A post hoc analysis of the DECLARE-TIMI 58 trial may provide a new compelling indication for dapagliflozin in reducing atrial fibrillation risk.
The recent phase III, randomized, double-blind, placebo-controlled DECLARE-TIMI 58 trial found that the SGLT2 inhibitor dapagliflozin significantly reduced the risk of hospitalization for heart failure (HHF) in patients with diabetes and established ASCVD or multiple ASCVD risk factors. In the post hoc subgroup analysis of the DECLARE-TIMI 58 trial by Zelniker et al. discussed here, researchers explored whether dapagliflozin reduced the risk of atrial fibrillation (AF) and atrial flutter (AFL). While the exact mechanism by which SGLT2 inhibitors exact their cardiac effects is unknown, the authors postulate that “mitigation of inflammation, endothelial and left ventricular dysfunction, and improved glucose control may improve atrial remodeling and thereby favorably impact the incidence of AF/AFL.“
The primary outcome of the post hoc analysis was the overall incidence of AF/AFL. To gain a complete understanding of the effects of dapagliflozin on AF/AFL, the researchers conducted sensitivity analyses on AF/AFL events that: met criteria as serious adverse events, were associated with hospitalization, were not followed or preceded by an HHF within 14 days, and occurred in patients who were not hospitalized for HF at any point during the trial. Subgroups identified and analyzed were: patients with or without ASCVD, history of HF, history of AF/AFL, age (<70,≥70), sex, HbA1c (<8%,≥8%), BMI (<30, ≥30 kg/m2), SBP (<135, ≥135), and eGFR (<60, 60-90, >90 mL/min/1.73m2).
Dapagliflozin reduced the incidence of AF/AFL events by 19% compared to the placebo. Sensitivity analysis confined to AF/AFL events that met criteria as severe adverse events found similar results (HR: 0.79; CI: 0.63-0.99) and were also similar when confined to events associated with hospitalization (HR: 0.77; CI: 0.60-0.98). Due to AF/AFL often co-presenting with HF, researchers conducted analyses restricting AF/AFL events to those not followed or preceded by HHF within 14 days and also in patients not hospitalized for HF at any point to determine if dapagliflozin decreased AF/AFL independently of HF. AF/AFL incidence was found to be similar to the overall incidence of AF/AFL when looking at events not followed or preceded by HHF within 14 days (HR: 0.82; CI: 0.69-0.97) and also in events occurring in patients not hospitalized for HF at any point. In the subgroup analyses, the incidence of AF/AFL did not differ amongst the groups: previous AF/AFL (HR: 0.79; CI: 0.58-1.09) vs. no AF/AFL at baseline (HR: 0.81; CI: 0.67-0.98), presence of ASCVD (HR: 0.83; CI: 0.66-1.04) vs. multiple risk factors for ASCVD (HR: 0.78; CI: 0.62-0.99), history of HF (HR: 0.78; CI 0.55-1.11) vs. no history of HF (HR: 0.81; CI 0.68-0.97). The analysis also found no treatment effect differences when stratifying groups based on age, sex, HbA1c, BMI, SBP, or eGFR.
Notable limitations to this post hoc analysis include AF/AFL not being a prespecified outcome of the original trial. Consequently, researchers did not collect electrocardiograms as they were not required, AF/AFL events were not confirmed by central adjudication, AF/AFL events not classified as severe or led to study drug discontinuation were not required to be reported, and also Holter-monitoring and serial electrocardiograms were not needed. These limitations prevented the quantification of the AF/AFL burden. Despite these limitations, this analysis provides strong evidence that dapagliflozin is useful in primary and secondary prevention of AF/AFL in patients with diabetes and ASCVD or multiple risk factors for ASCVD. In clinical practice, this author’s opinion is that a patient with type 2 diabetes not at HbA1c goal and concomitant atrial fibrillation would benefit from the addition of dapagliflozin to their drug regimen.
- In patients with type 2 diabetes and ASCVD or ASCVD risk factors, dapagliflozin reduces the risk of developing atrial fibrillation and atrial flutter in the setting of primary and secondary prevention.
- The AF/AFL reducing effect of dapagliflozin persists across a broad population. Age, sex, HbA1c, body mass, eGFR, blood pressure, and comorbidities such as heart failure or ASCVD did not alter the AF/AFL risk lowering effect of dapagliflozin.
- While the mechanism of dapagliflozin’s cardiac effect isn’t completely understood, researchers believe it works through reduction of inflammation, improvement in left ventricular function, and improvement in atrial remodeling.
Wiviott, Stephen D et al. “Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes”
Zelniker, Thomas A, et al. “Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus.”
David Clarke, PharmD Candidate, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences