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Effect of metformin and lifestyle on
coronary artery calcium in the Diabetes
Prevention Program
Circulation
Take-home message
•
This long-term intervention study investigated the incidence of coronary heart
disease (CHD) among 3234 individuals with prediabetes. After an average 14 years
of follow-up, 2029 participants had subclinical atherosclerosis based on coronary
artery calcium (CAC) measurement. Participants with lifestyle interventions did not
have a significant difference in CAC from the placebo group. Men in the metformin
group had a significant reduction in the presence and severity of CAC compared
with the placebo group. However, there was no significant difference between
women in the metformin and placebo groups.
•
Among men with prediabetes or early diabetes, metformin may protect against
coronary atherosclerosis.
Abstract
BACKGROUND
Despite the reduced incidence of
coronary heart disease (CHD) with intensive risk
factor management, people with diabetes and
prediabetes remain at increased CHD risk. Dia-
betes prevention interventions may be needed
to reduce CHD risk. This approach was exam-
ined in the Diabetes Prevention Program (DPP)
and its Outcome Study (DPPOS), a long-term
intervention study in 3234 subjects with predia-
betes (mean [±SD] age 64±10 yrs) which showed
reduced diabetes risk with lifestyle and met-
formin compared to placebo over 3.2 years.
METHODS
The DPPOS offered periodic group
lifestyle sessions to all participants and con-
tinued metformin in the originally randomized
metformin group. Subclinical atherosclerosis
was assessed in 2029 participants using coro-
nary artery calcium (CAC) measurements after
14 years of average followup. The CAC scores
were analyzed continuously as CAC sever-
ity, and categorically as CAC presence (CAC
score>0), and reported separately in men and
women.
RESULTS
Therewere no CAC differences between
lifestyle and placebo intervention groups, in
either sex. CAC severity and presence were
significantly lower among men in the metformin
versus the placebo group (age-adjusted mean
CAC severity: 39.5 vs 66.9 AU, p=0.04; CAC
presence: 75% vs 84%, p=0.02), but no metformin
effect was seen inwomen. Inmultivariate analysis,
the metformin effect in men was not influenced
by demographic, anthropometric or metabolic
factors, by the development of diabetes, or by
use/non-use of statin therapy.
CONCLUSIONS
Metformin may protect against
coronary atherosclerosis in prediabetes and
early diabetes among men.
Effect of long-term metformin and lifestyle
in the Diabetes Prevention Program and its
outcome study on coronary artery calcium.
Circulation
2017 May 05;[EPub Ahead of Print],
RB Goldberg, VR Aroda, DA Bluemke, et al.
COMMENT
By Benjamin Morgan Scirica
MD
T
he DPP study, published in 2002,
demonstrated that, compared with
placebo, an intensive lifestyle modi-
fication program or metformin significantly
reduced the risk of developing diabetes
and improved cardiometabolic risk factors
over an average follow-up of 3.2 years. In
this publication, the investigators from the
follow-up extension study (named DPPOS)
report the long-term effect on coronary
artery calcium (CAC) measurements of the
initial randomization to metformin or life-
style compared with placebo.
After 10 additional years of follow-up, CAC
was measured in 2029 patients. Overall,
CAC severity was greater in men than
in women. And, in men, those patients
originally randomized to metformin had
less severe CAC than those randomized
to placebo (age-adjusted mean CAC
severity: 39.5 vs 66.9 AU, P = 0.04; CAC
presence: 75% vs 84%, P = 0.02). There
was no difference in CAC between the
group assigned to lifestyle modifica-
tion compared with those assigned to
placebo, or between any treatment in
women. It is reasonable to hypothesize
that the degree of CAC in women in this
study was low enough that there was no
opportunity to prevent calcifications, but
it could also signal a potential differentia-
tion in treatment effect. It is disappointing
to see no difference in men assigned to
the lifestyle modification arm, although
CAC can be modulated (worsened) with
intense exercise.
In the original DPP study, intensive
lifestyle intervention was more effective
than metformin for glucose control and
prevention of diabetes; yet, in this long-
term follow-up, metformin was the only
strategy to reduce CAC therapy, thus
raising the possibility of both direct
glucose-dependent and independent
vascular protective benefit of metformin.
This observation is particularly relevant
because, in contrast to the recent
experience with empagliflozin and
liraglutide, there are no contemporary
data supporting a cardioprotective role
of metformin. Metformin remains the
first-line therapy for diabetes, and also
a reasonable treatment for patients with
prediabetes, but its “pole-position” should
be tested in contemporary management
strategies against other new agents.
Dr Scirica is Cardiologist
and Director at Inovation,
Cardiovascular Division,
Brigham and Women’s
Hospital, and Associate
Professor of Medicine at
Harvard Medical School.
Metformin remains the first-
line therapy for diabetes, and
also a reasonable treatment
for patients with prediabetes,
but its “pole-position” should
be tested in contemporary
management strategies
against other new agents.
EDITOR’S PICKS
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VOL. 1 • NO. 1 • 2017