JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
3, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
EDITORIAL COMMENT
A Diabetes-Atrial Fibrillation Conundrum
Does Duration Trump Glycemia?*
Zachary Bloomgarden, MD, Sameer Bansilal, MD, MS
T he disease and cost burden of atrial fibrilla-
tion (AF) is expected to double over the
next 25 years (1). With availability of newer
therapies, efforts to refine the triage of who receives
therapies, when, and for how long have assumed
center stage. Over the last few years, a host of
new scores such as CHADS-VASc (congestive heart
failure [or Left ventricular systolic dysfunction],
hypertension, age$75 years, diabetes, prior Stroke,
TIA, or thromboembolism, vascular disease [e.g.
peripheral artery disease, myocardial infarction,
aortic plaque], age 65–74 years, sex category) and
ATRIA (Anticoagulation and Risk Factors in Atrial
Fibrillation) have emerged on the scene where the
age-old CHADS score had reigned supreme (2–4).
SEE PAGE 239
The presence of diabetes as a dichotomous measure
uniformly appears as a risk marker in each of these
scores. Does this simplistic view of a complex disease
process capture all the necessary information? In this
issue of the Journal, Ashburner et al. (5) explore the
duration of diabetes, the extent of diabetes control
and the likelihood of a specific but highly important
subset of events, that of ischemic stroke among per-
sons with diabetes and AF during periods when the
*Editorials published in the Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology.
From the Department of Medicine, Icahn School of Medicine at Mount
Sinai, New York, New York. Dr. Bloomgarden has served on the advisory
boards for AstraZeneca, Johnson and Johnson, Merck, Boehringer Ingel-
heim, and Amgen; has served as a consultant for AstraZeneca, Johnson
and Johnson, Merck, Novartis, Boehringer Ingelheim, and Amgen; is a
shareholder in Baxter International, CVS Caremark, Roche Holdings, St.
Jude Medical, Novartis, and Pfizer; and has served on the speakers bu-
reau for Merck, Novo Nordisk, AstraZeneca, Boehringer Ingelheim, and
Regeneron. Dr. Bansilal has reported that he has no relationships relevant
to the contents of this paper to disclose.
VOL. 67, NO.
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2015.11.035
observed population was not receiving warfarin. The
authors report that individuals with AF having dura-
tion of diabetes of 3 or more years had 1.74-fold more
strokes than those with diabetes of shorter duration,
while event rates were similar among diabetic persons
with A1c <7%, 7% to 8.9%, and >9%.
The first order of business is to understand the
study population: patients from a single healthcare
system, recruited nearly 2 decades ago, studied
during periods when they did not receive guideline-
indicated therapy. Had warfarin recently been dis-
continued, with increased rebound thrombosis risk?
Varying reasons for patients in AF with a CHADS score
above 2 being off warfarin for $30 days include
bleeding, major surgery, and noncompliance.
Certainly, the risk of stroke in that situation would be
elevated (6). What might be the relation of these
clinical factors to diabetes duration and control?
Given the linear relationship between diabetes dura-
tion with insulin resistance, vascular inflammation,
and a prothrombotic milieu, the greater risk of stroke
makes biological sense (7). It may therefore be
reasonable to further explore and validate the utility
of adding duration of diabetes to existent risk scores,
as the authors have previously done with age for the
ATRIA score (4).
The authors’ findings suggest that glycemic control
is not relevant to macrovascular event rates, while
non-glycemic factors are present among persons with
diabetes and have progressively greater effect with
increasing time. Two concerns must temper this
interpretation: the first, addressed by the authors of
the study, is that there may be important differences
between stroke in persons in AF, and other macro-
vascular events in persons with diabetes. Not
addressed by the authors, but perhaps of greater
importance, is the limited observation period avail-
able in this study. Using the numbers of observed
persons in their Table 1 and the person-years of
JACC VOL. 67, NO. 3, 2016 Bloomgarden and Bansilal 249
JANUARY 26, 2016:248–50 The Diabetes-AF Conundrum: Duration Over Depth?

