JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO.

11, 2022

ª 2022 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

ATRIAL FIBRILLATION - PHARMACOLOGICAL THERAPY

Efficacy of Sodium-Glucose
Cotransporter 2 Inhibitors on
Outcomes After Catheter Ablation
for Atrial Fibrillation
Hideyuki Kishima, MD,a,b Takanao Mine, MD,a Eiji Fukuhara, MD,a Ryo Kitagaki, MD,a Masanori Asakura, MD,a
Masaharu Ishihara, MDa

ABSTRACT

BACKGROUND Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been a significant focus of attention
because of their multiple pleiotropic effects. However, the impact of SGLT2i on atrial fibrillation (AF) remains unclear.

OBJECTIVES The goal of this study was to examine the effects of SGLT2i on AF after catheter ablation (CA).

METHODS This prospective, randomized controlled study compared the suppressive effect of SGLT2i vs dipeptidyl
peptidase-4 inhibitors on AF recurrence after CA. Eighty AF patients with type 2 diabetes mellitus were randomized (by a
computer-generated random sequence) to the tofogliflozin group (20 mg/d) or the anagliptin group (200 mg/d)
stratified according to left atrial diameter and AF type (paroxysmal AF [PAF] or non-paroxysmal atrial fibrillation [PAF])
at screening. The primary outcome was AF recurrence at 12 months after CA.

RESULTS Seventy patients were analyzed (mean age 70.3
8.1 years; 48 male; 30 with paroxysmal AF; 38 tofogliflozin
treated). Recurrent AF was detected in 24 (34.3%) of 70 patients, and the AF recurrence ratio was higher in the anagliptin
group than in the tofogliflozin group (15 of 32 patients [47%] vs 9 of 38 patients [24%]; P ¼ 0.0417). Moreover, uni-
variate analysis revealed that compared with the nonrecurrence group (n ¼ 46), the recurrence group (n ¼ 24) had a
higher prevalence rate of non-PAF, elevated brain natriuretic peptide, higher urinary albumin-creatinine ratio, lower rate
of SGLT2i use, larger left atrial diameter, elevated E wave, lower left ventricular ejection fraction, and lower rate of
cryoballoon pulmonary vein isolation.

CONCLUSIONS Compared with anagliptin, tofogliflozin achieved greater suppression of AF recurrence after CA
in patients with type 2 diabetes mellitus. (J Am Coll Cardiol EP 2022;8:1393–1404) © 2022 by the American College of
Cardiology Foundation.

D iabetes mellitus (DM) is a well-known risk

factor for the development of atrial fibrilla-
tion (AF). Benjamin et al, 1 in the Framing-
ham Heart Study, reported that DM was significantly
associated with risk for AF (OR: 1.4 for men and 1.6
for women). Another study reported that DM was
associated with higher risk of developing AF, and
risk was higher with longer duration of treated DM

From the aDepartment of Cardiovascular and Renal Medicine, Hyogo College of Medicine, Nishinomiya, Japan; and bInternal
Medicine, Kishima Hon-in Hospital, Yao, Japan.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received April 13, 2022; revised manuscript received July 19, 2022, accepted August 5, 2022.

ISSN 2405-500X/$36.00 https://doi.org/10.1016/j.jacep.2022.08.004

1394 Kishima et al
Efficacy of SGLT2i on Atrial Fibrillation
ABBREVIATIONS and worse glycemic control. 2 Various mecha-
AND ACRONYMS nisms, such as atrial fibrosis due to promote
oxidative stress, atrial remodeling, inflam-
AAD = antiarrhythmic drugs
mation, and autonomic imbalance, have
AF = atrial fibrillation
been suggested as causes. 3
BMI = body mass index
With the development of antidiabetic
BP = blood pressure drugs, various medications have become
CA = catheter ablation available for the treatment of patients with
Cryo-PVI = cryoballoon DM. Of these, the sodium-glucose cotrans-
pulmonary vein isolation
porter 2 inhibitors (SGLT2i) have recently
CTI = cavotricuspid isthmus been a significant focus of attention for pa-
DM = diabetes mellitus tients with heart failure, cardiovascular dis-
DPP4i = dipeptidyl peptidase-4 ease, or kidney disease, and they have been
inhibitors
shown in randomized trials to reduce heart
eGFR = estimated glomerular failure, hospitalization, and cardiovascular
filtration rate
death in patients with DM. 4-6
HbA1c = glycated hemoglobin
SEE PAGE 1405
LAD = left atrial diameter
PAF = paroxysmal AF
SGLT2i are oral antidiabetic drugs that act
RF-PVI = radiofrequency primarily by increasing the urinary elimina-
current pulmonary vein
tion of glucose.7 In addition, SGLT2i have
isolation
multiple pleiotropic effects
SGLT2i = sodium-glucose
cotransporter 2 inhibitors independent and direct cardiac protection
that may improve atrial remodeling. In the
post hoc analysis of the DECLARE-TIMI 58 (Dapagli-
flozin Effect on Cardiovascular Events–Thrombolysis In
Myocardial Infarction 58) trial, SGLT2i significantly
reduced the risk of atrial tachyarrhythmias in patients
8
with type 2 DM. In contrast, other studies have failed
9,10
to show the efficacy of SGLT2i for AF.
is divided regarding whether SGLT2i enable the sup-
pression of AF. Moreover, these studies were retro-
spective in design or were subanalyses, and assessment
of AF was not the primary endpoint. We consider it
F I G U R E 1 Flowchart of Enrolled Participants
Of 80 patients, 10 withdrew from the study during the observation period. Therefore, 70 patients were included in the prospective study
analysis. AF ¼ atrial fibrillation; CA ¼ catheter ablation; DM ¼ diabetes mellitus.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022
NOVEMBER 2022:1393–1404
essential to reevaluate the effect of SGLT2i on AF in a
prospective study. Therefore, the present study aimed
to examine the effects of SGLT2i for AF after catheter
ablation (CA) compared with dipeptidyl peptidase-4
inhibitors (DPP4i).
METHODS
STUDY DESIGN. This prospective, single-center,
open-label, randomized controlled study was con-
ducted at Hyogo College of Medicine between April
2017 and March 2020. The study protocol complied
with the principles of the Declaration of Helsinki and
was reviewed and approved by the Ethics Review
Board of Hyogo College of Medicine (No. 2537). The
study is registered in the University Hospital Infor-
mation Network Clinical Trials Registry
(UMIN000024326T). All patients provided written
informed consent before enrollment.
After applying the following inclusion and exclu-
sion criteria, we recruited 80 patients with AF and
of glucose- type 2 DM who were referred for CA of AF in the
Hyogo College of Medicine. The inclusion criteria
were: 1) type 2 DM (6.5% < glycated hemoglobin
[HbA1c] <10%) combined with AF; 2) treated with oral
anticoagulants; 3) duration of AF <1 year; 4) not
taking SGLT2i and/or DPP4i for >2 weeks before
enrollment; and 5) age 20 to 80 years. The exclusion
criteria were: 1) stroke or transient ischemic attack
Thus, opinion within 3 months; 2) valvular AF; 3) New York Heart
Association functional class III or IV; 4) severe liver or
renal function damage, defined as alanine amino-
transferase >80 U/L, aspartate aminotransferase >80
U/L, or estimated glomerular filtration rate
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022 Kishima et al 1395
NOVEMBER 2022:1393–1404 Efficacy of SGLT2i on Atrial Fibrillation

