Practice Update: Diabetes

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Long-TermMetformin Treatment Found to Reduce Risk of Heart
Disease in Adults with Type 1 Diabetes
Metformin may be an effective long-term strategy worthy of adding to an individual’s diabetes care plan in order to
reduce the risk of heart disease in adults with type 1 diabetes. This conclusion, based on results of the Results of the
JDRF Reducing with Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) trial, was presented at the
American Diabetes Association’s 77th Scientific Sessions, from June 9–13.
John Petrie, MD, PhD, of the University
of Glasgow, UK, explained that met-
formin is an inexpensive medication
considered first-line therapy to control glu-
cose in individuals with type 2 diabetes. It is
also widely used to improve cardiovascular
risk in adults with type 2 diabetes.
Dr Petrie and colleagues set out to determine
whether similar benefits could be expected
for people with type 1 diabetes. Metformin
may be prescribed for patients with type 1
diabetes who are also overweight, to help
control blood sugar and weight, and to allow
a lower daily insulin dose.
The multicenter, international REMOVAL
trial enrolled patients at 23 centers across
the UK, Australia, Canada, Denmark, and
The Netherlands. Dr Petrie and his team
investigated whether 3 years of treatment
with metformin reduced heart disease in
middle-age adults with type 1 diabetes at
increased risk of cardiovascular disease.
Ultrasound was used to measure ath-
erosclerosis in the carotid arteries as a
surrogate marker of heart disease.
REMOVAL studied 428 middle-aged adults
with longstanding (average 33 years) type
1 diabetes.
Patients harbored three or more risk fac-
tors for cardiovascular disease, including
body mass index >27 kg/m2; hemoglobin
A1C >8.0; known cardio/peripheral vas-
cular disease; current smoker; high blood
pressure; high cholesterol or triglycerides;
strong family history of cardiovascular dis-
ease; or duration of diabetes >20 years.
Participants were assigned 3 years of oral
metformin (two 500 mg tablets titrated
up to twice daily); or matching placebo.
Metformin reduced the progression of ath-
erosclerosis, measured using the Diabetes
Control and Complications Trial ultrasound
protocol significantly over 3 years and
trended toward reduction when measured
by the protocol recommended for individ-
uals without diabetes.
Short-term reduction in hemoglobin A1C
meant that glucose did not account for
this reduction. Metformin exerts direct
effects against atherosclerosis, including
white blood cell inhibition, improvement
of aspects of endothelial function, and
slowed production of advanced glycation
end-products.
Patients who received metformin lost
weight, and their insulin doses were
reduced during the study. Hemoglobin
A1C levels, however, exhibited reduction
during the first 3 months of metformin treat-
ment only.
Cholesterol was also reduced, though
>80% of l participants had been taking stat-
ins prior to the trial. Weight reduction and
cholesterol lowering may have played a
role in reducing atherosclerosis.
Estimated glomerular filtration rate by the
Modification of Diet in Renal Disease equa-
tion rose sharply on initiation of metformin.
Dr Petrie asserted, however, that this rise
needs to be studied further to determine
any clinical significance.
Some patients stopped taking metformin
because of nausea or abdominal pain. No
increase in hypoglycemia risk was observed.
Dr Petrie concluded, “A decrease in
weight and insulin dose was more or less
expected, but we were surprised to dis-
cover a reduction in LDL cholesterol and
atherosclerosis progression with metformin
treatment. Results of REMOVAL support
wider prescribing of metformin to help
reduce heart disease risk factors over a
lifetime of type 1 diabetes, mirroring its use
in adults with type 2 diabetes.”
He added, “Since our study confirmed that
metformin improved blood sugar control
only in the very short term, guidelines in the
US and UK should be updated to reflect the
lack of a sustained effect of metformin on
blood glucose levels in adults with type 1
diabetes. So, REMOVAL may result in less
prescribing of metformin for blood glucose
control in type 1 diabetes.”
REMOVAL, with 3 years of follow-up, was
one of the longest studies to have been
conducted of metformin for type 1 diabetes.
Evidence is needed of long-term effects of
metformin on cardiovascular events rather
than intermediate markers of cardiovascu-
lar health.
PracticeUpdate Editorial team.
A decrease in weight and insulin dose was more or
less expected, but we were surprised to discover a
reduction in LDL cholesterol and atherosclerosis
progression with metformin treatment.
© ADA/Rodney White 2017
CONFERENCE COVERAGE 14
PRACTICEUPDATE DIABETES