Cerebrovascular, Cognitive and Cardiac Benefits of SGLT2 Inhibitors Therapy in Patients with Atrial Fibrillation and Type 2 Diabetes Mellitus: Results from a Global Federated Health Network Analysis

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are effective anti-diabetic drugs improving cardiovascular outcomes in type 2 diabetes mellitus (T2DM) patients. This study investigated cardiovascular, cerebrovascular and cognitive outcomes of SGLT2i therapy in patients with atrial fibrillation (AF) and T2DM. Methods: Observational study using TriNetX, a global health research network of anonymised electronic medical records from real-world patients between January 2018 and December 2019. The network includes healthcare organisations globally but predominately in the United States. AF patients (ICD-10-CM code: I48) with T2DM were divided according to SGLT2i use or not, and balanced using propensity score matching (PSM). Patients were followed-up for 3-years. The primary endpoints were ischaemic stroke/transient ischemic attack (TIA), intracranial haemorrhage (ICH), and incident dementia. Secondary endpoints were incident heart failure and mortality. Results: We identified 89,356 AF patients with T2DM of which 5061 (5.7%) were taking a SGLT2i. After PSM, 5049 patients (mean age 66.7 ± 10.6 years; 28.9% female) were included in each group. At 3-years follow-up, the risk of ischaemic stroke/TIA was higher in patients not receiving SGLT2i (HR 1.12, 95% CI 1.01–1.24) and for ICH (HR 1.57, 95% CI 1.25–1.99) and incident dementia (HR 1.66, 95% CI 1.30–2.12). Incident heart failure (HR 1.50, 95% CI 1.34–1.68) and mortality (HR 1.77, 95% CI 1.58–1.99) risks were increased in AF patients not receiving SGLT2i. Conclusions: In our large ‘real world’ analysis of patients with concomitant AF and T2DM, SGLT2i reduced the risk of cerebrovascular events, incident dementia, heart failure and death.


Introduction
The sodium-glucose co-transporter 2 inhibitors (SGLT2i) are new effective anti-diabetic drugs, which act by inhibiting glucose and sodium reabsorption at the level of proximal convoluted tubule of the nephron, and improving glycemic control in patients with type 2 diabetes mellitus (T2DM) [1]. Currently, four SGLT2i are approved by the European Medicines Agency and the Food and Drug Administration and available to prescribe: canagliflozin, dapagliflozin, empagliflozin and ertugliflozin [1].
Two features of SGLT2i are of particular interest: (i) a mechanism of action not linked to insulin secretion, which makes the detrimental occurrence of hypoglycemia less likely compared to other anti-diabetic drug classes; and (ii) cardiovascular and renal protective effects independent of its' glycemic control and noted early after initiation of the therapy, suggesting mechanisms of action beyond blood glucose lowering [1,2].
Three randomized clinical trials, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) [3], CANagliflozin car-dioVascular Assessment Study (CANVAS) [4], and Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial [5], have reported that SGLT2i improved cardiovascular outcomes in patients with T2DM, including a reduced risk of cardiovascular death and hospitalization for heart failure. In expanding the applicability of SGLT2i therapy, the 'EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure (EMPEROR-reduced)' investigated 3730 patients with reduced ejection fraction (<40%) of whom 49% had T2DM, and showed a reduction of the combined primary endpoints (cardiovascular death and heart failure hospitalization) in the empagliflozin group compared to placebo (19.4% vs. 24.7% respectively; hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.67-0.87; p < 0.0001). The 'Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved)' showed that empagliflozin was superior to placebo in improving heart failure outcomes (cardiovascular death and hospitalization) among patients with symptomatic stable heart failure and preserved ejection fraction (>40%), irrespective of diabetes status (HR 0.79, 95% CI 0.69-0.90, p < 0.001).
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial [6] testing the efficacy of SGLT2i in patients with T2DM and evidence of albuminuric chronic kidney disease showed a reduction in the risk of progression toward end-stage renal failure (HR 0.68, 95% CI 0.54-0.86; p = 0.002). A subanalysis of the CREDENCE trial suggested that there may be a potential effect of SGLT2i on ischaemic stroke prevention and reduction in non-traumatic brain haemorrhages [7]. More recently, a sub-analysis of the DECLARE-TIMI 58 trial found a decrease in new episodes of atrial fibrillation (AF) or atrial flutter (AFl) with SGLT2i independent from the prior history of AF, atherosclerotic cardiovascular disease or heart failure [8].
Together these data lead to the hypothesis that SGLT2i may be beneficial in patients with AF which are at risk of developing incident comorbidities including heart failure and dementia. This is further supported by the anti-inflammatory, metabolic and neuro-modulatory actions of this class of medications [2]. Nonetheless, there is limited evidence from large-scale datasets on whether these trial data translate into real-world clinical practice.
Therefore, in this study we investigated the effect of SGLT2i therapy in reducing the occurrence and risk of adverse cerebrovascular cardiovascular, and cognitive outcomes using a cohort of patients with AF and T2DM.

