Association of SGLT2 inhibitors with arrhythmias and
sudden cardiac death in patients with type 2 diabetes
or heart failure: A meta-analysis of 34 randomized
controlled trials
Gilson C. Fernandes, MD,* Amanda Fernandes, MD,† Rhanderson Cardoso, MD,‡
Jorge Penalver, MD,* Leonardo Knijnik, MD,† Raul D. Mitrani, MD, FHRS,*
Robert J. Myerburg, MD,* Jeffrey J. Goldberger, MD, MBA, FHRS*
From the *Division of Cardiology, University of Miami Miller School of Medicine, Miami, Florida,
†
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, and
‡
Division of Cardiology, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts.
BACKGROUND Sodium-glucose cotransporter 2 inhibitors
(SGLT2is) reduce hospitalizations and death from heart failure
(HF), but their effect on arrhythmia expression has been poorly
investigated.
OBJECTIVE The purpose of this study was to evaluate the associa-
tion of SGLT2is with arrhythmias in patients with type 2 diabetes
mellitus (T2DM) or HF.
METHODS We searched PubMed and ClinicalTrials.gov. Two inde-
pendent investigators identified randomized double-blind trials
that compared SGLT2is with placebo or active control for adults
with T2DM or HF. Primary outcomes were incident atrial arrhythmias,
ventricular arrhythmias (VAs), and sudden cardiac death (SCD).
RESULTS We included 34 randomized (25 placebo-controlled and 9
active-controlled) trials with 63,166 patients (35,883 SGLT2is vs
27,273 control: mean age 53–67 years; 63% male). Medications
included canagliflozin, dapagliflozin, empagliflozin, or ertugliflo-
zin. Except for 1 study of HF, all patients had T2DM. Follow-up
Introduction
Patients with type 2 diabetes mellitus (T2DM) are at increased
risk of cardiovascular events, including atrial and ventricular
arrhythmias and sudden cardiac death (SCD).1,2 Large-scale
randomized studies of sodium-glucose cotransporter 2 inhibi-
tors (SGLT2is) in patients with T2DM have consistently
demonstrated a significant reduction in hospitalizations for
incident heart failure (HF).3–7 Recently, Dapagliflozin
and Prevention of Adverse Outcomes in Heart Failure
Funding sources: The authors have no funding sources to disclose. Dis-
closures: The authors have no conflicts of interest to disclose. Address
reprint requests and correspondence: Dr Jeffrey J. Goldberger, Division
of Cardiology, University of Miami Miller School of Medicine, 1120 NW
14th St, Miami, FL 33136. E-mail address: j-goldberger@miami.edu.
1547-5271/$-see front matter © 2021 Heart Rhythm Society. All rights reserved.
ranged from 24 weeks to 5.7 years. The cumulative incidence of
events was low: 3.6, 1.4, and 2.5 per 1000 patient-years for atrial
arrhythmias, VAs and SCD, respectively. SGLT2i therapy was associ-
ated with a significant reduction in the risk of incident atrial ar-
rhythmias (odds ratio 0.81; 95% confidence interval 0.69–0.95; P
5 .008) and the “SCD” component of the SCD outcome (odds ratio
0.72; 95% confidence interval 0.54–0.97; P 5 .03) compared with
control. There was no significant difference in incident VA or the
“cardiac arrest” SCD component between groups.
CONCLUSION SGLT2is are associated with significantly reduced
risks of incident atrial arrhythmias and SCD in patients with T2DM.
Prospective trials are warranted to confirm the antiarrhythmic effect
of SGLT2is and whether this is a class or drug-specific effect.
KEYWORDS Sodium-glucose cotransporter 2 inhibitors; Atrial fibril-
lation; Ventricular arrhythmia; Sudden cardiac death; Meta-analysis
(Heart Rhythm 2021;18:1098–1105) © 2021 Heart Rhythm Society.
All rights reserved.