observation in their Table 2 and Table 3, it is possible
to calculate that the diabetes duration analyses
allowed mean follow-up of 2.7 and 2.3 years per
person for those with diabetes duration <3 and
$3 years, respectively, while the principal HbA1c
analysis, by time-varying HbA1c, allowed mean
follow-up of 1.9, 2.2, and 1.6 years per person for those
with HbA1c <7%, 7% to 8.9%, and $9%, respectively.
A 2-year period appears insufficient to observe
benefits of glycemic control on macrovascular
outcome. In the UKPDS (United Kingdom Prospective
Diabetes Study) study, 4,075 recently diagnosed type
2 diabetic persons with mean age of 52 years were
randomized to adequate glycemic treatment with
metformin, sulfonylureas, or insulin versus initial
treatment with diet alone, and followed for an
average of 10 years; the intervention group, with
mean HbA1c 7.0% versus 7.9%, showed a 16% reduc-
tion in myocardial infarction that just failed to ach-
ieve statistical significance (8,9), and it was not until
a decade post-trial that a significant 15% reduction in
myocardial infarction was found (10). In the VADT
(Veterans Affairs Diabetes Trial) of 1,791 persons with
type 2 diabetes for 11.5 years followed for 5.6 years
with median HbA1c of 6.9% versus 8.4%, although no
overall on-trial benefit was reported (11), post-hoc
analysis showed a U-shaped relationship of duration
to a composite of myocardial infarction, cardiovas-
cular (CV) death, stroke, amputation due to ischemia,
surgical intervention for vascular disease, new or
worsening congestive failure, and inoperable coro-
nary artery disease with an intensive glycemic inter-
vention. No significant reduction in primary
outcomes was seen with diabetes duration of 0 to 6
years, outcomes were significantly reduced with
improved glycemia at diabetes durations of 7 to 15
years, and event rates were higher at diabetes dura-
tion exceeding 20 years (12). A partial explanation of
this effect was suggested by a different analysis,
wherein VADT participants with coronary calcium
scores of 0 to 10 and 11 to 100 showed significant
reduction in event rates with intensive glycemic
treatment, while those with scores of 101 to 400
and >400 failed to show benefit (13). Furthermore,
post-trial follow-up for a median of 9.8 years did
show a significant 17% lower risk of the primary
outcome in the intensive-therapy group compared
with the standard-therapy group (14). Similar obser-
vations were made in the ACCORD (Action to Control
Cardiovascular Risk in Diabetes) study, in which 10,251
patients with type 2 diabetes of 10 years’ duration were
maintained over 3.5 years at a mean HbA1c of 6.4%
versus 7.5%: subgroup analysis showed a significant
reduction in the composite primary outcome of
nonfatal myocardial infarction, nonfatal stroke, or
death from cardiovascular causes among those per-
sons with no prior CV event, while those participants
with prior CV events failed to show benefit of the
intervention (15). Thus, rather long periods of obser-
vation are required to assess the effect of glycemic
control. Furthermore, once the atherosclerotic process
becomes manifest, improvement in glycemic control
may be of less benefit, perhaps suggesting an optimal
“window” during which intensive efforts to lower
blood glucose are particularly important. Similar con-
clusions appeared to apply to a microvascular
complication in the VADT, diabetic retinopathy, with
participants $70 years of age having paradoxical in-
crease in retinopathy with intensive glycemic control,
while those #55 years of age showed significant benefit
of the intervention (16).
It appears entirely possible, then, that the apparent
lack of effect of important differences in glycemic
control in the present analysis may be an artifact of an
insufficient period to ascertain the effect of such an
intervention. Furthermore, the cohort studied, in-
dividuals ascertained based on the presence of AF,
represents a group for whom the benefit of glycemic
control may be inherently limited. We must be careful
not to use observations of such cohorts to incorrectly
conclude that glycemic interventions for persons
with diabetes as a group are unlikely to offer macro-
vascular benefit (17).
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Zachary Bloomgarden, Icahn School of Medicine at
Mount Sinai, 35 East 85th Street, New York, New
York 10028. E-mail: zbloom@gmail.com.

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KEY WORDS atrial fibrillation, diabetes
mellitus, risk factors, stroke, thromboembolism