JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 74, NO.

8, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

JACC REVIEW TOPIC OF THE WEEK

Atrial Fibrillation and Diabetes Mellitus

JACC Review Topic of the Week

Allen Wang, BS,a Jennifer B. Green, MD,b Jonathan L. Halperin, MD,c Jonathan P. Piccini, SR., MD, MHSa,b

ABSTRACT

Diabetes mellitus is one of the most common chronic medical conditions, and is a risk factor for the development of
atrial fibrillation (AF). The presence of diabetes in patients with AF is associated with increased symptom burden and increased
cardiovascular and cerebrovascular mortality. The pathophysiology of diabetes-related AF is not fully understood, but is
related to structural, electrical, electromechanical, and autonomic remodeling. This paper reviews the complex interaction
between diabetes and AF, and explores its effect on the prevention and treatment of AF. (J Am Coll Cardiol 2019;74:1107–15)
© 2019 by the American College of Cardiology Foundation.

D iabetes mellitus is one of the most common

chronic medical conditions, with type 2 dia-
betes mellitus (T2DM) affecting >9.4% of
the U.S. population (1). Diabetes is a major cardiovas-
cular risk factor, and is associated with increased
cardiovascular events and mortality (2). Atrial fibrilla-
tion (AF) is the most common sustained cardiac
arrhythmia, and its prevalence is expected to more
than double in the next 3 decades (3). Diabetes in-
creases the risk of developing AF, and has been associ-
ated with increased symptom burden, lower quality of
life, and increased hospitalization and mortality rates
(4). Significant questions remain regarding: 1) the
interaction between diabetes and AF; and 2) the path-
ogenesis and effect of diabetes on the management of
AF. These questions will be the focus of this review.
EPIDEMIOLOGY
Many epidemiological studies have established dia-
betes as an independent risk factor
development of AF. The Framingham Heart Study, a
long-term prospective cohort study, was one of the
first to demonstrate an increased risk of AF in men and
women with diabetes (5). In a meta-analysis of several
cohort and case-control studies, patients with diabetes
had a 34% greater risk of developing AF (6). In addi-
tion, cumulative exposure to DM also seems to affect
the risk of AF. In a population-based case-control
study of 311 patients with treated diabetes, the risk of
developing AF increased by 3% for each additional
year of treatment (Figure 1) (7). In the same study,
higher glycemic levels were also associated with
increased risk of AF, with an adjusted OR of 1.14 per 1%
increase in HbA1c. In a recent meta-analysis, higher
serum glycated hemoglobin levels were significantly
associated with incident AF in prospective cohort
studies, but not in retrospective case-control studies
(8). Therefore, the overall evidence seems to support
the link between diabetes and AF.
The presence of comorbid diabetes and AF may
for the confer worse prognosis than either condition alone.

Listen to this manuscript’s
audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
From the aDuke Center for Atrial Fibrillation, Department of Medicine, Duke University Medical Center, Durham, North Carolina;
b
Duke Clinical Research Institute, Durham, North Carolina; and the cMount Sinai Hospital, New York, New York. Dr. Green has
received grants to her institution from AstraZeneca, Boehringer Ingelheim, Sanofi, Boehringer Ingelheim/Lilly Alliance, and
GlaxoSmithKline; and has served as a consultant for AstraZeneca, Boehringer Ingelheim, Boehringer Ingelheim/Lilly Alliance,
Novo Nordisk, and Merck. Dr. Halperin has received funding from Bayer, Boehringer Ingelheim, Medtronic, Janssen, and Pfizer.
Dr. Piccini has received grants for clinical research from Abbott, American Heart Association, Boston Scientific, Gilead, Janssen
Pharmaceuticals, and the National Heart, Lung, and Blood Institute; and has served as a consultant to Abbott, Allergan, ARCA
Biopharma, Bayer, Biotronik, LivaNova, Medtronic, Milestone, Motif Bio, Sanofi, Philips, and Up-to-Date. Dr. Wang has reported
that he has no relationships relevant to the contents of this paper to disclose.