(eGFR) <30 mL/min/1.73 m 2; 5) a history of cardiac

T A B L E 1 Patient Baseline Characteristics and Medication Therapy
surgery; 6) contraindication for SGLT2i and/or DPP4i;
and 7) pregnant/planning to become pregnant or Tofogliflozin Anagliptin P Value
All Patients Group Group (Tofogliflozin vs
lactating women. (N ¼ 70) (n ¼ 38) (n ¼ 32) Anagliptin)

Patient characteristics
GROUP DESIGN. The rate of recurrent AF after CA has
11 Male 48 (69.0) 26 (68.0) 22 (69.0) 0.9764
been reported as w30%. To show a difference of
Age, y 70.3
8.2 70.3
8.6 70.3
7.7 0.9674
20% with regard to the rate of recurrent AF, at least 30 Weight, kg 69.5
13.8 69.7
14.8 69.3
12.4 0.8957
patients are required per arm (type I error a ¼ 0.1; Waist circumference, cm 93.2
11.1 93.2
11.3 93.3
10.8 0.989
power ¼ 0.8). Assuming a dropout rate of 10%, a total Body mass index, kg/m2 25.4
4.5 25.5
4.6 25.3
4.3 0.8282
of 80 patients (40 patients per group) were invited to Systolic blood pressure, mm Hg 133.4
18.7 137.2
18.8 128.8
18.5 0.0644

participate in the study. Participants were assigned Diastolic blood pressure, mm Hg 79.3
13.6 82.1
13.3 75.9
14.0 0.066
Heart rate, beats/min 77.4
20.7 78.4
20.6 76.3
20.9 0.6717
randomly into 1 of 2 treatment groups: tofogliflozin
Nonparoxysmal AF 40 (57.0) 22 (58.0) 18 (56.0) 0.8898
20 mg once a day (tofogliflozin group, n ¼ 40) or
AF duration, mo 38.5
47.7 35.9
50.4 41.5
44.2 0.6224
anagliptin 100 mg twice a day (anagliptin group,
Hypertension 45 (64.0) 26 (68.0) 19 (59.0) 0.4314
n ¼ 40). Randomization was conducted by using Dyslipidemia 45 (64.0) 26 (68.0) 19 (59.0) 0.4314
computer-generated random sequencing, stratified Structural heart disease 19 (27.0) 12 (32.0) 7 (22.0) 0.3631
by left atrial diameter (LAD) and type of AF (parox- Ischemic 4 (6.0) 2 (5.0) 2 (6.0) 1.0000
ysmal or nonparoxysmal) at screening. None of the Nonischemic 15 (21.0) 9 (24.0) 6 (19.0) 0.6162

investigators was involved directly or indirectly with Prior heart failure 19 (27.0) 10 (26.0) 9 (28.0) 0.8654
Prior stroke/TIA 15 (21.0) 6 (16.0) 9 (28.0) 0.2102
randomization. After enrollment, the patients were
CHADS2 score 2.6
1.2 2.6
1.1 2.7
1.3 0.6310
treated with tofogliflozin (20 mg/d) or anagliptin
HAS-BLED score 2.0
0.8 2.1
0.9 1.8
0.7 0.2521
(200 mg/d) for 2 to 6 weeks before the CA procedure, Medication therapy
and they continued daily treatment at this dose dur- Beta-blocker 36 (51.0) 21 (55.0) 15 (47.0) 0.4842
ing the 1-year follow-up period. ACE inhibitor/ARB 38 (54.0) 22 (58.0) 16 (50.0) 0.5089
Calcium-channel blocker 30 (43.0) 16 (42.0) 14 (44.0) 0.8898
DATA COLLECTION. Study visits were scheduled at Statin 34 (49.0) 18 (47.0) 16 (50.0) 0.8263
baseline (2-6 weeks before CA) and at 1, 3, 6, 9, and Diuretics 13 (19.0) 6 (16.0) 7 (22.0) 0.5142

12 months after CA. Measurements included blood Antiplatelet 16 (23.0) 6 (16.0) 10 (31.0) 0.1249
Direct oral anticoagulant 65 (93.0) 35 (92.0) 30 (94.0) 1.0000
pressure (BP), heart rate, waist circumference, body
Antiarrhythmic drug 10 (14.0) 4 (11.0) 6 (19.0) 0.495
mass index (BMI), Atrial Fibrillation Quality of Life
Antidiabetic drug 22 (31.0) 14 (37.0) 8 (25.0) 0.2877
Questionnaire, and electrocardiogram at each study
Sulfonylurea 9 (13.0) 7 (18.0) 2 (6.0) 0.1658
visit.12 CHADS2 and HAS-BLED scores were calculated Metformin 13 (19.0) 8 (21.0) 5 (16.0) 0.5608
at baseline.13,14 Blood and urinary samples were Glinide 0 0 0 1
assessed at baseline, on the day of CA, and at 3 and Glitazone 0 0 0 1.0000
12 months after CA. Transthoracic echocardiography Acarbose 4 (6.0) 2 (5.0) 2 (6.0) 1.0000

and Holter electrocardiogram were scheduled at Insulin 3 (4.0) 1 (3.0) 0 0.4571

baseline and at 3 and 12 months after CA.