(DAPA-HF),3 a randomized trial of dapagliflozin in patients
with symptomatic HF with reduced ejection fraction of
,40%, demonstrated a significant reduction in HF hospitaliza-
tions, cardiovascular death, and all-cause death, regardless of
the presence or absence of diabetes mellitus. Three large ran-
domized trials4,6,7 demonstrated a significantly reduced risk
of all-cause or cardiovascular mortality with SGLT2is, but it
has not been determined whether this is driven by the preven-
tion of SCD. The precise mechanisms for the cardiovascular
benefits of SGLT2is remain unknown, and postulated explana-
tions include its diuretic effect, blood pressure lowering,
weight reduction, attenuation of myocardial hypertrophy,
fibrosis, remodeling, systolic dysfunction, and HF.8–10
Despite compelling data suggesting improved cardiovas-
cular outcomes, the effect of SGLT2is on cardiac arrhythmias
https://doi.org/10.1016/j.hrthm.2021.03.028
Fernandes et al SGLT2i and Arrhythmias in Diabetes or Heart Failure
has been poorly investigated. We aimed to perform a system-
atic review of the literature and meta-analysis of arrhythmia
endpoints in randomized controlled trials of SGLT2is use
for T2DM or HF.
Methods
Search strategy
This study was designed in accordance with the Preferred Re-
porting Items for Systematic Reviews and Meta-Analysis
protocol. MEDLINE (via PubMed) and ClinicalTrials.gov
were systematically searched. References of eligible papers
and systematic reviews were also searched for additional
studies of interest. We adopted a broad search strategy to
maximize the identification of all trials that involved
SGLT2is use, even if arrhythmia endpoints were not reported
in the manuscript text. The search strategy (title and abstract)
was as follows: (“sodium-glucose cotransporter” OR SGLT2
OR canagliflozin OR dapagliflozin OR empagliflozin OR er-
tugliflozin OR ipragliflozin OR luseogliflozin OR tofogliflo-
zin) AND (randomized OR randomised OR randomly). The
database search was performed on December 31, 2020.
Eligibility criteria and data extraction
There was no restriction with respect to the date of publica-
tion, publication status, or language. Studies with the
following characteristics were included: (1) randomized
and double-blind design; (2) at least 1 arm with the use of
an SGLT2i; (3) presence of a control group (either placebo-
controlled or active-controlled); (4) adult patients older
than 18 years with diagnosed type 2 diabetes, HF, or both;
and (5) at least 24 weeks of follow-up.
We excluded studies without arrhythmia endpoints and
those with duplicate data, identified as studies published by
the same authors or same institution in an overlapping period.
In cases of duplicate data, only the study with the larger num-
ber of patients that contained the variables of interest was
selected.
Initially, studies of interest were selected for full manu-
script review. If no variables of interest (arrhythmia
endpoints) were reported in the manuscript, we searched
the supplementary material and the results (adverse event)
section of the study page on ClinicalTrials.gov.
Two investigators (G.C.F. and A.F.) independently per-
formed the data search and study selection. Disagreements
were resolved by author consensus after reviewing the full
article and the eligibility criteria with the senior author
(J.J.G.).
Variables of interest and outcomes
Controlled studies commonly report serious adverse events
according to the Medical Dictionary for Regulatory Activities
(medDRA) terminology, and its list of diagnoses was re-
viewed to determine the prespecified outcomes of interest
to be collected from the studies included. Two investigators
(G.C.F. and J.P.) independently extracted the data of interest
1099
from the studies, and all data points were confirmed by the
senior author (J.J.G.).
We extracted the following data from individual studies:
(1) study characteristics: study site and period, study design,
sample size per group, study population, length of follow-up,
SGLT2i type, and dose; (2) patient characteristics: age, sex,
race, time since diagnosis of diabetes, and mean glycosylated
hemoglobin; and (3) outcomes: incident atrial arrhythmias
(atrial fibrillation and atrial flutter), incident ventricular ar-
rhythmias (ventricular tachycardia, ventricular fibrillation,
ventricular flutter, ventricular arrhythmia, and torsades de
pointes), SCD (sudden cardiac death, sudden death, and car-
diac arrest; as these diagnoses may represent different mech-
anisms and were not adjudicated, data for this outcome are
presented individually for each component and cumula-
tively), and cumulative incidence of events.
Assessment of the risk of bias
Risk of bias was assessed through the Cochrane tool for as-
sessing risk of bias, according to the recommendations
from the Cochrane Handbook for Systematic Reviews of In-
terventions,11 and was documented by 2 independent inves-
tigators (G.C.F. and L.K.) on a risk of bias table for every
study included. Disagreements were resolved with the senior
author (J.J.G.). The information was presented as a risk of
bias graph and a risk of bias summary figure (Online
Supplemental Figures 1 and 2). Publication bias was assessed
with funnel plots for each outcome (Online Supplemental
Figure 3).