Manuscript received May 2, 2019; revised manuscript received June 29, 2019, accepted July 2, 2019.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.07.020

1108 Wang et al.
AF and Diabetes
ABBREVIATIONS In the ADVANCE (Action in Diabetes and
AND ACRONYMS
Vascular Disease: Preterax and Diamicron-
MR Controlled Evaluation) study, T2DM pa-
AERP = atrial effective
refractory period
tients with AF had increased risks of major
coronary events, stroke, heart failure, car-
AF = atrial fibrillation
diovascular death, and all-cause mortality
AGE = advanced glycation end
products compared with T2DM patients without AF
DM = diabetes mellitus
(9). Similarly, in ORBIT-AF (Outcomes Reg-
istry for Better Informed Treatment of Atrial
Fibrillation), AF patients with diabetes had signifi-
cantly higher hospitalization rates, cardiovascular
mortality, and overall mortality, as well as worse
symptoms and lower quality of life compared with AF
patients without diabetes (4). The greater burden of
persistent and permanent AF, and higher prevalence
of comorbidities, such as heart failure, chronic kidney
disease, and coronary artery disease, among patients
with diabetes may explain this overall pattern.
PATHOGENESIS
STRUCTURAL REMODELING. Atrial structural remodeling—
primarily atrial fibrosis and dilatation—is a major
substrate for diabetes-related AF (Central Illustration).
Most of the evidence from preclinical and clinical
studies have shown that diabetes is independently
associated with myocardial fibrosis, and that these
fibrotic changes promote the initiation and mainte-
nance of AF (10). The mechanisms underlying
diabetes-related cardiac fibrosis can be attributed to a
combination of factors, including oxidative stress,
inflammation, increased production of advanced gly-
cation end products (AGEs), and increased expression
of growth factors (10–12). In diabetic rats, oxidative
stress and inflammation from prolonged exposure to
hyperglycemia have been shown to promote the
expression of transforming growth factor beta
(TGF-b), which activates profibrotic signaling path-
ways (10,11). In addition, increased production of
AGEs and AGE receptors also contributes to atrial
fibrosis by up-regulating connective tissue growth
factor (12). Finally, activation of the renin-
angiotensin-aldosterone system has also been impli-
cated in promoting fibrosis through the TGF-b
signaling pathway (10). Extensive myocardial fibrosis
and stiffening can lead to diastolic dysfunction, which
is commonly seen in patients with diabetes (13). Dia-
stolic dysfunction predisposes to abnormal ventricu-
lar filling and can result in left atrial dilatation, which
is another stimulus for the development of AF (14).
ELECTRICAL REMODELING. Diabetes may also be
associated with proarrhythmic electrophysiologic
changes. Several animal studies have shown that dia-
betes is associated with higher interatrial conduction
JACC VOL. 74, NO. 8, 2019
AUGUST 27, 2019:1107–15
HIGHLIGHTS
 Diabetes mellitus is an independent risk
factor for AF.
 The complex underlying pathophysiology
is related to structural, electrical, elec-
tromechanical, and autonomic
remodeling.
 Glucose-lowering therapies may affect
development of AF.
 Further research is needed to determine
the optimal stroke prevention and long-
term rhythm control strategies for AF
patients with diabetes.
times, increased atrial effective refractory period
dispersion, and prolonged action potential duration,
which are correlated with increased susceptibility to
AF (11,15). At the cellular level, decreased Na þ current
and increased L-type Ca 2þ current densities were
observed in the diabetic rabbit atrium, which may
contribute to conduction slowing and increased
arrhythmogenicity (11). Increased expression of gap
junction protein connexin-43 and decreased expres-
sion of connexin-40 may also explain some of the
predisposition to AF observed with diabetes (15). In the
clinical setting, patients with abnormal glucose
metabolism were found to have significantly longer
atrial activation times and lower bipolar voltages
during catheter ablation (16). These patients were also
found to have higher recurrence of AF after ablation,
suggesting the presence of proarrhythmic elec-
trical remodeling.
ELECTROMECHANICAL REMODELING. Diabetes may
also affect atrial excitation-contraction coupling. In
the experimental setting, alloxan-induced diabetic
rabbits were found to have impaired atrial electro-
mechanical function, which was associated with
increased atrial fibrosis, interatrial conduction delay,
and greater inducibility of AF (17). In the clinical
setting, patients with impaired fasting glucose were
found to have significantly prolonged conduction
times, with reductions in both left atrial emptying
volume and emptying fraction (18). Similarly, intera-
trial and intra-atrial electromechanical delay (EMD)
were significantly higher in patients with T2DM
compared with healthy control subjects (19). Previous
studies have shown that EMD is an independent
predictor of both new and recurrent AF (19,20).
AUTONOMIC REMODELING. Cardiac autonomic
neuropathy is a known complication of diabetes,
JACC VOL. 74, NO. 8, 2019 Wang et al. 1109
AUGUST 27, 2019:1107–15 AF and Diabetes