Values are n (%) or mean
SD unless otherwise indicated.
ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; ARB ¼ angiotensin receptor blocker;
CA PROCEDURE FOR AF. Antiarrhythmic drugs (AAD) TIA ¼ transient ischemic attack.

were discontinued for at least 5 half-lives prior to CA.

All patients underwent radiofrequency current pul-
monary vein isolation (RF-PVI) using a 4-mm exter-
nally irrigated-tip quadripolar ablation catheter
(FlexAbility; Abbott Medical) or cryoballoon PVI
(Cryo-PVI) using the Arctic Front system (Medtronic).
In the radiofrequency current procedure, PVI was
achieved by using a focal “point-by-point” catheter
approach, which delivers heat energy to the cardiac
tissue. The circumferential ablation lines were
created under the guidance of a 3-dimensional
mapping system (EnSite Precision system, Abbott
Medical). In the cryoballoon procedures, PVI was
achieved by using fluoroscopic guidance to position
the cryoballoon catheter. After confirming PV-to-
balloon occlusion by retrograde radiopaque contrast
agent retention, adenosine triphosphate was admin-
istered to provoke reconnection of the PVs (dormant
PV conduction) at least 20 minutes after successful
PVI. Upon observation of any dormant PV conduc-
tion, additional ablation was applied at the earliest PV
activation site until the absence of any dormant PV
conduction. The endpoint was the establishment of a
bidirectional conduction block between the left
atrium and the PV. The strategy of CA and additional
superior vena cava isolation or cavotricuspid isthmus
(CTI) ablation were conducted at the operator’s
discretion. No additional LA lesions were permitted.
1396 Kishima et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022

Efficacy of SGLT2i on Atrial Fibrillation NOVEMBER 2022:1393–1404

T A B L E 2 Patient Baseline Biochemistry and Echocardiographic Findings

P Value
All Patients Tofogliflozin Anagliptin (Tofogliflozin vs
(N ¼ 70) Group (n ¼ 38) Group (n ¼ 32) Anagliptin)

Biochemistry findings
Hemoglobin, g/dL 14.2
1.6 14.4
1.6 14.0
1.6 0.2691
C-reactive protein, mg/dL 0.24
0.67 0.14
0.16 0.35
0.98 0.1919
Brain natriuretic peptide, pg/mL 199.3
216.5 179.7
152.4 222.5
274.1 0.4128
eGFR, mL/min/1.73 m2 73.1
22.0 70.7
22.8 76.1
21.1 0.3104
Sodium, mEq/L 141.0
2.1 141.1
1.5 140.8
2.7 0.7157
Potassium, mEq/L 3.8
0.4 3.9
0.5 3.7
0.4 0.221
HbA1c, % 6.7
0.8 6.7
0.6 6.8
0.9 0.5399
LDL-C, mg/dL 105.7
28.4 104.8
29.7 106.8
26.7 0.7743
HDL-C, mg/dL 53.5
13.2 54.8
12.1 52.0
14.4 0.3725
Triglycerides, mg/dL 142.9
59.0 149.3
66.6 135.2
48.4 0.3236
Total serum ketones, mmol/L 118.7
122.5 109.7
102.4 129.3
142.8 0.5057
Acetoacetic acid, mmol/L 38.2
33.5 34.7
26.6 42.2
40.2 0.3552
b-hydroxybutyrate acid, mmol/L 80.6
91.4 75.2
79.5 87.1
103.8 0.588
Urinary microalbumin, mg/mL 96.0
212.0 114.3
257.5 74.3
139.6 0.4338
Urinary albumin-creatinine ratio 115.6
238.5 111.8
229.9 120.1
248.4 0.8852
Urinary excretion of electrolytes
Sodium, mEq/L 107.4
47.5 114.5
49.1 99.1
45.5 0.1816
Potassium, mEq/L 41.2
19.8 42.7
17.5 39.5
22.2 0.4992
Echocardiographic findings
LAD, mm 45.2
6.5 45.6
7.5 44.7
5.0 0.5611
E wave, cm/s 78.9
20.0 79.3
20.0 78.6
20.0 0.8841
Deceleration time, ms 184.2
53.0 176.0
40.5 194.0
64.9 0.1632
LV diameter during end diastole, mm 50.2
5.6 50.0
5.9 50.4
5.1 0.7437
LV hypertrophy 8 (11.0) 5 (13.0) 3 (9.0) 0.7188
LV ejection fraction, % 59.9
13.3 61.5
11.3 58.0
15.4 0.2775
E/e0 ratio 12.4
4.2 12.3
4.5 12.7
3.7 0.6673
Procedural findings
Cryoballoon PVI 18 (26.0) 8 (21.0) 10 (31.0) 0.3308
CTI ablation 50 (71.0) 30 (79.0) 20 (63.0) 0.1292
SVCI 12 (17.0) 8 (21.0) 4 (13.0) 0.526

Values are mean
SD or n (%), unless otherwise indicated.

CTI ¼ cavotricuspid isthmus, eGFR ¼ estimated glomerular filtration rate; HbA1c ¼ glycated hemoglobin; HDL-C ¼ high-density lipoprotein cholesterol; LAD ¼ left atrial
diameter; LDL-C ¼ low-density lipoprotein cholesterol; LV ¼ left ventricular; PVI ¼ pulmonary vein isolation; SVCI ¼ superior vena cava isolation.

FOLLOW-UP AND ENDPOINT. All patients were fol-
lowed up at our hospital at 1, 3, 6, 9, and 12 months
after the CA procedure, and they were referred to the
emergency department if any symptoms suggesting
an arrhythmia occurred between scheduled visits.
Recurrence of AF was defined as an episode of atrial
tachyarrhythmia lasting for >30 seconds after a 3-
month blanking period. The primary endpoint was
the recurrence of AF at 12 months after the CA pro-
cedure. Safety was assessed based on laboratory
findings and the occurrence of adverse events and
side effects documented during study visits.
with 1-way analysis of variance. Categorical variables
were compared by using the chi-square test or
Fisher exact test. A P value <0.10 was considered to
indicate statistical significance. Kaplan-Meier curves
were used to estimate AF-free survival rates and were
compared by using the log-rank test. Kaplan-Meier
curves were analyzed according to an intention-to-
treat analysis and per-protocol analysis. All analyses
were performed by using JMP Pro statistical software
version 10 (SAS Inc.) and Microsoft Excel (Microsoft
Corporation).

