Abstract
Background
The association between sodium‐glucose cotransporter 2 inhibitors (SGLT2i) and atrial fibrillation (AF) recurrence after catheter ablation among patients with diabetes and AF remains unclear.
Methods and Results
Patients with AF undergoing initial catheter ablation with a history of diabetes from the China AF registry were included. Patients using SGLT2i were identified and matched by propensity score with non‐SGLT2i patients in a 1:3 ratio. The main outcome was AF recurrence during the 18‐month follow‐up. A total of 138 patients with diabetes with SGLT2i therapy and 387 without SGLT2i were analyzed. AF recurrence occurred in 37 patients (26.8%) in the SGLT2i group and 152 patients (39.3%) in the non‐SGLT2i group during a total of 593.3 person‐years follow‐up. The SGLT2i group was associated with lower AF recurrence compared with the non‐SGLT2i group (hazard ratio, 0.63 [95% CI, 0.44–0.90], P=0.007). A total of 4 studies were analyzed in our meta‐analysis demonstrating that SGLT2i was associated with lower AF recurrence after catheter ablation (odds ratio, 0.61 [95% CI, 0.54–0.69]; P<0.001, I 2=0.0%).
Conclusions
Our prospective study coupled with a meta‐analysis demonstrated a lower risk of AF recurrence with the use of SGLT2i among patients with diabetes after AF ablation.
Keywords: atrial fibrillation, catheter ablation, diabetes, recurrence, SGLT2 inhibitor
Subject Categories: Arrhythmias, Catheter Ablation and Implantable Cardioverter-Defibrillator, Electrophysiology, Sudden Cardiac Death, Ventricular Fibrillation
Nonstandard Abbreviations and Acronyms
- CA
catheter ablation
- PSM
propensity score matching
- SGLT2i
sodium‐glucose cotransporter 2 inhibitors
Clinical Perspective.
What Is New?
This study was the first cohort coupled with meta‐analysis to evaluate the impact of sodium‐glucose cotransporter 2 inhibitor on atrial fibrillation (AF) recurrence in patients with diabetes after AF ablation.
What Are the Clinical Implications?
The results of our study indicated that the use of sodium‐glucose cotransporter 2 inhibitor is associated with a lower risk of AF recurrence among patients with diabetes after AF ablation.
Patients with diabetes and larger body mass index (≥24 kg/m2), persistent AF, and longer AF duration (>1 year) seem to benefit more with sodium‐glucose cotransporter 2 inhibitor therapy after AF ablation.
Atrial fibrillation (AF) is the most prevalent arrhythmia, influencing nearly 33.5 million people in the world, and is often seen in association with diabetes or other comorbidities. 1 Recommended by the latest international guidelines and clinical trials, 2 , 3 , 4 catheter ablation (CA) is an established method for maintaining sinus rhythm and improving the quality of life and long‐term prognosis among patients with AF but who remain at high risk for tachycardia recurrence. 5 Sodium‐glucose cotransporter 2 inhibitors (SGLT2i)such as dapagliflozin are a new type of oral antidiabetic agents that significantly reduce the risk of heart failure events and cardiovascular mortality, largely driven by heart failure hospitalization in patients with diabetes or heart failure. 6 Recent publications showed that SGLT2i reduce the risk of AF or atrial flutter in patients with diabetes by 20%. 7 Several studies demonstrated that SGLT2i might reduce AF/atrial flutter events as well as stroke risks among patients with diabetes. 8 , 9 However, the effect of SGLT2i on the reduction of AF recurrence rate after CA is still unclear. This study aims to explore the effect of SGLT2i on the recurrence of AF among patients with diabetes after initial CA and provide evidence for improving the success rate of CA in this population.
Methods
The authors declare that all supporting data are available within the article (and its online supplementary files).
Study Population
Data were collected in the China‐AF Registry, a prospective, multicenter, and ongoing study of patients with AF in Beijing, China, and were analyzed retrospectively. This study was conducted according to the Declaration of Helsinki and was approved by the ethics committee of Beijing Anzhen Hospital (No. D11110700300000). The rationale and design of the registry study were published previously. 10 Informed consent was collected from all study participants.
Patients meeting the following criteria were included in the study: (1) patients with AF aged ≥18 years undergoing initial CA and (2) patients with a history of diabetes. We excluded patients with the following conditions from the analysis: (1) patients who did not complete the 18‐month follow‐up and (2) patients with rheumatic heart disease or valvular surgery history. Patients were further identified and divided into 2 groups based on the use of SGLT2i at baseline.