F I G U R E 1 Effect of Glycemic Control and Duration of Diabetes on Risk of AF

HbA1c Level OR (95% CI)

No History of
N/A
Diabetes

≤7 1.06 (0.74-1.51)

7-8 1.48 (1.09-2.01)

8-9 1.46 (1.02-2.08)

>9 1.96 (1.22-3.14)

0 1 2 3

Diabetes Duration

No History of
N/A
Diabetes

≤5 years 1.07 (0.75-1.51)

5-10 years 1.51 (1.05-2.16)

>10 years 1.64 (1.22-2.20)

0 1 2 3

Poor glycemic control and longer duration of diabetes is associated with increased risk of AF. Dots indicate OR, whereas horizontal lines indicate 95% CI. Data from
Dublin et al. (7). CI ¼ confidence interval; HbA1c ¼ hemoglobin A1c; OR ¼ odds ratio.

which is characterized by parasympathetic dener-
vation, unregulated sympathetic activity, and sub-
sequent sympathetic denervation
imbalance in sympathetic and parasympathetic ac-
tivity may contribute to the development of AF. In
the experimental setting, streptozotocin-induced
diabetic rats showed significantly higher incidence
of AF after sympathetic stimulation (22). These
findings were related to increased heterogeneity of
sympathetic nerve distribution in the diabetic rat
atria, suggesting the presence of
remodeling. In the clinical setting, significantly
lower heart rate variability, a marker of autonomic
dysfunction, has been identified in patients with
diabetes (23). Changes in heart rate variability,
particularly elevated low- to high-frequency ratio,
have been strongly associated with asymptomatic
AF (24).
(21). The OXIDATIVE STRESS AND INFLAMMATION. Oxidative
stress and inflammation are key mediators of proar-
rhythmic atrial remodeling in patients with diabetes.
Studies on atrial samples from diabetic patients have
shown increased production of reactive oxygen spe-
cies (ROS) due to impaired mitochondrial metabolism
and electron transport (25). Other major sources of
ROS include NADPH oxidase and xanthine oxidase.
autonomic Decreased expression of enzymes that normally
degrade ROS, such as superoxide dismutase and
glutathione peroxidase, exacerbate oxidative stress
(26). Increased burden of ROS activates the nuclear
factor kappa B pathway, which promotes atrial
fibrosis by increasing TGF- b and TNF-a expression,
1110 Wang et al.
AF and Diabetes
C E NT R AL IL L U STR AT IO N Pathophysiology of Diabetes and Atrial Fibrillation
Wang, A. et al. J Am Coll Cardiol. 2019;74(8):1107–15.
Glycemic fluctuations, oxidative stress, and inflammation in patients with diabetes can lead to structural, electrical, electromechanical, and autonomic remodeling.
These changes promote development of atrial fibrillation; APD ¼ action potential duration.
and slows conduction by decreasing sodium channel
SCN5A expression, providing key substrates for AF
(26,27). Increased levels of oxidative stress can also
promote inflammation, which contributes to pro-
arrhythmic structural remodeling. In the diabetic
population, inflammatory markers such as C-reactive
protein, TNF-a , and interleukin-6 are significantly
elevated, and are associated with left atrial dilatation
and increased incidence of AF (27,28).
GLYCEMIC FLUCTUATIONS. Chronic hyperglycemia
is another key mediator of atrial remodeling and
initiation of AF (11). However, intensive glycemic
control has not been found to reduce the incidence of
AF compared with standard glycemic control (29).
This finding may be related to increased episodes of
severe hypoglycemia, which has been associated with
sympathetic activation, shortening of the refractory
JACC VOL. 74, NO. 8, 2019
AUGUST 27, 2019:1107–15
period, and increased risk for AF (30–32). Recent
studies suggest that glycemic fluctuations, rather
than hyperglycemia alone, contribute to the devel-
opment of AF in diabetes. In diabetic rats, glucose
fluctuations were associated with increased atrial
fibrosis, oxidative stress, and susceptibility to AF (33).
These findings were related to increased levels
of ROS, caused by up-regulation of thioredoxin-
interacting protein (Txnip). In patients with dia-
betes, glucose fluctuations were more strongly
correlated with increased oxidative stress than
chronic hyperglycemia, suggesting that wide varia-
tions in glucose levels may be a more important risk
factor for AF (34). Finally, in a recent cohort study,
long-term glycemic variability was significantly
associated with new-onset atrial fibrillation (NAF)
(30). Therefore, treatment of diabetes should be
JACC VOL. 74, NO. 8, 2019 Wang et al. 1111
AUGUST 27, 2019:1107–15 AF and Diabetes

