Using SGLT-2 Inhibitors to Significantly Reduce AFib

Diabetes causes metabolic changes that promote oxidative stress within the heart, resulting in changes that can impede its electrical signaling and increase atrial fibrillation (AFib) risk – can SGLT-2 inhibitors help?

A recent study posted by Victor Okunrintemi et al. in Diabetes, Obesity, and Metabolism shows significant evidence that SGLT-2 inhibitors can lower the risk of developing atrial fibrillation.  

SGLT-2 inhibitors are a relatively new diabetic medication class that targets the sodium-glucose cotransporter-2 receptors in renal cells. Targeting this receptor results in increased excretion of glucose through the urine and decreased glucose reabsorption rates. Besides blood glucose management, studies have shown that SGLT-2 inhibitors also provide cardiovascular and renal benefits. 

Patients with diabetes mellitus often undergo various metabolic changes that promote oxidative stress within the heart, resulting in structural and mechanical changes that could impede electrical signaling within it, thus increasing the rate of atrial fibrillation. 

Recently in the DECLARE-TIMI 58 trial, it was shown that patients had a statistically lower rate of incidence of atrial fibrillation (by 19%) when taking the SGLT-2 inhibitor dapagliflozin compared to placebo (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68–0.95]; P=0.009).  

Due to this evidence, a meta-analysis of eight trials was conducted to include other SGLT-2 inhibitors such as empagliflozin and canagliflozin to see if this is a class-wide effect. The trials included in this meta-analysis were the EMPA‐REG OUTCOME trial, CANVAS, CANVAS‐R, the DECLARE‐TIMI 58 trial, CREDENCE, DAPA‐HF, VERTIS CV, and DAPA‐CKD. The study analyzed the rate of incidence of atrial fibrillation (often reported as a severe adverse event) in each of these trials and found that 0.9% (295 of 31,261) of individuals who used the SGLT-2 inhibitor reported atrial fibrillation or atrial flutter compared to 1.1% (291 of 24,705) of individuals who received the placebo. The study also showed significantly lower atrial fibrillation rates in patients with and without diabetes (RR 0.79, 95% CI 0.67-0.93). 

The selected trials focused on cardiovascular or renal outcomes and reported atrial fibrillation as a severe adverse event in the meta-analysis.  

The exact mechanism of action as to how SGLT-2 inhibitors exert an influence on the heart regarding atrial fibrillation is currently unknown. One theory suggests that because SGLT-2 inhibitors promote natriuresis/diuresis, this causes a reduction in atrial dilation, reducing structural and electrical remodeling within the heart. An additional theory proposed by Yurista et al. states that SGLT-2 inhibitors can promote mitochondria to function at higher levels and increase mitochondria levels. People with diabetes often have higher levels of dysfunctional mitochondria, which produces increased reactive oxygen species levels. These reactive oxygen species cause oxidative damage to the heart, causing structural remodeling and increased atrial fibrillation rates. A third theory proposes a link between epicardial fat, inflammation, and arrhythmias. Those SGLT-2 inhibitors could have a role in lowering levels of epicardial fat and inflammation, thus reducing atrial rates of fibrillation. An additional rationale for how SGLT-2 promotes lower rates of atrial fibrillation is its effect on magnesium excretion. Because SGLT-2 inhibitors work on ion channels within the distal convoluted tubule of the kidney, SGLT-2 inhibitors can increase serum magnesium levels. Since hypomagnesemia may increase the risk of atrial fibrillation, SGLT-2 inhibitors can positively affect patients with diabetes, especially considering that the use of insulin shifts magnesium intracellularly and could be an additional factor in both hypomagnesemia and AFib. Higher magnesium levels have also been shown to be beneficial by having anti-ischemic and anti-inflammatory effects on the heart. Perhaps multiple facets of each of the above theories contribute slightly to reducing atrial fibrillation rates in patients with diabetes.  

Although there was a significantly lower incidence of atrial fibrillation in patients who used an SGLT-2 inhibitor, additional studies will be needed to see any clinical significance to these findings.  

PRACTICE PEARLS: 

• Metabolic changes caused by diabetes mellitus can cause oxidative stress to the heart, resulting in remodeling that can impede electrical signaling and increase atrial fibrillation rates. 
• SGLT-2 inhibitors, a newer class of antidiabetic drugs, can have both renal and cardiovascular benefits.  
• A recent meta-analysis of eight trials of SGLT-2 inhibitors found a significant difference in rates of fibrillation between the SGLT-2 inhibitor group (0.9%) compared to the placebo group (1.1%) (RR 0.79, 95% CI 0.67-0.93) 

References for “Using SGLT-2 Inhibitors to Significantly Reduce AFib”:

Baranwal, Medha.”SGLT2 Inhibitors Lowers Risk of Atrial Fibrillation“ Jan. 2021.  

Okunrintemi, Victor, et al. “Sodium‐Glucose Co‐Transporter‐2 Inhibitors and Atrial Fibrillation in the Cardiovascular and Renal Outcome Trials“.  

Wiviott, S. D., Raz, “Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.“  

Yurista, S. R., Silljé, “Sodium-glucose cotransporter 2 inhibition as a mitochondrial therapy for atrial fibrillation in patients with diabetes“  

Zelniker, T. A., Bonaca “Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus.“  

Adrian Gavre, PharmD Candidate, Philadelphia College of Osteopathic Medicine