Catheter Ablation
All ablation procedures were performed with radiofrequency ablation and guided by a 3‐dimensional electroanatomic mapping system (CARTO3; Biosense‐Webster, Inc., Diamond Bar, CA). For patients undergoing CA in the registry, the ablation strategy in the participating centers was described previously, as circumferential pulmonary vein isolation was routinely performed for patients with paroxysmal AF, and 3 additional linear ablations at the left atrial roof, cavotricuspid, and mitral isthmus were performed for patients with persistent AF. 11 The procedural end point was to achieve circumferential pulmonary vein isolation and bidirectional conduction block of the additional linear lesion.
Anticoagulation was given to all patients after CA for at least 3 months, and the continuation of anticoagulation was decided by physicians based on patients’ personal profiles. Antiarrhythmic drugs were prescribed as needed during the blanking period and stopped 3 months after ablation.
Follow‐Up and Outcome
Enrolled patients were followed at outpatient clinics or by telephone interviews at 1, 3, 6, 12, and 18 months after AF ablation. For each visit, a routine ECG or 24‐hour Holter was required. If patients had any symptoms related to AF recurrence between scheduled visits, additional ECG or 24‐hour Holter was performed. All patients’ documents were accessed by cardiologists from Beijing Anzhen Hospital.
Recurrence of AF was defined as an episode of atrial tachyarrhythmia lasting for >30 seconds without antiarrhythmic drugs after a 3‐month blanking period. ECG or 24‐hour Holter recorded during follow‐up was warranted for the confirmation of AF recurrence by cardiologists.
Statistical Analysis
Continuous variables were described as mean±SD or median (interquartile range) depending on whether the data were normally distributed and were compared between groups using 2‐sample t tests or rank‐sum test. Categorical variables were described as counts and percentages and compared using Pearson's chi‐square test. To control baseline differences, 1:3 propensity score matching (PSM) was used between SGLT2i and non‐SGLT2i groups. PSM calculations included the following variables: age, sex, estimated glomerular filtration rate, body mass index (BMI), persistent AF, hypertension, coronary heart disease, chronic heart failure, and ischemic stroke. We used 0.2 as a caliper for the PSM method. In the population after PSM, the survival rate was analyzed by plotting Kaplan–Meier curves to compare outcomes between the 2 groups. Univariate and multivariate Cox regression analyses were further applied in this population to assess the association between SGLT2i and AF recurrence. Hazard ratios (HRs) with 95% CIs were reported. Sensitivity analysis was performed by classifying patients into several subgroups. A 2‐sided P<0.05 was regarded as statistically significant. All statistical analyses were performed by STATA software (version 17).
Meta‐Analysis
Our systemic review and meta‐analysis were performed corresponding to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. 12 Literature was systematically reviewed by 2 reviewers on PubMed, EMBASE, and other databases from the beginning to January 1, 2023. Trials were included if they enrolled patients with AF and diabetes treated with or without SGLT2i including canagliflozin, dapagliflozin, tofogliflozin, or empagliflozin. For the search strategy, we combined the terms (atrial fibrillation) and (catheter ablation) with (SGLT2i), and a detailed search algorithm was shown in Data S1. The quality of cohort studies was assessed by using the Newcastle‐Ottawa Scale. 13 We used a random‐effects model to analyze our results in consideration of clinical diversity. The odds ratio (OR) with 95% CIs was used to assess the effect of SGLT2i on AF recurrence at 12 months, as HR was not provided in 1 of the included studies. 14 The difference between subgroups was assessed by Z test, and 2‐tailed P<0.05 was considered statistically significant.
Results
Baseline Characteristics
Of 30 174 patients with AF enrolled in the China‐AF cohort between August 2011 to December 2020, a total of 2069 patients met the eligibility criteria, of whom 141 patients were treated with SGLT2i after initial CA. In the SGLT2i group, 3 patients were further excluded due to unmatching with those in the non‐SGLT2i group by PSM. In the final matched cohort, 387 patients were selected from the non‐SGLT2i population to match with 138 patients in the SGLT2i group (Figure 1). Baseline characteristics in each group are summarized in the Table.
Figure 1. Flow chart of our research.
SGLT2i indicates sodium‐glucose cotransporter 2 inhibitor.
Table .