Data analysis
Binary endpoints were summarized using the Mantel-
Haenszel test with a fixed effects model, predicting a low het-
erogeneity for the outcomes measured, with odds ratio (OR)
and 95% confidence interval (CI) as a measure of effect size.
We assessed for heterogeneity using Cochrane’s Q statistic
and Higgins and Thompsons’ I2 statistic. Heterogeneity
was considered moderate to high if I2 . 25%. When signif-
icant heterogeneity was identified, a random effects model
was used. We assessed for publication bias using funnel
plot analysis. Review Manager 5.3 was used for statistical
analysis (The Nordic Cochrane Centre, The Cochrane
Collaboration, Denmark).
Subgroup analyses were prespecified as follows: (1) by
type of SGLT2i used, (2) placebo-controlled vs active-
controlled, (3) length of follow-up 1 year vs .1 year,
and (4) diabetes trials only. We also performed sensitivity an-
alyses with (1) restriction to studies with a low risk of bias
and (2) use of random and fixed effects models in all analyses
to search for a small study effect.
The cumulative incidence of events was estimated by
dividing the total number of events for each variable by the
number of patient-years included in the analysis and was pre-
sented as events per 1000 patient-years.
1100
Results
3–7,12–38
We included 34 randomized trials, 25 placebo-
controlled and 9 active-controlled, totaling 63,166 patients:
35,883 (56.8%) in the SGLT2i group and 27,273 (43.2%)
in the control group. The search strategy is summarized in
Figure 1. Follow-up ranged from 24 weeks to 5.7 years,
providing 177,087 patient-years. The mean age ranged
from 53 to 67 years; 63% were male and 75% white. Online
Supplemental Table 1 summarizes the baseline characteris-
tics of the studies included. All studies were multicenter, ran-
domized, and double-blind. SGLT2is used were
dapagliflozin (11 studies, 25,210 patients), canagliflozin
(10 studies, 19,732 patients), empagliflozin (9 studies,
12,066 patients) and ertugliflozin (4 studies, 3158 patients).
The study population had T2DM for all studies except for
1, DAPA-HF,3 which included patients with symptomatic
HF and ejection fraction  40% and had 42% of patients
Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analysis flowchart for search strategy and study selection.
Heart Rhythm, Vol 18, No 7, July 2021
with T2DM. Nine studies reported the percentage of patients
with HF at baseline (9555 patients with HF) and other 3
studies reported the percentage of patients with HF or cardio-
vascular disease at baseline (680 patients with HF or cardio-
vascular disease). The time from the diagnosis of T2DM
ranged from 5.5 to 15.8 years at the time of enrollment.
There was no study with a high risk of bias (Online
Supplemental Figures 1 and 2). There was no difference in
the results from random and fixed effects analyses in all com-
parisons, and fixed effects were used for all statistics because
of low heterogeneity.
Atrial arrhythmias
Atrial arrhythmias, defined as atrial fibrillation or flutter,
were reported in 32 trials. SGLT2i therapy was associated
with a significant 19% reduction in the odds of incident atrial
arrhythmias compared with control (OR 0.81; 95% CI
Fernandes et al SGLT2i and Arrhythmias in Diabetes or Heart Failure
0.69–0.95; P 5 .008) (Figure 2). The cumulative incidence of
atrial arrhythmias was low, averaged at 3.6 per 1000 patient-
years.
Subgroup analyses, including only studies of diabetes and
only placebo-controlled trials, yielded results similar to over-
all analysis (OR 0.81; 95% CI 0.68–0.96; P 5 .01 and OR
0.82; 95% CI 0.69–0.96; P 5 .01, respectively). For the 9
active-controlled trials, there were only 7 atrial arrhythmia
events in the SGLT2i group and 7 in the control group.
Because of the low number of events, meta-analysis of these
data was deemed not appropriate.
