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Association of SGLT2 Inhibitors With Risk of Atrial Fibrillation and Stroke in Patients With and Without Type 2 Diabetes: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Supplemental Digital Content is Available in the Text.


INTRODUCTION
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a leading cause of mortality worldwide. As is reported, the estimated prevalence of AF is 1%-4% in western countries and China, 1 and its prevalence is expected to surge in the next 3 decades owing to factors such as an aging population, economic growth, and increased prevalence of risk factors for AF. 2 AF increases the risk of heart failure and stroke that causes a huge burden on human health and social economy. Diabetes mellitus has been well established as a critical risk factor for AF. 3 Accumulating evidence demonstrates that diabetes is closely associated with increased risk of AF promotion. [4][5][6] As far back as the Framingham Heart Study, it was suggested that the risk of developing AF was significantly increased in patients with diabetes during a long-term followup. 5 A meta-analysis of 29 studies, which included 8,037,756 individuals, also found similar results that patients with diabetes had a 49% increased risk in the development of AF. 7 In addition, higher glycemic levels were shown to be correlated with increased risk of AF. 8 Generally, the link between diabetes mellitus and AF is clear and close.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a novel class of oral antihyperglycemic agents for treating type 2 diabetes by selectively inhibiting renal reabsorption of glucose and increasing urinary glucose excretion, 9,10 have been fully demonstrated to attenuate the risk of hospitalization for worsening heart failure and the risk of cardiovascular death or serious renal outcomes, in recent, large, multicenter, randomized controlled trials (RCTs). [11][12][13][14] Recently, an animal study suggested that canagliflozin had an effect on preventing developing AF and suppressing the promotion of atrial remodeling. 15 In addition, Zelniker et al 16 reported that dapagliflozin was associated with a decreased risk of AF in patients with type 2 diabetes regardless of the history of AF or other cardiovascular diseases in a post hoc analysis of the DECLARE-TIMI58. SGLT2 inhibitors seem to possess therapeutic potential for AF. However, the association has not been comprehensively established, and evidence is inconclusive. Thus, we carried out this present metaanalysis, pooling data from all available RCTs, which compared SGLT2 inhibitors with placebo and reported AF as an adverse event, to further evaluate the effect of SGLT2 inhibitors on AF risk, including sensitivity and subgroup analyses.

METHODS
This present meta-analysis was performed in accord with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. 17

Search Strategy
A comprehensive literature search of PubMed, Embase, and ClinicalTrials. gov was carried out for all relevant publications on SGLT2 inhibitors and the risk of AF from inception to May 2021 without language restriction. Keywords or mesh terms used in the searches included "AF" combined with "SGLT2 inhibitor", "empagliflozin", "canagliflozin", "dapagliflozin", "ertugliflozin", "sotagliflozin", "ipragliflozin", "remogliflozin", "sergliflozin", or "tofogliflozin". The detailed search strategies are shown in Supplemental Digital Content 1 (see Supplementary file, http://links.lww.com/JCVP/A733. In addition, a manual search of retrieving the references listed in identified studies and previous reviews to identify any additional studies was conducted.

Selection Criteria
Studies considered eligible for inclusion were RCTs that met the following criteria: (1) included patients with SGLT2 inhibitors exposure or nonexposure and (2) reported the risks of AF using hazard ratio, odds ratio (OR), or risk ratio (RR) estimates with 95% confidence intervals (CI) or sufficient data to calculate them. Letters to the editor, review articles, and case reports were excluded. Two reviewers independently identified all records by title and abstract and subsequently retrieved and evaluated the full text of any potential articles. When there were multiple RCTs from the same patient cohorts, only the trial with a larger sample size and more informative data was included. Disagreements were resolved by consensus.