Materials and Methods
This is an observational and retrospective study using TriNetX, a global federated health research network with real-time updates of anonymised electronic medical records (EMRs). The network includes healthcare organisations (HCOs, academic medical centres, specialty physician practices and community hospitals) with data for >85 million realworld patients, predominately based in the United States. In brief, the TriNetX research network database encompasses anonymized EMRs of patients registered with the network and has information on patient demographics, clinical details including diagnoses (using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes), medications and investigations as well as any procedures, from settings such as general practice surgeries, community and secondary hospitals. To comply with legal frameworks and ethical guidelines guarding against data re-identification, the identity of participating HCOs and their individual contribution to each dataset are not disclosed. As a federated research network, studies using the TriNetX health research network do not require ethical approval as no patient is identifiable.
For the present study, the TriNetX research network was searched for the inclusion of patients from 1 January 2018 to 31 December 2019. To be included in the study, all patients were aged ≥18 years with a diagnosis of AF (ICD-10-CM code: I48) and diabetes mellitus (ICD-10-CM code: E08-E13) during this period, and received oral anticoagulation therapy either with a vitamin K antagonist (VKA) or a non-VKA oral anticoagulant (NOAC). Patients were divided into two groups according to SGLT2i use (empagliflozin, dapagliflozin, or canagliflozin). In the group of patients on SGLT2i, only prevalent SGLT2i users were considered. Patients not receiving SGLT2i at inclusion, who were subsequently prescribed it, were censored when the drug was initiated. Patients with chronic rheumatic heart diseases (ICD-10-CM code I05-I09), acute rheumatic fever (ICD-10-CM code I00-I02) or prosthetic heart valves (ICD-10-CM code Z95.2) were excluded, with no other exclusion criteria.
We used ICD-10-CM codes to identify relevant diagnoses and the Anatomic Therapeutic Chemical (ATC) codes to identify pharmacotherapy. The searches were run in TriNetX on 3 May 2022. At the time of the search, there were 58 participating HCOs within the TriNetX research network.

Statistical Analysis
Continuous variables (age) were expressed as mean and standard deviation (SD), and tested for differences with independent-sample t test. Categorical variables (sex, ethnicity, comorbidities, and pharmacological therapy) were expressed as absolute frequencies and percentages, and tested for differences with chi-squared test. The TriNetX platform was used to run 1:1 propensity score matching (PSM) using logistic regression. The platform uses 'greedy nearest-neighbour matching' with a caliper of 0.1 pooled standard deviations and difference between propensity scores ≤0.1. Covariate balance between groups was assessed using standardised mean differences (SMDs). Any baseline characteristic with a SMD between cohorts <0.1 is considered well-matched [9].
HR and 95% CI were calculated following PSM, and displayed as Kaplan-Meier survival curves with log-rank tests. No imputations were made for missing data. Two-sided p-values < 0.05 were accepted as statistically significant. Statistical analysis was performed using the TriNetX Analytics function in the online research platform.

Results
The study identified 89,356 patients with AF and T2DM, and of these, 5061 (5.7%) patients were taking a SGLT2i. Table 1 summarises the baseline characteristics of patients with and without SGLT2i therapy. Prior to PSM, patients receiving SGLT2i were likely be male, not Hispanic or Latino, and suffered from ischemic heart disease, hyperlipidemia, and overweight/obesity. On the contrary, patients on SGLT2i presented lower prevalence of cerebrovascular disease, COPD, and renal disease, and were more frequently treated with NOACs instead of VKAs. These differences were attenuated after PSM and both cohorts, each including 5049 patients, were balanced.