In subgroup analysis based on SGLT2i used (Online
Supplemental Figure 4), only dapagliflozin was associated
with a significantly reduced risk of atrial arrhythmias (OR
0.74; 95% CI 0.60–0.91; P 5 .005). Canagliflozin led to a
numerically lower but not statistically significant rate of atrial
arrhythmias (OR 0.81; 95% CI 0.60–1.08; P 5 .15). Empa-
gliflozin was associated with no difference in the event rate
(OR 1.17; 95% CI 0.75–1.82; P 5 .49), and ertugliflozin
had a low number of reported events (4 events vs 1 event,
respectively), unsuitable for subgroup analysis. It should be
Figure 2 Incident atrial arrhythmias with sodium-glucose cotransporter 2 inhibitors (SGLT2is) vs control in patients with diabetes or heart failure. Summary
statistic favors SGLT2is (odds ratio 0.81; 95% confidence interval [CI] 0.69–0.95; P 5 .008) with a significant reduction in incident atrial fibrillation or flutter
compared with placebo or active control. M-H 5 Mantel-Haenszel.
1101
noted that subgroup analyses are more susceptible to type
II errors because of considerably less power than the pooled
analysis that includes all SGLT2is.
In the analysis based on the length of follow-up (Online
Supplemental Figure 5), SGLT2is were associated with a
significantly lower risk of events in studies with .1 year of
follow-up (OR 0.83; 95% CI 0.70–0.97; P 5 .02). In studies
with ,1 year of follow-up, there was a trend for a lower inci-
dence of atrial arrhythmias in the SGLT2i group as compared
with the control group (OR 0.60; 95% CI 0.33–1.07; P 5 .09).
Ventricular arrhythmias and SCD
Only 14 of the 34 trials reported incident ventricular arrhyth-
mias (49,963 patients and 161,737 patient-years), defined as
ventricular tachycardia, ventricular fibrillation, ventricular
flutter, ventricular arrhythmia, and torsades de pointes. The
risk of incident ventricular arrhythmias was not significantly
different between SGLT2is and control (OR 0.85; 95% CI
0.66–1.11; P 5 .23) (Figure 3). The overall cumulative inci-
dence of ventricular arrhythmias was low, averaged at 1.4 per
1000 patient-years, and only 0.6 per 1000 patient-years in
1102
Figure 3 Incident ventricular arrhythmias with sodium-glucose cotransporter 2 inhibitors (SGLT2is) vs control in patients with diabetes or heart failure. Sum-
mary statistic demonstrates no difference between groups in the incidence of ventricular arrhythmias (odds ratio 0.85; 95% confidence interval [CI] 0.66–1.11;
P 5 .23). M-H 5 Mantel-Haenszel.
studies of diabetes, which significantly reduces the power of
this analysis despite the large sample size. Furthermore, most
(55%) of the ventricular arrhythmias observed were reported
in the DAPA-HF study in patients with HF and reduced ejec-
tion fraction. In subgroup analysis, there were 4 trials in the
canagliflozin group and 5 trials in each dapagliflozin and em-
pagliflozin groups, and all showed no significant differences
between treatment and control groups (Online Supplemental
Figure 6).
SCD was reported in 19 of the 34 trials (54,929 patients
and 168,871 patient-years). The 3 prespecified components
of the SCD variable (SCD, sudden death, and cardiac arrest)
were individually plotted and presented in Figure 4. SGLT2i
treatment was associated with a significant 28% relative
reduction in the odds of the SCD component of this variable
when compared with placebo (OR 0.72; 95% CI 0.54–0.97; P
5 .03). The overall analysis of the composite SCD outcome
demonstrated no significant difference (OR 0.87; 95% CI
0.72–1.05; P 5 .14). The cumulative incidence of SCD
was 2.5 per 1000 patient-years.
Discussion
In this large meta-analysis involving 63,166 patients
(177,087 patient-years) and 34 randomized controlled trials
of SGLT2is for T2DM or HF, SGLT2is significantly lowered
the risk of incident atrial fibrillation or atrial flutter and of one
of the components of the SCD outcome. Thus, SGLT2is may
have clinically important antiarrhythmic effects that require
further evaluation both for T2DM and, in particular, for
HF, as only 1 dedicated study of patients with HF (both
with and without diabetes) was included.