Data Extraction and Outcome Assessment
Data were extracted onto a standardized form manually by 2 independent authors. Data extracted from the eligible studies were as follows: information regarding the quality of study, first author, year of publication, study design, participants characteristics, study period, interventions (dose and agent type of SGLT2 inhibitors), and effect estimates with 95% CIs for each outcome. We attempted to contact the corresponding authors to obtain additional data when complete information was unavailable. Any discrepancies were resolved by referring back to the original report.
The primary analyses were focused on evaluating the risk of overall AF among SGLT2 inhibitors users and nonusers. Besides, we also checked stroke as the primary outcome. Further subgroup analyses were performed to investigate the performance of SGLT2 inhibitor treatment between different agent types and length of follow-up.

Quality Assessment
Two authors independently assessed the methodological quality of the RCTs using the Cochrane risk-of-bias tool. 18 Any disagreement on the risk-of-bias assessments was resolved by discussion of the 2 authors.

Statistical Analysis
All meta-analyses were performed with the randomeffect model using STATA SE software (version 16.0, StataCorp, TX). The Mantel-Haenszel test with fixedeffects model, which predicted a low heterogeneity for the outcomes of interest, with pooled OR and corresponding 95% CIs was applied to summarized dichotomous data. Statistical heterogeneity was assessed using the Cochrane Q test and quantified by the I 2 statistics. A P value less than 0.1 was considered statistically significant for the Q test, and I 2 of $50% indicated a substantial level of heterogeneity. When significant heterogeneity was identified, random-effects model was performed. Several subgroup analyses were conducted to evaluate the robustness of results. Publication bias was investigated graphically with a funnel plot and quantitatively with Egger's test if numbers of included studies were more than 10 in accordance with Cochrane Handbook.

Study Selection and Characteristics
The search strategy is outlined in Figure 1. A total of 1284 records were initially identified. No records were identified through other sources. After the removal of duplicates, 384 records were further excluded with respect to titles and abstracts, leaving 138 records for full-text review. After careful assessment, 20 studies, comprising a total of 63,604 participants, matched our prespecified criteria and were included for the final meta-analysis. All of the included studies were RCTs. Table 1 summarized the characteristics of the included studies. These studies were published between 2012 and 2020 and had sample sizes ranging from 269 to 17,160 patients. The proportion of female subjects ranged from 28.5% to 51.6%. The study population was type 2 diabetes for all studies except for 2 trials, DAPA-HF, 12 and DAPA-CKD. 19 DAPA-HF included patients with symptomatic heart failure and an ejection fraction of 40% or less, and it had 42% of participants with type 2 diabetes. DAPA-CKD included patients with chronic kidney disease and an estimated glomerular filtration rate of 25

Quality Assessment
Randomized sequence generation and allocation concealment were conducted adequately in most studies. The risk of bias for most studies was assessed as low, and all data were derived from randomized trials ( Table 1).

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on AF
AF was reported in all 20 studies. SGLT2 inhibitors therapy was associated with a significant 18% reduction in the odds of incident AF compared with control (OR = 0.82; 95% CI, 0.72-0.93; P = 0.002; Fig. 2). In subgroup analysis based on the types of SGLT2 inhibitors used (see Figure 1, Supplemental Digital Content 1, http://links.lww.com/ JCVP/A733), only dapagliflozin was associated with Notably, the subgroup analyses were more susceptible to type II errors because of less power than the overall pooled analysis, which includes all studies regardless of the length of follow-up.