Discussion
The main findings of our analysis demonstrate that SGLT2i therapy is associated with a reduced incidence of cerebrovascular events and dementia in patients with AF and T2DM. In addition, there was a decrease in heart failure episodes and improved survival in patients with AF and T2DM treated with SGLT2i.
Given the high prevalence of AF and dementia worldwide, in particular among older people, our finding of a decreased incidence of dementia in the cohort of patients with AF treated with SGLT2i is important. Numerous observational studies over the past 10 years, including two meta-analyses, [10,11] have shown that AF is associated with cognitive impairment and dementia, even in the absence of clinically overt previous stroke. Patients with AF are also exposed to a significant risk of Alzheimer's disease [12]. This finding identifies a more complex interaction between AF and cognitive decline in which vascular and degenerative mechanisms, including cerebral amyloid deposition, co-exist and interact. Recently a novel SGLT2i mechanistic theory linking changes in glucose, free fatty acids (FFA) and AA metabolism to improvements in mitochondrial functioning, was proposed [13]. The SGLT2i drugs promote the loss of glucose in the urine, which can impact the mTOR signalling pathway and modulate AMPK activity; and both molecular pathways play a role in cerebral amyloid deposition and development of Alzheimer's disease [14]. Finally, in patients with non-alcoholic fatty liver disease, treatment with SGLT2i improves neural mitochondrial function as indicated by increased levels of circulating n-acetyl aspartate (NAA), a biomarker of neural mitochondrial viability [15]. Depletion of NAA, as occurs in Alzheimer's disease, may also play a direct role in promoting amyloid deposition [15]. One ongoing pilot study is evaluating the impact of dapagliflozin treatment on patients with Alzheimer's disease (NCT03801642). Considering the link between vascular amyloid angiopathy and Alzheimer's disease related amyloidosis, it may be hypothesized that SGLT2i may be effective in modifying the risk of dementia in patients with AF.
Sub-analysis of the major randomised controlled trials (RCTs) and a subsequent metaanalysis have proposed a possible benefit of SGLT2i in reducing the incidence of stroke; the effect seems to correlate with baseline kidney function being more evident for those with low estimated glomerular filtration rate [7,16]. Increasing evidence also suggests anti-arrhythmic effects of SGLT2i with a reduced incidence of newly diagnosed AF or AF burden in patients with already diagnosed AF [8,17]. Such anti-arrhythmic properties preventing the development of new incident AF/AFL, may underline the suggested impact of SGLT2i therapy on reducing stroke incidence. Indeed, the risk of AF is increased in patients with chronic kidney disease, thereby justifying the benefit in this group of patients. In our study, the two cohorts identified were adjusted for chronic kidney disease after PSM, which may confirm a benefit from SGLT2i therapy independently from baseline renal function. In addition, various vascular and systemic effects of SGLT2i have been described beside the lowering of blood glucose, which can help decrease the risk of cerebrovascular events, including modulation of anti-inflammatory effects with a decrease in epicardial fat, leptin and TNFα production, and improvements in vascular function with a decrease in blood pressure, vascular stiffness and uric acid levels [18].
Of note, our analysis shows a benefit of SGLT2i on reducing non-traumatic ICH. Our findings report an absolute difference in means of approximately 1.3% and the risk of ICH was 1.57-fold higher in AF patients without SGLT2i therapy, which may underline important clinical implication. Indeed, currently there are no drugs that have shown effect in preventing ICH.
Large prospective studies have shown that both hypoglycaemic and hyperglycaemic episode are associated with ICH [19]. The SGLT2i have a mechanism of action not linked to insulin secretion, which makes the detrimental occurrence of hypoglycemia less likely compared to other classes of anti-diabetic drugs and also allows the achievement of steady levels of blood glucose. This feature along with the aforementioned actions on blood pressure lowering and improvement in endothelial function and vascular stiffness may explain the possible benefits of SGLT2i on ICH.
In our analysis, the benefits of SGLT2i on the risk of heart failure and overall survival among patients with AF were evident from the early stages of follow-up. Indeed, large RCTs of SGLT2i have demonstrated improved cardiovascular outcomes in patients with T2DM, including a reduced risk of cardiovascular death and hospitalisations for heart failure [3][4][5]. Both the DAPA-HF [20] and EMPEROR-Reduced trial [21] have shown that in patients with heart failure and reduced ejection fraction, the benefit of SGLT2i are independent of diabetes mellitus. The EMPEROR-Preserved trial [22] has further extended this finding showing similar effects in terms of reduction of cardiovascular morbidity and mortality in patients with and without T2DM who have concomitant heart failure with preserved ejection fraction.

Limitations
Several limitations should be considered when interpreting the results of the current study. First our analysis was a retrospective study performed on EMR, and from this dose and duration of SGTL2i treatment could not be ascertained. Accordingly, a comparison between different SGLT2i and dose could not be performed. It is also possible that some changes to prescriptions may have been made outside of HCOs and not been captured within the TriNetX health research network. Furthermore, in our analysis, the cohorts were matched for factors including age, sex, ethnicity and co-morbidities, but residual confounding may still be present and some health conditions may be underreported in EMRs. Finally, an assessment of socio-economic and genetic factors biasing the associations between AF and dementia could not be performed.

Conclusions
In our large 'real-world' analysis of patients with concomitant AF and T2DM, SGLT2i therapy significantly reduced the risk of cerebrovascular events and incident dementia, heart failure and mortality. Considering the epidemiological relevance of the link between AF and dementia, the possible benefit of the metabolic effect of SGLT2i in preventing cognitive deterioration in this group of patients requires testing in a prospective study. Institutional Review Board Statement: As a federated research network, studies using the TriNetX health research network do not require ethical approval as no patient is identifiable.

Data Availability Statement:
The data that support the findings of this study are available from TriNetX. To gain access to the data, a request can be made to TriNetX (https://live.trinetx.com, accessed on 20 March 2023), but costs may be incurred, and a data sharing agreement is needed. There is nothing to disclose for other authors, DAL has received investigator-initiated educational grants from Bristol Myers Squibb (BMS) and Pfizer; been a speaker for Boehringer Ingelheim, Bayer, and BMS/Pfizer and consulted for Boehringer Ingelheim and BMS/Pfizer; all outside the submitted work. She is a co-applicant of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871.