There has been only 1 previously reported meta-analysis,
published in 2017, providing atrial fibrillation outcomes in
studies using SGLT2is for diabetes.39 That meta-analysis
was before most of the large SGLT2i trials, reporting only
Heart Rhythm, Vol 18, No 7, July 2021
17 events in 7191 patients in the SGLT2i group and 13 events
in 3321 patients in the placebo group. The authors found no
difference in rates of atrial fibrillation between groups. Our
study reported 624 atrial arrhythmia events, compared with
only 30 in the previous meta-analysis, overcoming the low
power limitation of the previous study. In contrast, this is
the first meta-analysis reporting outcomes for ventricular ar-
rhythmias or SCD in SGLT2i studies.
This study provides high quality evidence to support
the cardiovascular benefits of SGLT2is in patients with
T2DM. In addition to its well-documented effect on HF
hospitalizations, SGLT2is appear to reduce incident atrial
fibrillation and SCD. The DAPA-HF3 results are
intriguing and suggest that there may be cardiovascular
benefits with SGLT2is independent of diabetes, and it re-
mains unknown whether the observed decrease in atrial
fibrillation incidence in that study represents a primary ef-
fect of SGLT2is or secondary to the improvement in HF.
Given the known association between HF and atrial fibril-
lation, future studies should focus on testing the cardio-
vascular and antiarrhythmic benefits of SGLT2is in
other patient populations, such as patients with HF and
preserved ejection fraction. Whereas SGLT2is were found
to prevent incident atrial arrhythmias and sudden death, it
has not been determined whether they can also be effec-
tive as adjunctive therapy for the management of selected
patients with atrial and ventricular arrhythmias or for the
prevention of recurrences. A study of SGLT2is in HF
with preserved ejection fraction is currently underway
(Dapagliflozin in PRESERVED ejection fraction Heart
Failure [PRESERVED-HF], ClinicalTrials.gov identifier:
NCT03030235), but arrhythmia endpoints are not part
of their outcome measures. On the basis of our findings,
we suggest that future SGLT2i trials systematically eval-
uate for arrhythmias with routine cardiac monitoring and
report them as efficacy outcomes.
Fernandes et al SGLT2i and Arrhythmias in Diabetes or Heart Failure 1103

Figure 4 Sudden cardiac death events with sodium-glucose cotransporter 2 inhibitors (SGLT2is) vs control in patients with diabetes or heart failure. Analysis
stratified by prespecified groups of Medical Dictionary for Regulatory Activities (MedDRA) terms. Summary statistic favors SGLT2is (odds ratio 0.72; 95%
confidence interval [CI] 0.54–0.97; P 5 .03) only for the MedDRA term “sudden cardiac death,” with no difference for the summary statistic. M-H 5
Mantel-Haenszel.

Clinical and preclinical data provide significant evidence in arrhythmia risk. These include (1) hemodynamic effects,
to support that our results are clinically meaningful and not causing contraction of plasma volume and blood pressure
due to chance. SGLT2is are thought to be cardioprotective reduction, thereby reducing preload and afterload8–10; (2)
by several mechanisms that might contribute to a decrease inhibition of sodium-hydrogen exchange in myocardial cells,
1104
which has been linked to attenuation of myocardial hypertro-
phy, fibrosis, adverse remodeling, systolic dysfunction, and
HF8–10; and (3) possible suppression of the sympathetic
nervous system.10,40 A recently published population-based
propensity score–matched cohort study from Taiwan,41
including 79,150 diabetic patients treated with SGLT2is
compared with 79,150 matched diabetic patients not taking
SGLT2is, those receiving SGLT2is had a 45% reduction in
the adjusted risk of all-cause death and a 17% reduction in
new-onset arrhythmias, including atrial fibrillation, supra-
ventricular arrhythmias, and ventricular arrhythmias. These
were the first real-world data to describe the risk of arrhyth-
mias in diabetic patients taking SGLT2is. Further under-
standing of the primary and secondary cardiovascular
effects of SGLT2is in patients with diabetes and HF will
enhance its incorporation in the cardiovascular therapeutic
armamentarium.