Baseline Characteristics of the Study Population
| Total number | |||
|---|---|---|---|
| Baseline characteristic | SGLT2i group N=138 | Non‐SGLT2i N=387 | P value |
| Male sex, n (%) | 98 (71.0%) | 276 (71.3%) | 0.946 |
| Age, y, mean±SD, y | 63.9±8.7 | 64.0±9.5 | 0.898 |
| Body mass index, mean±SD | 26.4±3.2 | 26.3±3.4 | 0.702 |
| Medical history, n (%) | |||
| Hypertension | 103 (74.6%) | 314 (76.2%) | 0.708 |
| Coronary heart disease | 52 (37.7%) | 127 (32.8%) | 0.301 |
| Chronic heart failure | 29 (21.0%) | 57 (14.0%) | 0.087 |
| Transient ischemic attack | 4 (2.9%) | 4 (1.0%) | 0.125 |
| Ischemic stroke | 15 (10.9%) | 48 (11.1%) | 0.938 |
| Persistent AF | 64 (46.4%) | 203 (49.6%) | 0.514 |
| AF duration | |||
| Mean±SD, y | 3.5±3.8 | 3.6±5.2 | 0.877 |
| Median (IQR), y | 2 (1.0, 5.0) | 1.5 (0.1, 5.0) | 0.012 |
| Diabetes duration | |||
| Mean±SD, y | 4.4±1.4 | 4.3±1.7 | 0.837 |
| Median (IQR), y | 4.4 (3.7, 4.8) | 4.2 (3.7, 4.8) | 0.217 |
| Hemoglobin A1C, mean±SD, n (%) | 6.3±1.0 | 6.4±0.8 | 0.203 |
| Fasting blood glucose, mean±SD, mmol/L | 8.2±2.4 | 6.1±1.6 | <0.001 |
| Estimated glomerular filtration rate, mean±SD, mL/min per 1.73 m2 | 86.0±10.1 | 85.6±10.9 | 0.660 |
| CHA2DS2VASc, mean±SD | 2.9±1.1 | 2.7±1.5 | 0.097 |
| Ultrasound cardiogram | |||
| Left atrial diameter, mean±SD, mm | 41.8±5.8 | 41.4±5.2 | 0.443 |
| Left ventricular end‐diastolic dimension, mean±SD, mm | 48.3±4.7 | 48.8±4.6 | 0.303 |
| Left ventricular ejection fraction, mean±SD, % | 62.5±7.3 | 63.2±6.7 | 0.274 |
| Other antidiabetic agents, n (%) | |||
| Metformin | 66 (47.8%) | 162 (41.9%) | 0.225 |
| Sulfonylurea | 13 (9.4%) | 31 (8.0%) | 0.608 |
| Alpha‐glucosidase inhibitors | 42 (30.4%) | 107 (27.7%) | 0.533 |
| Insulin | 21 (15.2%) | 48 (12.4%) | 0.401 |
| Dipeptidyl peptidase 4 inhibitor inhibitors | 5 (3.6%) | 13 (3.4%) | 0.884 |
| Glucagon‐like peptide‐1inhibitor receptor agonist | 3 (2.2%) | 14 (3.6%) | 0.411 |
AF indicates atrial fibrillation; IQR, interquartile range; and SGLT2i, sodium‐glucose cotransporter 2 inhibitors.
The comparative differences between groups calculated by 2‐sample t‐tests or rank‐sum test or Pearson’s chi‐square test based on statistic forms (in bold).
Differences in most variables in baseline between 2 groups were insignificant, whereas a statistically significant difference remained in terms of fasting blood glucose (SGLT2i 8.2±2.4 mmol/L, non‐SGLT2i 6.1±1.6 mmol/L; P<0.001) and median AF duration (SGLT2i 2 [1.0–5.0] years, non‐SGLT2i 1.5 [0.1–5.0] years; P=0.012). Results from the assessment of covariate distribution by standard mean difference and the chi‐square test showed that all covariates were balanced by PSM, as shown in Tables S1 through S3 and Figure S1.
AF Recurrence
AF recurrence occurred in 33 patients (23.9%) in the SGLT2i group and in 150 patients (38.7%) in the non‐SGLT2i group during a total of 593.3 person‐years follow‐up. The Kaplan–Meier curve for survival from AF recurrence is shown in Figure 2, as the SGLT2i group was associated with lower AF recurrence compared with the non‐SGLT2i group in 18‐month follow‐up (HR, 0.63 [95% CI, 0.44–0.90], P=0.007).
Figure 2. Freedom from AF recurrence without antiarrhythmia drugs in the SGLT2i group and non‐SGLT2i group during 18‐month follow‐up after catheter ablation among patients with diabetes.
AF indicates atrial fibrillation; HR, hazard ratio; and SGLT2i, sodium‐glucose cotransporter 2 inhibitor.