F I G U R E 2 Comparison of the Effect of Glucose-Lowering Therapies on Incident AF

Drug Class OR (95% CI) (Ref.#)

Metformin 0.81 (0.71-0.95) (35)

Sulfonylurea 1.07 (0.94-1.22) (39)

TZDs (all) 0.73 (0.62-0.87) (36)

Pioglitazone 0.56 (0.32-0.98) (36)

Rosiglitazone 0.78 (0.57-1.07) (36)

GLP-1 agonists 0.87 (0.71-1.05) (48)

DPP-4 inhibitors 1.07 (0.94-1.21) (41)

SGLT-2 inhibitors 0.61 (0.31-1.19) (51)

Insulin 1.19 (1.06-1.35) (41)

0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4

Metformin and TZDs are associated with significantly reduced risk of AF, whereas insulin is associated with increased risk of AF. Dots indicate study-specific OR, whereas
horizontal lines indicate 95% CI. DPP-4 ¼ dipeptidyl peptidase-4; GLP-1 ¼ glucagon-like peptide-1; SGLT-2 ¼ sodium-glucose cotransporter-2; TZD ¼ thiazolidinediones;
other abbreviations as in Figure 1.

focused on not only reducing blood glucose levels,
but also preventing glycemic fluctuations.
MANAGEMENT
GLUCOSE-LOWERING THERAPIES. Several oral dia-
betes medications may reduce atrial remodeling and
lower risk for AF (Figure 2). Metformin is the most
commonly prescribed medication for diabetes, and
has been associated with decreased risk of AF. In a
large population-based cohort study, metformin
monotherapy was associated with a lower risk of NAF
after adjusting for comorbidities and medications
(hazard ratio [HR]: 0.81; 95% confidence interval [CI]:
0.76 to 0.86; p < 0.0001) (35). In vitro experiments
with atrial myocytes have shown that metformin re-
duces tachycardia-induced myolysis and oxidative
stress. These findings suggest a potential mechanism
for the antiarrhythmic effects of metformin.
Thiazolidinediones (TZDs) have also been associ-
ated with a decreased risk for AF. In a large cohort
study, TZDs were independently associated with a
lower risk of NAF (HR: 0.69; 95% CI: 0.49 to 0.91;
p ¼ 0.028) (36). In a recent meta-analysis, patients
treated with TZDs had a 27% lower risk of developing
AF compared with control subjects (37). Subgroup
analysis suggested that pioglitazone was associated
with lower risk of NAF, but rosiglitazone was not.
Animal studies have shown that TZDs attenuate in-
flammatory atrial fibrosis, which may lower the risk
for diabetes-related AF (38).
Sulfonylureas are the most commonly prescribed
second-line hypoglycemic drug therapy, but may not
offer the same protection against AF. In a population-
based nested case-control study, there was no asso-
ciation between use of sulfonylurea and NAF after
adjusting for comorbidities and medications (odds
ratio [OR]: 1.07; 95% CI: 0.94 to 1.22; p < 0.05) (39). It
is important to note that sulfonylurea therapy is
associated with 4.5-fold increase in risk of severe
hypoglycemia compared with metformin (40). Acute
hypoglycemia has been associated with proar-
rhythmia due to sympathetic activation, and may
explain the overall association between sulfonylurea
use and NAF (31).
Insulin use can also cause hypoglycemia, and has
been associated with increased incidence of AF. In a
nested case control study, insulin users were at
higher risk of developing NAF than nonusers, even
after adjusting for diabetes duration (OR: 1.19;
95% CI: 1.06 to 1.35; p < 0.05) (41). However, insulin
use may indicate a heavier burden of comorbidities;
thus, true causality is often difficult to determine.
The ORIGIN (Outcome Reduction With Initial Glargine
1112 Wang et al.
AF and Diabetes
Intervention) trial, which randomized over 12,000
