Anti-arrhythmic effects of SGLT2 inhibitors 'may be an alias for improving heart failure'
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SGLT2 inhibitors may directly or indirectly impact factors associated with diabetes and atrial fibrillation/atrial flutter, according to a speaker at the Heart in Diabetes CME Conference.
Stephen D. Wiviott, MD, senior investigator and chairman of the clinical events committee with the TIMI Study Group, cardiovascular medicine specialist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, discussed the potential anti-arrhythmic effects of SGLT2 inhibitors, as observed in several large clinical trials and subsequent post hoc and meta-analyses.
“The pathophysiology that may causally link diabetes with atrial arrhythmias is not fully known, but has several potential mechanisms, and that includes structural changes in the heart; electric, magnetic, energetic and mechanical myocardial remodeling; and potentially an imbalance in sympathetic and parasympathetic tone,” Wiviott said during a presentation. “SGLT2 inhibitors have been shown to affect several of the things that seem to be related to diabetes and atrial fibrillation: lowering blood pressure, reducing weight and having some beneficial effects on left ventricular remodeling. So, we hypothesized that SGLT2 inhibitors may have a favorable effect on atrial fibrillation.”
As Healio previously reported, the DECLARE-TIMI 58 trial found that dapagliflozin (Farxiga, AstraZeneca) for patients with diabetes led to a 17% lower risk for the coprimary composite efficacy endpoint of CV death or heart failure hospitalization, compared with placebo.
It was also observed that dapagliflozin lowered the risk for renal specific outcomes in DECLARE-TIMI 58 (HR = 0.53; 95% CI, 0.43-0.66; P < .001).
In a subgroup analysis published in Circulation, participants in the dapagliflozin arm experienced lower risk for incident atrial fibrillation/atrial flutter compared with the placebo group (3.7% vs. 3%; HR = 0.81; 95% CI, 0.68-0.95; P = .009). These findings were consistent regardless of baseline characteristics such as age, sex, systolic BP, HbA1c, BMI or estimated glomerular filtration rate, as well as prior histories of atrial fibrillation, atherosclerotic CVD or heart failure.
Not only was dapagliflozin associated with lower risk for a first-time atrial fibrillation event, Wiviott said, it reduced the risk for additional atrial fibrillation events thereafter (incidence rate ratio = 0.67; 95% CI, 0.44-1.01).
“Certainly, there are some limitations in this analysis that we should all be aware of. It was post hoc,” Wiviott said during the presentation. “We did not have this as a prespecified hypothesis at the time of initiation of the trial and, as you would do in an atrial fibrillation trial, ECGs were not systematically collected. These were reports from the investigators [on atrial fibrillation occurrence] and were not prespecified outcomes, as in, we did not specifically ask them to report atrial fibrillation or atrial flutter on all occasions.”
However, post hoc analyses of DECLARE-TIMI 58 are not the only insight available into the anti-arrhythmic effects of SGLT2 inhibitors.
Wiviott cited a post hoc and meta-analysis by Zhao and colleagues in which researchers observed a trend for fewer atrial fibrillation/atrial flutter events among patients in the canagliflozin (Invokana, Janssen) group compared with placebo (HR = 0.76; 95% CI, 0.53-1.1; P = .02).
As Healio previously reported, canagliflozin lowered the risk for kidney failure and prevented CV events in patients with diabetes and chronic kidney disease, according to data from the CREDENCE trial presented at the International Society of Nephrology’s World Congress of Nephrology Annual Meeting in 2019.
In another meta-analysis that included both DECLARE-TIMI 58, CREDENCE and six other large randomized trials, Okunrintemi and colleagues reported that SGLT2 inhibitors were associated with an approximately 21% risk reduction for atrial fibrillation/atrial flutter, compared with placebo (HR = 0.79; 95% CI, 0.67-0.93).
“What are the mechanisms by which this reduction in the atrial fibrillation or atrial flutter be occurring? We’ve broken it into two possibilities,” Wiviott said. “Indirect cardiovascular effects such as decongestant effects; less left atrial stretch; blood pressure lowering, which may result in less left ventricular strain; weight loss; and the possibility that there could be some direct effect related to glucose lowering. Direct cardiac effects from SGLT2 inhibitors may include cardiac remodeling; a reduction in sympathetic overdrive; reductions in oxidative stress and inflammation; and reductions in epicardial fat.”
Unrelated to atrial fibrillation/atrial flutter, new data from the DAPA-HF trial presented at the 2021 European Society of Cardiology Congress, suggest that dapagliflozin may also lower the risk for ventricular arrhythmias, cardiac arrest and sudden cardiac death (HR = 0.79; 95% CI, 0.63-0.99; P =.037).
“Certainly, much of this may be an alias for improving heart failure, but what we’re developing here is a thesis on the reduction of arrhythmias as a complication of cardiovascular disease and diabetes,” Wiviott said. “I would caution that these are secondary and post hoc analysis of published clinical trials, and so directed prospective trials would be needed to rigorously determine the effect of SGLT2 inhibitors on atrial fibrillation.”
References:
- Curtain JP, et al. Eur Heart J. 2021;doi:10.1093/eurheartj/ehab560.
- Okunrintemi V, et al. Diabetes Obes Metab. 2021;doi:10.1111/dom.14211.
- Zelniker TA, et al. Circulation. 2020;doi:10.1161/CIRCULATIONAHA.119.044183.
- Zhao Z, et al. Stroke. 2021;doi:10.1161/STROKEAHA.120.031623.
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Wiviott SB. Joint Symposium with Circulation. Presented at: Heart in Diabetes Annual Meeting; Sept. 10-12, 2021 (hybrid meeting).
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