STATISTICAL ANALYSIS. Continuous variables are RESULTS

presented as mean
SD, and they were analyzed with
Student’s t-tests if they conformed to a normal dis- PARTICIPANT CHARACTERISTICS. A total of 632 pa-
tribution and Mann-Whitney U tests if they did not. tients with AF who were referred for CA for AF at our
Comparisons between >2 groups were performed hospital between April 2017 and March 2020 were
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022 Kishima et al 1397
NOVEMBER 2022:1393–1404 Efficacy of SGLT2i on Atrial Fibrillation

T A B L E 3 Change in Each Marker Compared with Baseline

1: Tofogliflozin Group (n ¼ 38) 2: Anagliptin Group (n ¼ 32) P Value

A: Baseline B: CA Day C: 12-Month A: Baseline B: CA Day C: 12-Month 1-B vs 2-B 1-C vs 2-C

Weight, kg 69.7
14.8 –0.9
1.4 –2.3
3.8 69.3
12.4 0.6
2.0 -0.1
4.1 0.0006 0.0196
Waist circumference, cm 93.2
11.3 –1.4
3.6 –2.7
5.0 93.3
10.8 0.7
3.6 -0.1
5.8 0.0138 0.0426
Body mass index, kg/m2 25.5
4.6 –0.3
0.5 –0.8
1.4 25.3
4.3 0.2
0.7 0.0
1.6 0.0007 0.0229
Systolic blood pressure, mm Hg 137.2
18.8 –15.3
15.9 –11.8
18.3 128.8
18.5 –2.2
11.6 8.0
12.3 0.0002 <0.0001
Diastolic blood pressure, mm Hg 82.1
13.3 –8.1
15.9 –8.6
15.2 75.9
14.0 –2.4
11.2 0.3
11.7 0.0956 0.0082
Heart rate, beats/min 78.4
20.6 –3.8
20.3 –5.9
23.6 76.3
20.9 –3.4
18.8 –1.9
26.4 0.9214 0.5067
Brain natriuretic peptide, pg/mL 179.7
152.4 –37.1
75.0 –92.8
140.2 222.5
274.1 –42.3
127.6 –130.4
257.5 0.8319 0.4408
Renin, ng/mL/h 22.3
52.8 –9.5
46.2 –1.1
61.4 15.9
18.5 3.0
31.7 3.1
22.7 0.2021 0.7158
Aldosterone, pg/mL 146.9
78.5 –33.4
73.2 –2.8
57.3 136.7
91.6 –20.4
71.1 33.2
84.0 0.4565 0.0375
Serum creatinine, mg/dL 0.83
0.26 0.02
0.07 0.01
0.10 0.75
0.20 0.00
0.11 0.04
0.12 0.5594 0.2438
eGFR, mL/min/1.73 m2 70.7
22.8 –1.1
7.0 –0.8
9.4 76.1
21.1 –0.2
10.9 –4.3
12.3 0.6803 0.1805
Sodium, mEq/L 141.1
1.5 0.9
1.5 0.0
1.8 140.8
2.7 0.5
1.3 0.1
1.7 0.2855 0.6032
Potassium, mEq/L 3.9
0.5 –0.2
0.3 0.0
0.2 3.7
0.4 –0.2
0.1 0.0
0.3 0.7472 0.7274
HbA1c, % 6.7
0.6 0.1
0.3 –0.1
0.6 6.8
0.9 0.2
0.3 –0.4
0.8 0.0847 0.1039
LDL-C, mg/dL 104.8
29.7 3.1
19.0 1.7
28.4 106.8
26.7 6.0
15.4 –2.7
20.0 0.4952 0.4703
HDL-C, mg/dL 54.8
12.1 5.5
6.8 8.4
12.5 52.0
14.4 4.1
8.9 4.2
10.6 0.4592 0.1361
Triglycerides, mg/dL 149.3
66.6 16.8
44.7 –6.3
74.1 135.2
48.4 8.7
40.1 3.2
60.9 0.4297 0.5645
Total serum ketones, mmol/L 109.7
102.4 239.9
338.4 18.5
137.6 129.3
142.8 10.8
29.0 –55.2
154.7 0.0008 0.0386
Acetoacetic acid, mmol/L 34.7
26.6 70.1
92.8 0.8
30.7 42.2
40.2 4.6
50.1 –15.8
43.8 0.0006 0.0665
b-hydroxybutyrate acid, mmol/L 75.2
79.5 170.3
252.6 17.4
109.6 87.1
103.8 6.3
116.6 –39.3
112.2 0.0012 0.0363
Urinary microalbumin, mg/mL 114.3
257.5 43.8
602.0 –57.9
139.2 74.3
139.6 –27.0
70.3 22.3
130.6 0.5109 0.016
Urinary albumin-creatinine ratio 111.8
229.9 90.6
996.6 –40.0
126.4 120.1
248.4 –46.4
142.9 58.4
263.2 0.4439 0.0471
Urinary excretion of electrolytes
Sodium, mEq/L 114.5
49.1 –16.5
45.4 –31.0
51.4 99.1
45.5 6.2
48.1 12.6
50.6 0.0465 0.0007
Potassium, mEq/L 42.7
17.5 –13.6
19.1 –10.3
16.9 39.5
22.2 –8.2
23.6 14.8
27.1 0.2874 <0.0001
LAD, mm 45.6
7.5 –2.1
4.4 –1.9
4.8 44.7
5.0 –0.6
4.6 –2.6
4.0 0.1812 0.5657
LV diameter during end diastole, mm 50.0
5.9 –0.3
3.5 –0.8
4.2 50.4
5.1 –0.6
3.0 –0.7
4.9 0.7223 0.8874
LV ejection fraction, % 61.5
11.3 –0.1
7.1 3.6
9.5 58.0
15.4 3.7
7.0 5.2
13.1 0.027 0.569
E/e0 ratio 12.3
4.5 –0.5
4.7 0.0
5.4 12.7
3.7 –0.4
3.9 0.3
4.6 0.8957 0.8537
Total AFQLQ 76.6
15.1 5.6
13.1 7.9
20.2 69.1
22.9 10.5
20.4 11.7
22.7 0.2318 0.4624
Frequency of symptoms 18.0
5.3 1.3
5.6 1.9
7.2 14.9
6.2 4.6
7.6 3.8
8.3 0.0379 0.326
Severity of symptoms 15.1
2.8 0.0
3.1 0.7
4.4 12.6
4.7 2.2
5.5 2.6
5.1 0.0391 0.0961
Mental anxiety 43.5
10.3 4.4
8.3 5.5
11.6 41.3
14.1 4.3
11.2 5.6
12.8 0.972 0.9731

Values are mean
SD.