patients with impaired fasting glucose, impaired
glucose tolerance, or T2DM to early use of insulin
glargine or standard of care, reported no increase in
AF with assignment to insulin therapy (42). Further
prospective randomized studies are needed to
determine the role of insulin use in the development
of AF.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a
new class of diabetes medications with possible car-
dioprotective effects. In a recent cohort study, use of
DPP-4 inhibitors for second-line diabetes therapy was
associated with a lower risk of AF compared with use
of other antidiabetic drugs (43). However, in a large
case control study, DPP-4 inhibitors were not associ-
ated with risk of AF after adjusting for comorbidities
and concurrent medications (OR: 1.07; 95% CI: 0.94 to
1.21; p > 0.05) (41). Furthermore, several cardiovas-
cular outcomes trials, including the EXAMINE (Car-
diovascular Outcomes Study of Alogliptin in Patients
With Type 2 Diabetes and Acute Coronary Syndrome),
SAVOR-TIMI (Does Saxagliptin Reduce the Risk of
Cardiovascular Events When Used Alone or Added to
Other Diabetes Medications), and CARMELINA (Car-
diovascular and Renal Microvascular Outcome Study
With Linagliptin in Patients With Type 2 Diabetes
Mellitus), have not shown any significant interactions
between DPP-4 inhibitors and incidence of AF
(44–46).
Glucagon-like peptide-1 receptor agonists (GLP-
1RA) are another new class of diabetes medication
that have been associated with a lower risk of major
adverse cardiovascular events (47). However, in a
recent meta-analysis of data from several clinical
trials, there was no association between GLP-1RA
therapy and the incidence of NAF (OR: 0.87; 95% CI:
0.71 to 1.05; p ¼ 0.15) (48). Recent cardiovascular
outcomes trials, including EXSCEL (Exenatide Study
of Cardiovascular Event Lowering Trial) and Harmony
Outcomes (Effect of Albiglutide, When Added to
Standard Blood Glucose Lowering Therapies, on Ma-
jor Cardiovascular Events in Subjects With Type 2
Diabetes Mellitus), have reported nonsignificant re-
ductions in the incidence of NAF (49,50). Therefore,
current evidence does not support any association
between GLP-1RA and risk of AF.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors
have also been shown to reduce the risk of major
adverse cardiovascular events and hospitalization for
heart failure (47). In a recent meta-analysis of several
clinical trials, SGLT2 inhibitors were not associated
with NAF when compared with placebo (OR: 0.61;
95% CI: 0.31 to 1.19; p ¼ 0.15) (51). Furthermore,
recent cardiovascular outcome trials, such as EMPA-
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AUGUST 27, 2019:1107–15
REG OUTCOME (BI 10773 [Empagliflozin] Cardiovas-
cular Outcome Event Trial in Type 2 Diabetes Mellitus
Patients), CANVAS (CANagliflozin cardioVascular
Assessment Study), and DECLARE (Dapagliflozin Ef-
fect on Cardiovascular Events), have not reported any
significant difference in NAF for patients on SGLT2
inhibitors (52–54). Evidence from these studies sug-
gest that although SGLT2 inhibitors may prevent
adverse cardiovascular events, they have no effect on
the incidence of AF.
Additional data are needed to determine the role of
newer diabetes medications in primary or secondary
prevention of AF. Importantly, DPP-4 inhibitors, GLP-
1RA, and SGLT2 inhibitors lower glucose without
independently posing a risk of severe hypoglycemia
(47). This enhanced safety profile and the now