DISCUSSION
This large meta-analysis of 20 RCTs involving 63,604 patients suggests that SGLT2 inhibitors treatment significantly attenuated the risk of incident AF for patients with type 2 diabetes, heart failure, or chronic kidney disease. In addition, we also found that the use of SGLT2 inhibitors did not affect the risk of stroke in individuals with and without type 2 diabetes. According to previous animal experiments and clinical studies, SGLT2 inhibitors have been hypothesized a sympathetic inhibitory effect, which may be involved in the antiarrhythmic effect. 36 However, up to now, the molecular mechanisms underlying the antiarrhythmic effect of SGLT2 inhibitors remain unclear. Thus, more studies should be conducted to further explain how SGLT2 inhibitors exert antiarrhythmic effects.
Except for the well-established effect on rehospitalization for heart failure and cardiovascular mortality, SGLT2 inhibitors appear to attenuate the incidence of AF. Experimental and clinical data have provided several possible explanations for the protective heart benefits of SGLT2 inhibitors. SGLT2 inhibitors are thought to play a key role in reducing glucose, body weight, and blood pressure. By suppressing SGLT2 in the proximal renal tube, SGLT2 inhibitors induce glucosuria and natriuresis. 37,38 Increased glucose and sodium excretion, causing osmotic diuresis and contraction of plasma volume, thereby reducing atrial blood pressure and atrial dilation. 39 Owing to the natriuretic and diuretic effects, a 7% reduction in the plasma volume in patients with type 2 diabetes using dapagliflozin was found at week 12. 40 In diabetic patients, the sodium-hydrogen exchanger 1 upregulates, leading to a significant increase in the intracellular sodium content, which results in a higher activity of the Na + /Ca 2+ exchanger and subsequently an increase in the calcium levels in the sarcoplasmic reticulum. However, this mechanism is burdened by a high risk of arrhythmia because of the mitochondrial activation of the Na + /Ca 2+ exchanger. 41,42 SGLT2 inhibitors suppress sodiumhydrogen exchange, promote natriuresis, and lower cardiac intracellular Na + and Ca 2+ , which have been connected to the reduction of myocardial hypertrophy, 43,44 adverse remodeling and fibrosis, and hence decrease the risk of arrhythmia. Epicardial fat could lead to localized inflammation and is thought to increase the incidence of AF. Besides, some studies have shown that SGLT2 inhibitors are associated with a reduction in epicardial fat, contributing to the antiarrhythmic effect. 45 Recently, a population-based propensity scorematched cohort study involving 79,150 diabetic patients on SGLT2 inhibitors compared with 79,150 matched diabetic patients on DDP-4 inhibitors 46 showed that there was a 17% reduction of new-onset AF. This is the first real-world study focusing on the risk of AF among type 2 diabetes patients treated with SGLT2 inhibitors. More studies should be conducted to further understand the relationship between SGLT2 inhibitors and arrhythmia.
AF as a known risk factor for incident stroke has been well demonstrated in previous studies. However, it is still unclear whether a reduced risk of incident AF associated with SGLT2 inhibitors affects the incidence of stroke. In EMPA-REG OUTCOME, there was a higher incidence of AF in the empagliflozin-treated group, as well as fatal or nonfatal stroke. Similarly, CANVAS-R and CANVAS trials suggested that a lower risk of incident AF in the canagliflozin group was associated with a decreased risk of stroke compared with control. In contrast, similar incidence of ischemic stroke was found in the dapagliflozin and placebo groups, whereas the DECLARE-TIMI 58 trial reported the lowest incidence of AF with dapagliflozin. In this present meta-analysis, we found that SGLT2 inhibitors do not significantly affect the risk of stroke (95% CI, 0.85-1.15; P = 0.908). Taken all together, the association between SGLT2 inhibitors and the risk of stroke ought to be interpreted cautiously due to currently insufficient data.
There are several limitations to this meta-analysis. AF in the included studies was reported as a serious adverse event, not as an outcome. Thus, no clear predefinitions and no standard method for assessing AF events were described, which may cause reporting bias. Because AF was not the outcome of interest in the included studies, risk factors for AF may not balance in SGLT2 inhibitors and control groups. Although a significantly decreased incidence of AF with SGLT2 inhibitors was detected in this present meta-analysis, more studies are needed to conduct and identify whether it is clinically important.

CONCLUSIONS
Overall, SGLT2 inhibitors are associated with a lower risk of incident AF and do not significantly affect stroke risk in patients with and without type 2 diabetes. Based on the above limitations, these findings should be interpreted with caution until more specifically designed trials are available.