AFQLQ ¼ Atrial Fibrillation Quality of Life Questionnaire; CA ¼ catheter ablation; other abbreviations as in Table 2.

screened for eligibility. Of these, 80 met the inclu-
sion/exclusion criteria and were randomized into the
treatment groups. Ten patients withdrew from the
study during the observation period. Two patients
withdrew from the tofogliflozin group because of
diarrhea (n ¼ 1) and frequent urination (n ¼ 1). Eight
patients withdrew from the anagliptin group because
of aortic dissection (n ¼ 1), worsening heart failure
(n ¼ 1), canceled CA due to LA appendage thrombus
(n ¼ 3), and incomplete follow-up (n ¼ 3). Therefore,
70 patients were included in the prospective study
analysis (Figure 1), 38 in the tofogliflozin group and 32
in the anagliptin group. Tables 1 and 2 list the pa-
tients’ baseline characteristics, medication therapy,
biochemistry findings, and echocardiographic find-
ings. Patients’ data at enrollment (n ¼ 80) are
described in Supplemental Tables 1-2 and 2-2. The
mean age of all patients was 70.3
8.2 years. Male
subjects comprised 69% of the study cohort. The
tofogliflozin group had elevated systolic and diastolic
BPs. There were no statistically significant differ-
ences in baseline characteristics without BP between
the 2 groups. Medication therapy, biochemistry, and
echocardiographic findings were well matched be-
tween the groups.
The use of AAD was permitted during the first
3 months after CA, and discouraged thereafter.
Overall, 25 (35.7%) of 70 patients were taking AAD
after CA (Vaughan Williams classification class III:
amiodarone [n ¼ 4], calcium-channel blocker bepridil
[n ¼ 16]; C Ib: aprindine [n ¼ 1]; class Ib: cibenzoline
[n ¼ 1] and bepridil þ aprindine [n ¼ 3]). The rate of
1398 Kishima et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022

Efficacy of SGLT2i on Atrial Fibrillation NOVEMBER 2022:1393–1404

F I G U R E 2 Kaplan-Meier Analyses of the Freedom from AF Recurrence After the CA

(A) Kaplan-Meier analysis of the freedom from AF recurrence after the CA (per-protocol analysis). During the 12-month follow-up period, AF
recurrence was detected in 24 patients (34.3%). The AF recurrence ratio was higher in the anagliptin group than in the tofogliflozin group
(log-rank test, P ¼ 0.0415). (B) Kaplan-Meier analysis of the freedom from AF recurrence after the CA (intention-to-treat analysis). During the
12-month follow-up period, AF recurrence was detected in 27 patients (33.8%). The AF recurrence ratio was higher in the anagliptin group than
in the tofogliflozin group (log-rank test, P ¼ 0.0377). Abbreviations as in Figure 1.

use of AAD at 3 months after CA differed between the
tofogliflozin group (11 patients [amiodarone: n ¼ 2;
bepridil: 9 patients], 29.0%) and the anagliptin group
(n ¼ 14 [amiodarone: n ¼ 2; bepridil: n ¼ 7; aprindine:
n ¼ 1; cibenzoline: n ¼ 1; bepridil þ aprindine: n ¼ 3],
43.8%; P ¼ 0.1979). Moreover, 13 (18.6%) of 70 pa-
tients were taking AAD at the discretion of the treat-
ing clinician at 12 months. The rate of use of AAD at
12 months after CA did not differ between the
tofogliflozin group (n ¼ 9 [bepridil:
amiodarone: n ¼ 1], 23.7%) and the anagliptin group
(n ¼ 4 [bepridil: n ¼ 3; bepridil þ aprindine: n ¼ 1],
12.5%; P ¼ 0.2306). No patients began to use AAD
during the 3- to 12-month period after CA.
CHANGES IN EACH MARKER AFTER EXPOSURE TO
TOFOGLIFLOZIN OR ANAGLIPTIN. Table 3 summa-
rizes the changes in each marker between the baseline
values and those obtained on the day of CA (2-6 weeks
n ¼ 8; after baseline) and at 12 months. Comparing values
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022
NOVEMBER 2022:1393–1404
obtained on the day of CA vs those at baseline, there
was a significantly greater decrease in values in the
tofogliflozin group compared with the anagliptin
group in terms of waist circumference, BMI, systolic
BP, urinary excretion of sodium, and left ventricular
ejection fraction; there was a significantly greater in-
crease in values in the tofogliflozin group compared
with the anagliptin group in terms of total serum ke-
tones, acetoacetic acid, and b-hydroxybutyrate acid.
Comparing values obtained at the 12-month follow-
up vs those at baseline, there was a significantly
greater decrease in values in the tofogliflozin group
compared with the anagliptin group in terms of waist
circumference, BMI, systolic BP, diastolic BP, urinary
microalbumin, urinary albumin-creatinine ratio, uri-
nary excretion of sodium, and urinary excretion of