Our univariate Cox regression analysis showed that treatment with SGLT2i was associated with a lower risk of AF recurrence, and a larger left atrial diameter was associated with a higher risk of recurrence (Table S4). After adjustment for parameters including age, sex, BMI, AF types, AF duration, diabetes duration, left atrial diameter, left ventricular ejection fraction, and hemoglobin A1c, SGLT2i was independently associated with a lower risk of AF recurrence (HR, 0.58 [95% CI, 0.42–0.84], P<0.001) as shown in Table S5.
Subgroup Analysis
The risk of AF recurrence in the follow‐up was evaluated in different subgroups by sex, age, BMI, left atrial diameter, types of AF, AF duration, diabetes duration, left ventricular ejection fraction, and level of hemoglobin A1c (Figure 3). The results were consistent across most subgroups, showing the efficacy of SGLT2i on the reduction of AF recurrence over the non‐SGLT2i group. In addition, patients with larger BMI (≥24 kg/m2), persistent AF, and longer AF duration (>1 year) seemed to benefit more from SGLT2i therapy after AF ablation (P for interaction <0.05).
Figure 3. Sensitivity analysis for AF recurrence during follow‐up.
AF indicates atrial fibrillation; BMI, body mass index; LAD, left atrial diameter; LVEF, left ventricular ejection fraction; and SGLT2i, sodium‐glucose cotransporter 2 inhibitor.
Meta‐Analysis
For the meta‐analysis, a total of 1146 articles were yielded after searching from PubMed, MEDLINE, and other resources. After removing duplicates, the titles, abstracts, and full‐text articles were screened for all potentially eligible studies for inclusion. A total of 4 studies 14 , 15 , 16 (including this study) met the inclusion criteria and were analyzed in our meta‐analysis (Figure 4). The risk of bias was rated as low by the Newcastle‐Ottawa Scale, and basic information and patients’ baseline are shown in Table S6. Results from the meta‐analysis demonstrated that SGLT2i was associated with lower AF recurrence in comparison to the non‐SGLT2i group (OR, 0.61 [95% CI, 0.54–0.69]; I 2=0.0%) in 1‐year follow‐up. Further sensitivity studies were performed, and our results showed that SGLT2i was associated with a lower risk of AF recurrence by excluding the Abu‐Qaoud et al study 16 or retrospective studies (Figure S2 and S3).
Figure 4. Pooled analysis of 4 eligible studies (including our study) evaluating the association between SGLT2i use and AF recurrence after catheter ablation among patients with diabetes in 1‐year follow‐up.
AF indicates atrial fibrillation; OR, odds ratio; and SGLT2i, sodium‐glucose cotransporter 2 inhibitor.
Discussion
Our multicenter study coupled with a comprehensive meta‐analysis showed a lower incidence of AF recurrence with the use of SGLT2i. Moreover, patients with larger BMI, persistent AF, and longer AF duration seem to benefit more from SGLT2i therapy after AF ablation.
As one of the most common comorbidities, diabetes is associated with a higher risk of developing AF and increases symptom burden and cerebral‐cardiovascular mortality among patients with AF history. 17 , 18 Underlying pathophysiological mechanisms that link diabetes to AF include electrical and structural remodeling caused by oxidative stress inflammation, metabolic abnormalities, and changed blood constituents with the presence of diabetes. 19 Other mechanisms such as electromechanical and autonomic remodeling have also been proposed to explain the association between diabetes and AF. 20
Results from our cohort study along with comprehensive meta‐analysis showed that the use of SGLT2i was associated with a lower risk of AF recurrence after CA, which is in line with recent clinical trials and meta‐analysis that have demonstrated that SGLT2i may reduce atrial tachyarrhythmia. 7 , 8 , 21 Data from the DAPA‐HF (Dapagliflozin and Prevention of Adverse‐Outcomes in Heart Failure) trial and EMPA‐REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial showed that SGLT2i seemed to reduce the risk of worsening heart failure events and cardiovascular death in patients with AF. 22 , 23
A series of randomized clinical trials (RCTs) demonstrated AF ablation, as an initial treatment, has shown its superiority to antiarrhythmic drugs. 3 , 4 However, postablation arrhythmia could relapse in at least 20% to 40% of patients after initially successful ablation in the first year. 24 , 25 , 26 In a recent small‐sample RCT, Kishima et al showed that tofogliflozin, a type of SGLT2i drug, achieved greater suppression of AF recurrence in patients with diabetes after CA. 14 A similar conclusion was also drawn in 2 other retrospective studies, as the use of SGLT2i among patients with AF and comorbid diabetes undergoing ablation was associated with lower incidence of AF recurrence comparing to those without SGLT2i. 15 , 16 Our results alone and the pooled results from our meta‐analysis were in line with conclusions from the aforementioned studies, showing the potential attenuating effect of SGLT2i on AF recurrence after CA. Further large RCTs are required to testify to the effect of SGLT2i on AF recurrence in patients with diabetes undergoing CA.