demonstrated cardiovascular benefit of GLP-1RA and
SGLT2 inhibitors may affect AF risk quite differently
than has been seen in studies of older agents.
STROKE PREVENTION. DM is a known risk factor for
thromboembolic events in patients with AF, and is
associated with a 70% relative increase in risk of
stroke (55). Diabetes is included in the CHA 2DS2-VASc
risk score, which is widely used to assess stroke risk
and guide anticoagulation therapy (56). However, the
optimal stroke prevention strategy in patients with
diabetes and AF has not been established.
In subgroup analyses of 4 phase III trials comparing
direct oral anticoagulants (DOACs) with warfarin, the
relative safety and efficacy of DOACs versus warfarin
was similar regardless of diabetes status (57). Among
patients with diabetes, use of DOACs resulted in 20%
reduction of stroke or systemic embolic events, 43%
reduction in intracranial bleeding, and 17% reduction
in cardiovascular death compared with warfarin (55).
Previous studies have shown that the presence of
diabetes is associated with lower time in therapeutic
range among warfarin users, which may contribute to
lower safety and efficacy in this population (58). For
patients with diabetes and CHA2DS2-VASc scores $2,
DOACs may be recommended over warfarin.
For AF patients with diabetes and CHA 2DS2-VASc
score of 1, whether oral anticoagulation is indicated is
not clear. In a recent cohort study, duration of dia-
betes >3 years was found to be an independent pre-
dictor of ischemic stroke among AF patients (HR: 1.74;
95% CI: 1.10 to 2.76) (59). Furthermore, a large, pro-
spective, multicenter study showed that patients
with insulin-requiring diabetes had approximately
2.5-fold higher risk of stroke or systemic embolism at
1 year compared with patients with noninsulin-
requiring diabetes (HR: 2.96; 95% CI: 1.49 to 5.87)
(60). These results suggest that patients with longer
duration of diabetes or insulin-requiring diabetes
JACC VOL. 74, NO. 8, 2019
AUGUST 27, 2019:1107–15
T A B L E 1 Selected Studies on Diabetes and Catheter Ablation Outcomes
First Author, Year (Ref. #) Study
Tang et al., 2006 (68) Cohort
Bogossian et al., 2016 (69) Cohort
Lin et al., 2014 (70) Meta-analysis
Wokhlu et al., 2010 (71) Cohort
Chao et al., 2010 (16) Cohort
Anselmino et al., 2015 (72) Meta-analysis
BMI ¼ body mass index; CI ¼ confidence interval; DM ¼ diabetes mellitus; HbA1c ¼ hemoglobin A1c; HR ¼ hazard ratio; RR ¼ risk ratio.
may benefit more from oral anticoagulation, even in
the absence of other major risk
thromboembolism.
ANTIARRHYTHMIC DRUGS. Previous animal studies
suggest that antiarrhythmic drugs (AADs) may be less
effective for patients with diabetes. In a rat model,
induction of diabetes was associated with signifi-
cantly reduced efficacy of flecainide and E-4031
(experimental class III AAD) compared with the con-
trol (61). Currently, no clinical studies have evaluated
the efficacy of AADs in patients with diabetes. How-
ever, diabetic patients may be at increased risk for
adverse side effects from AADs, due to the large
prevalence of silent coronary artery disease, heart
failure, and chronic kidney disease in this population
(4,62). Furthermore, high incidence of QTc prolon-
gation among patients with diabetes may further in-
crease proarrhythmic risk (63).
CARDIOVERSION. Several studies have
reduced efficacy of cardioversion in patients with
diabetes. In a recent case-control study, the presence
of diabetes was associated with significantly lower