potassium; there was also a significantly greater in-
crease in values in the tofogliflozin group compared
with the anagliptin group in terms of total serum ke-
tones and b -hydroxybutyrate acid (Table 3). A signif-
icant increase in total serum ketones between the day
of CA and the 12-month follow-up was observed in the
tofogliflozin group compared with the anagliptin
group. Heart rate, eGFR, serum electrolytes, HbA1c,
lipid levels, echocardiographic findings, and Atrial
Fibrillation Quality of Life Questionnaire findings in
the 2 groups were similar throughout the study.
EFFECT OF TOFOGLIFLOZIN ON OUTCOME OF CA
FOR AF. PVI was successful in all patients. Fifty-two
patients (74%) underwent RF-PVI and 18 patients
(26%) underwent Cryo-PVI. Additional CTI ablation
was performed in 50 patients (71%), and additional
superior vena cava isolation was performed in 12 pa-
tients (17%). All patients showed sinus rhythm at the
end of the procedures. There was no difference in CA
strategy (Cryo-PVI or RF-PVI, CTI ablation, superior
vena cava isolation) between the groups (Table 2).
The use of AAD was permitted during the first
3 months after CA, after which their use was
discouraged. Recurrent AF after the blanking period
was detected in 24 patients (34%) during the follow-
up period. The AF recurrence ratio was higher in the
anagliptin group than in the tofogliflozin group (15 of
32 patients [47%] vs 9 of 38 patients [24%];
P ¼ 0.0417). Moreover, the AF recurrence ratio was
higher in the anagliptin group than in the tofogliflozin
group if the 10 excluded patients were added into the
analysis (17 of 40 patients [43%] vs 10 of 40 patients
[25%]; P ¼ 0.0979). The Kaplan-Meier curve for
freedom from AF recurrence is shown in Figure 2A
(per-protocol analysis, P ¼ 0.0415, log-rank test) and
Figure 2B (intention-to-treat analysis, P ¼ 0.0377). No
Kishima et al 1399
Efficacy of SGLT2i on Atrial Fibrillation
thromboembolic events occurred in the validation
cohort during the follow-up period.
RISK FACTORS OF RECURRENCE OF AF AFTER
CA. We classified all patients into 1 of 2 groups ac-
cording to recurrence (recurrence group, n ¼ 24;
nonrecurrence group, n ¼ 46). Data from the 2 groups
were then subjected to univariate and multivariate
analyses. Univariate analysis revealed that compared
with the nonrecurrence group, the recurrence group
had a higher prevalence rate of nonparoxysmal AF
(non-PAF), elevated brain natriuretic peptide, higher
urinary albumin-creatinine ratio, higher rate of
SGLT2i use, larger LAD, elevated E-wave, lower left
ventricular ejection fraction, and a lower rate of Cryo-
PVI (Table 4). There was no difference between the
recurrence and nonrecurrence groups in terms of any
other CA strategy (CTI ablation, superior vena cava
isolation). Multivariate analysis was not performed
because the sample size was not of sufficient power to
identify all risk factors (Central Illustration).
DISCUSSION
To the best of our knowledge, this is the first pro-
spective, randomized controlled, open-label study to
evaluate the risk of recurrent AF after CA in patients
with type 2 DM who were treated with SGLT2i vs
DPP4i. Our results showed that tofogliflozin use was
associated with a significantly lower risk of recurrent
AF after CA compared with anagliptin in univariate
analysis. However, these results were observed in the
setting of patients who underwent CA for AF. There-
fore, whether SGLT2i suppress the incidence of AF in
patients in other settings remains unclear. In other
words, we consider that SGLT2i might serve as an
adjunct treatment option to CA for AF.
It has been established that DM is an important risk
factor for the development of AF, which leads to a
higher risk of heart failure or death. 15-17 There are
various mechanisms responsible for the association
between DM and AF. The predominant view is that
atrial electrical and structural remodeling due to DM
may lead to the development of AF. Kato et al18
studied the pathophysiological mechanisms of the
relationship between DM and the development of AF
in 40-week-old DM rats. They found that DM rats had
increased atrial arrhythmogenicity with intra-atrial
conduction disturbance and increased diffuse
fibrotic deposition compared with control rats. Other
mechanisms such as autonomic disorder, inflamma-
tion, and glycemic fluctuations have also been sug-
gested to explain the association between DM and
AF.19,20
1400 Kishima et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022