It is well known that diabetes mellitus is associated with
increased risk of cardiovascular events, cardiovascular mor-
tality, atrial arrhythmias, and ventricular arrhythmias, which
is related to multiple potential mechanisms including inflam-
mation, endothelial dysfunction, myocardial steatosis, and
fluctuations in glucose levels, leading to myocardial fibrosis
and structural remodeling.1,10 The incidence of SCD in
young diabetic patients (age, 35–50 years) has been reported
as 1.2 per 1000 patient-years, 6 times higher than in nondia-
betic patients in the same age group.2 This is the first meta-
analysis to summarize SCD events in SGLT2i trials and the
potential benefit of this therapy. Of note, the lower incidence
of the component SCD in the SGLT2i group was mostly
driven by Empagliflozin Cardiovascular Outcomes Event
Trial in Type 2 Diabetes Mellitus Patient-Removing Excess
Glucose (EMPA-REG OUTCOME)7 and DAPA-HF,3 which
are the studies with patients with the highest cardiovascular
risk. In DAPA-HF, all patients had HF with reduced EF,
and .55% had ischemic cardiomyopathy. In EMPA-REG
OUTCOME, all patients had established cardiovascular
risk factors, including 75% with coronary artery disease. It
is therefore possible that the effect of SGLT2is on reducing
the risk of SCD is higher in patients with high cardiovascular
risk, including those with structural heart disease and coro-
nary artery disease.
In population studies, the cumulative incidence of atrial
fibrillation in patients with diabetes mellitus ranged from
0.8% to 1.3% per year,1 3 times higher than the incidence
of atrial arrhythmias in our study, which suggests underre-
porting or underdiagnosis of events. In a recently published
post hoc analysis of the Dapagliflozin Effect on Cardiovascu-
lar Events-Thrombolysis in Myocardial Infarction 58
(DECLARE TIMI-58) trial42 that evaluates the effect of da-
pagliflozin on atrial fibrillation and flutter in patients with
diabetes, the authors reported an overall cumulative inci-
dence of atrial arrhythmias (0.82% per year), which was 2
times higher than the incidence of atrial arrhythmias that
met criteria for serious adverse events (0.41% per year) re-
ported in the original study. These findings suggest that the
true cumulative incidence of atrial arrhythmias may be
Heart Rhythm, Vol 18, No 7, July 2021
approximately twice of that reported as serious adverse
events in the studies included in our analysis.
Multiple studies have compared the risk of atrial fibrilla-
tion with different classes of diabetes medications. Metfor-
min, Dipeptidyl peptidase-4 (DPP-4) inhibitors, and
pioglitazone (but not rosiglitazone) have been associated
with a lower risk of atrial fibrillation, whereas insulin and sul-
fonylureas have been associated with increased risk of atrial
fibrillation.1 The case of pioglitazone raises the hypothesis
that its antiarrhythmic properties might be drug specific,
and not class related. Whether SGLT2is may also have a
drug-specific effect on arrhythmias versus a class effect is un-
known. In our analysis, dapagliflozin was the only SGLT2i to
significantly reduce event risk while canagliflozin had a
nonsignificant numerical reduction in events and empagliflo-
zin showed no difference in arrhythmia risk.
There are limitations to our meta-analysis. First,
arrhythmia events in all studies were reported as serious
adverse events, and not as an outcome; therefore, no system-
atic method to evaluate for arrhythmias was described for any
of the studies. Although serious adverse events were coded
according to the medDRA, there was likely underreporting
of arrhythmia events, such as those not considered as serious
adverse events, but there is no reason to suspect differential
reporting between groups, thus biasing results toward the
null. Also, there were no standardized definitions for the
arrhythmia endpoints in the individual studies, which may
lead to reporting bias. It is not known whether the variables
sudden death and cardiac arrest represented death from an
arrhythmia or from another mechanism. Finally, ventricular
arrhythmias were not described as sustained or nonsustained.
Conclusion
SGLT2is are associated with a significantly reduced risk of
incident atrial arrhythmias and may be associated with a
reduced risk of SCD in patients with type 2 diabetes. More
specifically designed studies are needed to confirm these ben-
efits in patients with type 2 diabetes and, in particular, HF.
Prospective trials are warranted to confirm the antiarrhythmic
effect of SGLT2is and to investigate whether this is related to
improvement in HF and a class or drug-specific effect.
Appendix
Supplementary data
Supplementary data associated with this article can be found
in the online version at https://doi.org/10.1016/j.hrthm.2021.
03.028.
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