success rates of immediate cardioversion (OR: 0.372;
95% CI: 0.19 to 0.73) and maintenance of sinus
rhythm (OR: 0.398; 95% CI: 0.203 to 0.730) at median
follow-up of 74.5 days (64). Further regression anal-
ysis showed that glycemic control was an indepen-
dent predictor of cardioversion failure. Similarly, in
the FinCV study, a retrospective multicenter study of
2,868 patients, diabetes was identified as an inde-
pendent risk factor for failure of cardioversion within
30 days (65). Finally, diabetes has also been corre-
lated with higher risk of cardioversion failure for
early AF recurrence (#7 days) after ablation (66).
CATHETER ABLATION. Catheter ablation
established therapy for symptomatic AF refractory to
AADs, and has been shown to be an effective
Wang et al. 1113
AF and Diabetes
Patients, n (DM) Findings
263 (31) No difference in post-ablation recurrence between DM and non-DM patients after mean
follow-up of 13.4 months (32.3% vs. 22.4%; p ¼ 0.240)
8,175 (944) No difference in subjective post-ablation recurrence between DM and non-DM patients at
1-yr follow-up (46.4% vs. 46.8%; p ¼ 0.90)
12,924 (N/A) No difference in post-ablation recurrence between DM and non-DM patients
(RR: 1.11; 95% CI: 0.97–1.26)
774 (47) Diabetes independent predictor of overall recurrence at median follow-up of 3.0 yrs
(HR: 1.9; 95% CI:1.3–2.9; p ¼ 0.002)
228 (65) Abnormal glucose metabolism associated with increased post-ablation recurrence at
mean follow-up of 18.8 months (18.5% vs. 8.0%; HR: 3.247; 95% CI: 1.209–8.720;
p ¼ 0.019)
1,464 (1,464) Advanced age, higher BMI, higher HbA1c related to higher incidence of recurrence
(p < 0.001)
treatment option for patients with diabetes (56). In a
factors for randomized trial of 70 patients with T2DM, catheter
ablation was found to have significant clinical bene-
fits over AADs, resulting in better AF control,
improved quality of life, and lower hospitalization
rates (67). Several studies have evaluated whether
diabetes is a risk factor for AF recurrence following
ablation, with conflicting results (Table 1) (16,68–72).
In a recent meta-analysis of 15 studies including 1,464
patients with DM, higher basal glycated hemoglobin
levels were associated with a higher incidence of AF
recurrence after catheter ablation (72). This suggests
that appropriate glycemic control may be important
in improving post-ablation outcomes among patients
with diabetes.
CONCLUSIONS
Both DM and AF are increasing in epidemic pro-
reported portions, and are associated with increased cardio-
vascular and cerebrovascular mortality. The
relationship between DM and AF is complex, and is
mediated by structural, electrical, electro-
mechanical, and autonomic changes of the atria,
triggered by oxidative stress, inflammation, and gly-
cemic fluctuations. Future studies should further
elucidate the mechanism of DM-related AF, and
evaluate the best treatment strategy for patients with
DM and AF. Significant questions remain regarding: 1)
the role of diabetes medications for AF prevention; 2)
the optimal stroke prevention strategy; and 3) pre-
vention of AF recurrence after catheter ablation.
ADDRESS FOR CORRESPONDENCE: Dr. Jonathan P.
Piccini, Electrophysiology Section, Duke University
is an Medical Center, Duke Clinical Research Institute, P.O.
Box 17969, Durham, North Carolina 27710. E-mail:
jonathan.piccini@duke.edu. Twitter: @JonPicciniSr.
1114 Wang et al.
AF and Diabetes
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KEY WORDS atrial fibrillation, diabetes
mellitus