Efficacy of SGLT2i on Atrial Fibrillation NOVEMBER 2022:1393–1404

inflammation, oxidative stress, endothelial dysfunc-

T A B L E 4 Predictors of AF Recurrence After the CA
tion, and left ventricular dysfunction. Although still
Nonrecurrence Recurrence unproven, these effects are expected to indicate the
Group Group
(n ¼ 46) (n ¼ 24) P Value effectiveness of SGLT2i for arrhythmia. 21,22 Ling
Male 31 (67.0) 17 (71.0) 0.7684 et al23 evaluated the risk of new-onset AF using
Age, y 69.6
8.2 71.6
8.0 0.3289 medical data from a multicenter health care provider
Waist circumference, cm 93.6
10.4 92.5
12.3 0.6935 (SGLT2i group, n ¼ 16,606; DPP4i group, n ¼ 12,383)
Body mass index, kg/m2 25.7
4.5 24.8
4.5 0.4542 and reported a lower risk of new-onset AF in the
Nonparoxysmal AF 18 (39.0) 22 (92.0) <0.0001
SGLT2i group compared with the DPP4i group.
Hypertension 32 (70.0) 13 (54.0) 0.2019
Moreover, the advantage of SGLT2i over DPP4i for
Dyslipidemia 32 (70.0) 13 (54.0) 0.2019
Structural heart disease 11 (24.0) 8 (33.0) 0.4002
lowering the risk of AF persisted with different SGLT2i
Prior stroke/TIA 12 (26.0) 3 (13.0) 0.2327 and at both low and standard doses of SGLT2i. Zelniker
CHADS2 score 2.6
1.2 2.7
1.1 0.7869 et al8 recently studied the efficacy and safety of SGLT2i
HAS-BLED score 1.9
0.9 2.1
0.8 0.4307 vs placebo in 17,160 patients with type 2 DM in sub-
Hemoglobin, g/dL 14.4
1.6 14.0
1.6 0.3441 group analyses of data from the DECLARE-TIMI 58
C-reactive protein, mg/dL 0.12
0.15 0.46
0.12 0.0501
trial. They found that SGLT2i reduced the risk of a
Brain natriuretic peptide, pg/mL 144.2
125.6 304.9
302.4 0.0025
2
first atrial tachyarrhythmia event during follow-up by
eGFR, mL/min/1.73 m 76.3
24.6 67.0
14.6 0.0955
19% and the number of total atrial tachyarrhythmia
Sodium, mEq/L 140.7
2.1 141.4
2.1 0.2065
Potassium, mEq/L 3.8
0.4 3.9
0.5 0.4415 events by 23%. In addition, these reductions were
HbA1c, % 6.8
0.9 6.6
0.4 0.349 found to be consistent in patients with and without a
LDL-C, mg/dL 104.2
30.9 108.5
22.5 0.5562 history of atrial tachyarrhythmia.
HDL-C, mg/dL 53.0
13.4 54.5
13.1 0.6639 The results of our prospective study showed that
Triglycerides, mg/dL 150.5
52.6 128.1
68.3 0.1321 the use of SGLT2i was associated with a lower risk of
Total serum ketones, mmol/L 105.1
81.6 144.7
174.7 0.1992
recurrent AF after CA compared with DPP4i. The
Acetoacetic acid, mmol/L 34.0
23.8 46.0
46.4 0.1560
present findings are supported by those of recent re-
b-hydroxybutyrate acid, mmol/L 71.0
61.9 99.0
129.6 0.2241
Urinary microalbumin, mg/mL 50.8
104.2 182.6
317.8 0.0123
ports indicating that SGLT2i reduced the risk of atrial
Urinary albumin-creatinine ratio 73.7
189.8 195.9
295.8 0.0395 tachyarrhythmia in patients with type 2 DM.8,23
Urinary excretion of electrolytes Moreover, assessment of AF was not the primary
Sodium, mEq/L 109.3
47.0 103.8
50.0 0.6475 endpoint in these previous studies (which were
Potassium, mEq/L 39.8
19.8 44.0
19.8 0.3956 retrospective in design or subanalyses). In contrast,
Medication therapy
our study is the first prospective study to show the
Beta-blocker 23 (50.0) 13 (54.0) 0.7406
efficacy of SGLT2i on recurrence of AF after CA in
ACE inhibitor/ARB 25 (54.0) 13 (54.0) 0.9885
patients with type 2 DM.
Calcium-channel blocker 19 (41.0) 11 (46.0) 0.7163
Statin 23 (50.0) 11 (46.0) 0.7406
We found that SGLT2i suppressed AF. However,
Diuretics 8 (17.0) 5 (21.0) 0.7252 the exact mechanism by which SGLT2i reduce AF is
Antiplatelet 9 (20.0) 7 (29.0) 0.3638 not well understood. It is well known that DM exac-
Antiarrhythmic drug 6 (13.0) 4 (17.0) 0.7269 erbates the development of AF. In our study, there
Antidiabetic drug 14 (30.0) 8 (33.0) 0.8042 was no difference between the SGLT2i and DPP4i
SGLT2i 29 (63.0) 9 (37.0) 0.0417
groups in change in HbA 1c after treatment (Table 3).
DPP4i 17 (37.0) 15 (63.0) 0.0417
These results suggest that glucose-independent ef-
Sulfonylurea 8 (17.0) 1 (4.0) 0.1507
fects of SGLT2i suppressed recurrent AF after CA. As
Metformin 8 (17.0) 5 (21.0) 0.7252
Glinide 0 0 1.0000 such, we hypothesize the following mechanism. First,
Glitazone 0 0 1.0000 SGLT2i might reduce electrical and structural
Acarbose 1 (2.0) 3 (13.0) 0.1131 remodeling of the atrium. Watanabe et al 24 studied
Insulin 0 1 (4.0) 0.3429 atrial characteristics in rats with and without DM, and
Continued on the next page
found that diabetic rat atrium had greater interstitial
fibrosis, lower connexin 40 expression, and
SGLT2i have recently been a significant focus of decreased conduction velocity. Shao et al 22 recently
attention because of their various effects on the heart investigated the effect of SGLT2i on atrial remodeling
and kidney. The main effect of SGLT2i is sodium in- in 96 rats with type 2 DM, and reported that SGLT2i
hibition and glucose reabsorption in the proximal attenuated DM-induced atrial structural and elec-
tubules of the kidney, thereby lowering blood glucose trical remodeling and thus reduced the risk of AF.
levels. SGLT2i have also shown mitigation of SGLT2i have also been shown to have some BP-
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022 Kishima et al 1401
NOVEMBER 2022:1393–1404 Efficacy of SGLT2i on Atrial Fibrillation

lowering effect and to promote natriuretic and

T A B L E 4 Continued
diuretic effects, which could reduce LA pressure.
These effects might have a positive influence on atrial Nonrecurrence Recurrence
Group Group
remodeling. In the present study, there was no dif- (n ¼ 46) (n ¼ 24) P Value
ference in LAD change between the tofogliflozin and Echocardiographic findings
anagliptin groups at 3 and 12 months (Table 3). In the LAD, mm 43.6
6.1 48.4
6.1 0.0026
46 patients with no recurrence of AF, the degree of E wave, cm/s 74.5
18.0 87.4
20.7 0.0091
reduction in LA volume index from baseline to Deceleration time, ms 184.1
41.2 184.5
72.4 0.9758
LV diameter during end diastole, mm 49.6
5.0 51.3
6.4 0.2170
12 months was greater in the tofogliflozin group than
2 LV hypertrophy 4 (9.0) 4 (17.0) 0.3198
in the anagliptin group (8.6
2.0 mL/m vs 2.0

LV ejection fraction (%) 63.7
9.6 52.6
16.5 0.0007
2.6 mL/m 2; P ¼ 0.0471). These findings suggest that
E/e0 ratio 12.0
4.4 13.2
3.4 0.2457
SGLT2i have a favorable effect on atrial remodeling Procedural findings
compared with DPP4i. Cryoballoon PVI 16 (35.0) 2 (8.0) 0.0207
Second, SGLT2i might promote mitochondrial CTI ablation 30 (65.0) 20 (83.0) 0.1113
biogenesis. Mitochondrial dysfunction has been SVCI 6 (13.0) 6 (25.0) 0.2077

described in many organs in patients with type 2 DM.

Values are n (%) or mean
SD, unless otherwise indicated.
Anderson et al25 investigated the impact of DM on DPP4i ¼ dipeptidyl peptidase-4 inhibitors; SGLT2i ¼ sodium-glucose cotransporter 2 inhibitors; other abbre-
mitochondrial metabolism using myofibers prepared viations as given in Tables 1 to 3.

