Sodium‐glucose co‐transporter‐2 inhibitors and atrial fibrillation in the cardiovascular and renal outcome trials

Abstract

Dapagliflozin is a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor that has recently been shown to reduce the incidence of reported episodes of atrial fibrillation (AF)/atrial flutter in the DECLARE‐TIMI 58 trial. This raises the question regarding whether SGLT2 inhibitors can reduce the incidence of AF in a high‐risk population. We searched for trials comparing SGLT2 inhibitors to placebo in high‐risk individuals with or without diabetes (ie, cardiovascular and renal outcome trials) and that reported the incidence of AF as a serious adverse event. The EMPA‐REG OUTCOME trial, CANVAS, CANVAS‐R, the DECLARE‐TIMI 58 trial, CREDENCE, DAPA‐HF, VERTIS‐CV and DAPA‐CKD were included. The incidence of AF, reported as a serious adverse event, was 0.9% in individuals who received an SGLT2 inhibitor compared to 1.1% in those who received placebo. Pooled results showed a significantly lower incidence of AF in individuals with and without diabetes (relative risk 0.79, 95% confidence interval 0.67,0.93). This review suggests that there is a significantly lower risk of incident AF for individuals on SGLT2 inhibitors versus placebo. While there was a statistically significant lower incidence of AF, reported as a serious adverse event, more research is needed to evaluate its clinical significance.

SGLT-2 inhibitors and atrial fibrillation in the Food and Drug Administration adverse event reporting system

“…Along with the results of individual randomized controlled trials (RCTs) and meta-analyses [6,7], this finding supports the suggested protective effect of SGLT2i against AF. To date, observational studies have provided conflicting results.…”

“…Interestingly, atrial fibrillation (AF) has been shown to occur less frequently among patients who received dapagliflozin than among those who received placebo in the DECLARE trial (HR 0.81; 95% CI 0.68-0.95) [5]. Other studies have reported similar lower rates of AF among patients randomized to SGLT2i, and two meta-analysis calculated a 21% relative risk reduction [6,7]. This finding is relevant because T2D is an established risk factor for AF [8,9], which can cause embolic stroke, precipitate HF [10], or result in hospitalization for the need of rate control.…”

Protective Effects of Sodium-Glucose Transporter 2 Inhibitors on Atrial Fibrillation and Atrial Flutter: A Systematic Review and Meta- Analysis of Randomized Placebo-Controlled Trials

“…Animal studies have demonstrated that SGLT2i could reduce the oxidative stress in cardiomyocytes, which in turn reverses myocardial structural/electronic remodeling (22,23). The posthoc analysis of the DECLARE-TIMI 58 trial confirmed that dapagliflozin has a lower incidence of AF over placebo, indicated the potential benefit of SGLT2i in preventing AF/AFL (24), as confirmed by subsequent meta-analyses (25,26). Recent studies have reported beneficial effects of SGLT2i in preventing atrial remodeling even in non-diabetic conditions.…”

“…In a recent meta-analysis, Li et al indicated that the AF/AFL reduction benefit of SGLT2i have no relevance with age, body weight, and systolic blood pressure at baseline (26). In another meta-analysis, Okunrintemi et al considered the AF/AFL reduction may be associated with decreased uric acid and increased magnesium induced by SGLT2i (25). Moreover, the protective effects of SGLT2i against AF/AFL may be direct actions on cardiac remodeling by reducing oxidative stress (62), which can prevent mitochondrial dysfunction and improve mitochondrial energetics (63).…”

Comparative effects of sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors on new-onset atrial fibrillation and stroke outcomes

“…The risk of AF was numerically lower in all, and statistically lower in some clinical trials comparing SGLT2I users and controls. (16-19) A recent meta-analysis of 16 randomized controlled trials demonstrated a significant reduction of AF and atrial flutter amongst SGLT2I and placebo users. (20) Although findings from the Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic) study demonstrated an insignificant difference in stroke and atrial fibrillation between dapagliflozin and DPP4I users, their analysis did not adjust for clinical or biochemical confounders, nor a history of the two diseases respectively.…”