Notably, current studies primarily focused on the effect of SGLT2i on AF recurrence among patients with diabetes with a well‐recognized indication for SGLT2i, which cannot generalize to the entire population. However, evidence has emerged continuously to prove that SGLT2i may process with a comprehensive cardiac protective effect with or without the existence of diabetes. First, SGLT2i could mitigate electrical and structural remodeling of the atrium. SGLT2i primarily acts by reducing the glucose reabsorption in the kidney via the inhibition of SGLT2 receptors, leading to glycosuria. 27 This causes a significant osmotic diuresis and natriuresis with the reduction in plasma volume 28 and a mild drop of blood pressure, 29 resulting in mitigation of structural remodeling of the atrium. A meta‐analysis of 13 RCTs showed that SGLT2i could significantly reverse cardiac remodeling, characterized by improved left ventricular systolic and diastolic function and reducing left ventricular mass and volume in patients with heart failure. 30 A prospective study evaluating the efficacy of SGLT2i on AF recurrence among patients after CA showed that the reduction of left atrial diameter index from baseline to follow‐up was significantly greater in SGLT2i than that in the non‐SGLT2i group. 14 In addition, SGLT2i may improve mitochondrial function, modify ionic homeostasis, and reduce oxygen‐reactive stress in cardiomyocytes. 31 In vitro experiments showed that SGLT2i impaired the sodium/hydrogen exchanger 1 and reducing cytosolic calcium and sodium concentration, protecting cardiomyocytes from heart failure. 32 , 33 Besides, SGLT2i showed a protective effect against oxidative stress in the hyperglycemia‐induced endothelial dysfunction model. 34 Other potential mechanisms include reduction of sympathetic nervous system overdrive and attenuation of autonomic imbalance. 35 Further studies, especially large RCTs, are required to verify these findings and expand the indication of SGLT2i in patients with AF.
Strengths and Limitations
Our study evaluates the impact of SGLT2i on AF recurrence among patients with diabetes after AF ablation procedures. A meta‐analysis was also conducted to pool our results with other homogeneous studies that assessed the difference between SGLT2i versus non‐SGLT2i in patients with diabetes and AF undergoing CA. The main limitation of our study concerns the lack of randomization and residual unmeasured confounding. Large RCTs are required to verify our conclusions. In addition, asymptomatic recurrences in patients might be missed. What is more, most of the studies included in the meta‐analysis were small‐sample cohort studies, largely affected by an included large‐sample study. 16 To testify to the solidarity and consistency of our results, we performed sensitivity tests by excluding the large‐sample study and found that SGLT2i was associated with a lower risk of AF recurrence. Besides, a significant difference for interaction in several subgroups including BMI, AF types, and AF duration was observed. Considering that false positives might be generated when performing multiple testing, these results should be interpreted cautiously. Further studies are warranted to test the efficacy of SGLT2i on AF recurrence in these subgroups.
Conclusions
Our study coupled with a meta‐analysis demonstrated a lower risk of AF recurrence with the use of SGLT2i among patients with diabetes after AF ablation. Moreover, patients with larger BMI, persistent AF, and longer AF duration seem to benefit more from SGLT2i therapy after AF ablation. Further RCTs are warranted to fully assess the impact of SGLT2i on AF recurrence after CA in patients with or without diabetes.
Sources of Funding
This work was supported by the National Key Research and Development Program of China (2022YFC3601303 and 2020YFC2004803) and the National Natural Science Foundation of China (82270316 and 82100326 and 82103904), and grants from the Beijing Municipal Science and Technology Commission (D171100006817001), the Beijing Municipal Education Commission (KM202210025012), and the Beijing Hospitals Authority Youth Program (QML20230606).
Disclosures
None.
Supporting information
Data S1
Tables S1–S6
Figures S1–S3
Acknowledgments
We are grateful for advice on statistics analysis from Professor Jing Du.
This article was sent to Luciano A. Sposato, MD, MBA, FRCPC, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.123.031269
For Sources of Funding and Disclosures, see page 8.
Contributor Information
Caihua Sang, Email: sch9613070@sina.com.
Changsheng Ma, Email: chshma@vip.sina.com.
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Associated Data
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Supplementary Materials
Data S1
Tables S1–S6
Figures S1–S3