from samples of right atrial appendage obtained from

24 patients undergoing coronary artery bypass graft
surgery. They found that mitochondria in diabetic
human heart displayed reduced mitochondrial respi-
ration and increased oxidative stress. Another study
has suggested that dysfunctional mitochondria pro-
duce more reactive oxygen species, which could
contribute to atrial arrhythmogenicity.26 In a recent
study, Yurista et al27 showed that SGLT2i have the
capacity to promote mitochondrial function. Third,
SGLT2i might reduce epicardial fat. Epicardial fat
causes localized inflammation that leads to the
development of atrial arrhythmias. Several studies
have shown that SGLT2i reduced epicardial fat, and
this effect may suppress AF. 28,29 Additional effects of
SGLT2i, such as increased serum magnesium, reduced
uric acid, and weight loss, have been reported in
previous studies.30,31
In the present study, SGLT2i had a good impact on
obesity (waist circumference and BMI), BP, and uri-
nary microalbumin. Obesity and hypertension are
well-known risk factors for AF. The existence of AF
also increases the risk of developing chronic kidney
disease; conversely, kidney disease increases the risk
of AF. 32,33 Microalbuminuria is defined as a persistent
elevation of albumin in a spot urine samples. Micro-
albumin is an established marker for the presence of
cardiovascular disease and also predicts the progres-
sion of chronic kidney disease. 34 Several studies have
reported an association between proteinuria/albu-
minuria and incident AF. Kim et al 35 studied the as-
sociation between the incidence of AF
proteinuria in a DM population and showed that
proteinuria was associated with an increased risk of
incident AF. In another study, Bansal et al36
examined the association between albuminuria and
incident AF in a meta-analysis of 3 prospective co-
horts, and they found that an elevated urine albumin-
to-creatinine ratio was significantly associated with
greater risk of incident AF. Interestingly, these 2
studies showed that the degree of proteinuria/albu-
minuria was associated with a higher rate of incident
AF in a dose-dependent manner.
In recent clinical trials, SGLT2i were shown to
suppress the progression of albuminuria and reduced
composite renal outcome in patients with type 2
DM.5,37 The present results might be explained by the
mechanism of correction of urinary microalbumin.
However, it remains unknown whether interventions
to reduce proteinuria/albuminuria suppress the inci-
dence of AF. In addition, the present study found a
greater elevation of serum ketones in the SGLT2i
group than in the DPP4i group. There has been
increasing awareness of the association between ke-
tones and the heart following a recent report on the
cardioprotective effects of ketones. 38 Elevated serum
ketones might have a good impact on outcomes after
CA. However, the association between serum ketones
and AF is unknown. Further prospective investiga-
tion will be necessary to determine whether in-
terventions to help resolve these factors have an
impact on AF.
STUDY LIMITATIONS. First, this prospective study
and included a small number of patients at a single center.
In addition, we could not perform multivariate anal-
ysis because the sample size was not of sufficient po-
wer to identify all risk factors. Second, recurrence of
1402 Kishima et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022

Efficacy of SGLT2i on Atrial Fibrillation NOVEMBER 2022:1393–1404

C E N T R A L IL L U ST R A T I O N Study Design and Kaplan-Meier Analyses of the Freedom From AF

Recurrence After the CA

Study Design: SGLT2i vs. DPP4i

SGLT2i group
(Tofogliflozin)
End-of-study
Screening Catheter
examination
ablation
(12-month)
DPP4i group
(Anagliptin)

Randomization was conducted using computer-generated random sequencing,

stratified by left atrial diameter and type of AF at screening

Kaplan-Meier Analysis of the Freedom From AF Recurrence After the CA

100
AF-Free Survival (%)

80

60

40

Per-protocol analysis
20
log-rank P = 0.0415

0
0 3 6 9 12
Months
No. at risk
Tofogliflozin Group 38 32 31 31 29
Anagliptin Group 32 24 20 19 17

100
AF-Free Survival (%)

80

60

40

Intention to treat analysis

20
log-rank P = 0.0377

0
0 3 6 9 12
Months
No. at risk
Tofogliflozin Group 40 33 32 31 29
Anagliptin Group 40 22 21 20 18
Kishima H, et al. J Am Coll Cardiol EP. 2022;8(11):1393–1404.

During the 12-month follow-up period, the AF recurrence ratio was higher in the anagliptin group than in the tofogliflozin group in per-
protocol analysis and intention-to-treat analysis. AF ¼ atrial fibrillation; CA ¼ catheter ablation.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 11, 2022 Kishima et al 1403
NOVEMBER 2022:1393–1404 Efficacy of SGLT2i on Atrial Fibrillation

asymptomatic AF could have been overlooked because FUNDING SUPPORT AND AUTHOR DISCLOSURES
assessment of AF was based on intermittent Holter
electrocardiogram monitoring and clinical symptoms. The authors have reported that they have no relationships relevant to
the contents of this paper to disclose.
Third, 31% patients had taken antidiabetic drugs
without SGLT2i/DPP4i prior to study entry. Fourth, we
ADDRESS FOR CORRESPONDENCE: Dr Hideyuki
assessed albumin levels in spot urine samples, which
Kishima, Department of Cardiovascular and Renal Medi-
are not a fully reliable measure for assessing renal
cine, Hyogo College of Medicine, 1-1 Mukogawa-cho,
impairment because the results can be influenced by
Nishinomiya 663-8501, Japan. E-mail: hideyukikishima@
factors, including circadian rhythm, hydration status,
gmail.com. Twitter: @HideyukiKishima.
and physical activity.39 Fifth, the use of AAD might
have had an impact on outcomes after CA for AF.
PERSPECTIVES
Although not significant, the rate of use of AAD was
higher in the tofogliflozin group than in the anagliptin
group (n ¼ 9 [23.7%] vs n ¼ 4 [12.5%]; P ¼ 0.2306). Sixth, COMPETENCY IN MEDICAL KNOWLEDGE: The results from
our data did not include lifestyle considerations such this analysis identified opportunities to modify medication ther-
as exercise, diet, smoking, or alcohol intake. Lastly, apy before/after CA for AF to further decrease the risk of AF
very few studies have focused on the association be- recurrence after CA.
tween tofogliflozin/anagliptin and AF.
TRANSLATIONAL OUTLOOK: Treatment of the risk factors of
AF, such as DM, obesity, and hypertension, is important from the
CONCLUSIONS
perspective of managing AF recurrence after CA. This analysis
identified the efficacy of SGLT2i on AF in patients with DM, and
A comparison of the effects of tofogliflozin and ana-
SGLT2i might be an adjunct treatment option to CA for AF.
gliptin on the suppression of recurrence of AF after
Further randomized trials are needed to evaluate the role of
CA in patients with type 2 DM revealed that tofogli-
SGLT2i on AF in patients other than in this setting.
flozin, and SGLT2i, was associated with a significantly
lower risk of recurrent AF.

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KEY WORDS atrial fibrillation, catheter
ablation, diabetes mellitus, sodium-glucose
cotransporter 2 inhibitors
A PPE NDI X For supplemental tables, please
see the online version of this paper.