestinal side effects. Starting dose is one tablet of
metformin 500 mg day 1-14, two tablets day 15-28, three tablets day 29-42 and
four tablets daily from day 43 till the remainder of the study. If a patient
misses one dose he/she is encouraged to take one extra tablet with the
following dose. No more than one dose should be compensated for if missed.

If a patient has severe side effects in the run-in phase, titration to target
dose will be slowed. If a patient has severe side effects at the target dose,
the target dose will be reduced to a level at which the side effects are
tolerable and stay at this level for the remainder of the study. Target dose
and compliance to this dose is recorded at each contact.

Target dose of metformin 2 gr is chosen to reflect doses given in observational
studies. It is predicted to be a sufficient dose to translate to a meaningful
biologic effect whilst still safe and with acceptable side effects. The option
to reduce the dose is expected to reduce drop-out rate. Once the final target
dose is reached a different metformin tablet strength may be used for
convenience i.e., 1 gr rather than 500 mg tablets.

The uncertain knowledge state supporting the study-hypothesis emphasizes the
importance of a risk assessment for each patient. A risk determination of
potential risks in this study has

Risks:
1. Suspected drug related adverse event, such as gastrointestinal events
2. Patient require surgery or intravenous contrast media during study
3. Patient develops suspect or manifest dehydration during study
4. Patient develops suspect or manifest hypoxia during study
5. Patient requiring continuous treatment with drugs that may temporarily
affect renal function, such as NSAIDs
6. Patient develops B12 deficiency secondary to metformin treatment

Actions:
1. If not tolerated, treatment with study drug should be reduced in dose or
stopped, temporarily or permanent, and appropriate medical action should be
initiated according to the nature and severity of the AE.
2. Temporary discontinuation of the study drug according to clinical praxis for
metformin. Typically 48 h after intravenous contrast media, in the
perioperative phase and during fasting.
3. If risk of dehydration for any reason the study drug is temporarily
discontinued. This typically includes but is not limited to fever, serious
infection, vomiting, diarrhoea and reduced fluid intake.
4. If risk of hypoxia for any reason the study drug is temporarily
discontinued. This typically includes but is not limited to, sepsis, chock,
myocardial infarction and decompensated heart failure.
5. Study drug should be discontinued during treatment if there is evidence of
renal impairment
6. S-B12 levels are controlled every 24 months and replacement therapy is
initiated if indicated

Benefits:
- Other than obtaining an extensive medical evaluation and close monitoring of
the AAA, no clear benefit was identified for the patients who participate in
the study.