Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: A meta-analysis of 34 randomized controlled trials

Fernandes, Gilson; Fernandes, Amanda; Cardoso, Rhanderson; Peñalver, Jorge; Knijnik, Leonardo; Mitrani, Raul D.; Myerburg, Robert J.; Goldberger, Jeffrey J.

doi:10.1016/j.hrthm.2021.03.028

Cited by 140 publications

(106 citation statements)

References 41 publications

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“…Several major clinical cardiovascular outcome trials, such as the EMPA-REG outcome trial [ 2 ], CANVAS trial [ 20 ], DECLARE-TIMI 58 trial [ 21 ], and VERTIS-CV trial [ 22 ] have all shown that SGLT2 inhibitors can significantly reduce the risk of cardiovascular complications, cardiovascular mortality and heart failure hospitalizations in T2DM patients. The follow-up meta-analysis also supports these results and suggests that SGLT2 inhibitors are associated with reduced risks of incident atrial arrhythmias and sudden cardiac death in patients with T2DM [ 23 ]. More importantly, these beneficial cardioprotective effects have now been shown to extend to non-T2DM patients [ 24 ].…”

Section: Discussionmentioning

confidence: 72%

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death

et al. 2021

Cardiovasc Diabetol

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Background Empagliflozin is a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor used to lower blood sugar in adults with type 2 diabetes. Empagliflozin also exerts cardioprotective effects independent from glucose control, but its benefits on arrhythmogenesis and sudden cardiac death are not known. The purpose of this study was to examine the effect of empagliflozin on myocardial ischemia/reperfusion-provoked cardiac arrhythmia and sudden cardiac death in vivo. Methods Male Sprague Dawley rats were randomly assigned to sham-operated, control or empagliflozin groups. All except for the sham-operated rats were subjected to 5-min left main coronary artery ligation followed by 20-min reperfusion. A standard limb lead II electrocardiogram was continuously measured throughout the experiment. Coronary artery reperfusion-induced ventricular arrhythmogenesis and empagliflozin therapy were evaluated. The hearts were used for protein phosphorylation analysis and immunohistological assessment. Results Empagliflozin did not alter baseline cardiac normal conduction activity. However, empagliflozin eliminated myocardial vulnerability to sudden cardiac death (from 69.2% mortality rate in the control group to 0% in the empagliflozin group) and reduced the susceptibility to reperfusion-induced arrhythmias post I/R injury. Empagliflozin increased phosphorylation of cardiac ERK1/2 after reperfusion injury. Furthermore, inhibition of ERK1/2 using U0126 abolished the anti-arrhythmic action of empagliflozin and ERK1/2 phosphorylation. Conclusions Pretreatment with empagliflozin protects the heart from subsequent severe lethal ventricular arrhythmia induced by myocardial ischemia and reperfusion injury. These protective benefits may occur as a consequence of activation of the ERK1/2-dependent cell-survival signaling pathway in a glucose-independent manner.

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Section: Discussionmentioning

confidence: 72%

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death

et al. 2021

Cardiovasc Diabetol

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“…Among these patients, an SGLT2i has shown a reduced risk of worsening HF or death from cardiovascular causes regardless of the presence of diabetes 35 . It seems that SGLT2i are associated with significantly reduced risks of SCD in patients with type 2 diabetes mellitus 39 . Prospective trials are warranted to confirm the antiarrhythmic effect of SGLT2i.…”

Section: Preventionmentioning

confidence: 99%

Sudden cardiac death - a known unknown?

Obrova¹,

Sovová²,

Kociánová³

et al. 2022

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…Furthermore, no studies reported the use of sodium-glucose cotransporter-2 inhibitors, which has been considered one of the modern cornerstones of GDMT for HFrEF patients, regardless of diabetic status, and has also been associated with decrease in atrial arrhythmic events and SCD. 41 Lastly, we advise caution when interpreting the BiV pacing results, since this variable was reported from device interrogation without analysis of BiV pacing morphology or unipolar electrograms to confirm true BiV pacing.…”

Section: Limitationsmentioning

confidence: 99%

Sacubitril/valsartan versus angiotensin inhibitors and arrhythmia endpoints in heart failure with reduced ejection fraction

Fernandes

Ternes³

et al. 2021

Heart Rhythm O2

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BACKGROUND Angiotensin receptor-neprilysin inhibitor (ARNI) therapy has been associated with improved survival for patients with symptomatic heart failure and reduced ejection fraction (HFrEF).OBJECTIVES We performed a meta-analysis of arrhythmia endpoints from studies comparing ARNI with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with HFrEF to assess for incremental benefit. METHODSWe searched PubMed, Embase, and ClinicalTrials.gov. Baseline study characteristics were collected and outcomes were sustained ventricular arrhythmias, atrial arrhythmias, appropriate implantable cardioverter-defibrillator (ICD) therapy, sudden cardiac death (SCD), and biventricular (BiV) pacing rate. RESULTSWe included 9 studies, 4 randomized trials, and 5 observational studies (5589 patients on ARNI vs 5615 on ACEIs/ARBs). Follow-up ranged from 2 to 51 months. The mean age was 65.4 6 9.8 years, with 77.3% male patients and a mean ejection fraction of 29.0% 6 7.6%. Ischemic cardiomyopathy was present in 62% of patients. In the ARNI group, there were less SCD (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.63-0.96; P 5 .02), ventricular arrhythmias (OR 0.45, 95% CI 0.25-0.79; P 5 .005), and appropriate ICD therapy (OR 0.39, 95% CI 0.21-0.74; P 5 .004). Higher rates of BiV pacing were seen (mean difference 3.13, 95% CI 2.58-3.68; P , .00001) when compared with ACEIs/ARBs. No difference in atrial arrhythmias was seen.CONCLUSION ARNI therapy provides incremental benefit with respect to ventricular tachyarrhythmias/SCD, which may, in part, explain improved outcomes in patients with HFrEF compared to ACEIs/ARBs. There was increased BiV pacing and decreased ICD therapy in the ARNI group.

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Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: A meta-analysis of 34 randomized controlled trials

Cited by 140 publications

References 41 publications

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death

Sudden cardiac death - a known unknown?

Sacubitril/valsartan versus angiotensin inhibitors and arrhythmia endpoints in heart failure with reduced ejection fraction

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