Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient

Abstract

Metformin has been shown to have various cardiovascular benefits beyond its antihyperglycemic effects, including a reduction in stroke, heart failure, myocardial infarction, cardiovascular death, and all-cause mortality. However, the roles of metformin in cardiac arrhythmias are still unclear. It has been shown that metformin was associated with decreased incidence of atrial fibrillation in diabetic patients with and without myocardial infarction. This could be due to the effects of metformin on preventing the structural and electrical remodeling of left atrium via attenuating intracellular reactive oxygen species, activating 5′ adenosine monophosphate-activated protein kinase, improving calcium homeostasis, attenuating inflammation, increasing connexin-43 gap junction expression, and restoring small conductance calcium-activated potassium channels current. For ventricular arrhythmias, in vivo reports demonstrated that activation of 5′ adenosine monophosphate-activated protein kinase and phosphorylated connexin-43 by metformin played a key role in ischemic ventricular arrhythmias reduction. However, metformin failed to show anti-ventricular arrhythmia benefits in clinical trials. In this review, in vitro and in vivo reports regarding the effects of metformin on both atrial arrhythmias and ventricular arrhythmias are comprehensively summarized and presented. Consistent and controversial findings from clinical trials are also summarized and discussed. Due to limited numbers of reports, further studies are needed to elucidate the mechanisms and effects of metformin on cardiac arrhythmias. Furthermore, randomized controlled trials are needed to clarify effects of metformin on cardiac arrhythmias in human.

Sudden Cardiac Death in Diabetes and Obesity: Mechanisms and Therapeutic Strategies

“…36,83 Metformin, a widely used anti-diabetic drug is considered to have potential beneficial effects beyond its antihyperglycemic action, and has been shown to ameliorate mitochondrial dysfunction, calcium dysregulation and repolarization abnormalities in animal models, in addition to decreasing plasma BCAA levels and activating AMPK. 84,85 However, whether these approaches also reduce arrhythmia risk remains to be investigated. Sodiumglucose cotransporter (SGLT2) inhibitors are now recommended as antidiabetic therapy, and have recently shown promising anti-arrhythmic effects in diabetic patients.…”

“…88 Drugs that modulate AMPK activity, such as for instance metformin and resveratrol, may also prove to have anti-arrhythmic effects. 71,85 As reviewed by Ren et al, 36 additional potential strategies include those targeting autophagy, adiponectin, inflammation (NF-kB, cytokines, TGF-beta), PPARɣ, as well as epigenetically based pharmacotherapies inhibiting DNA methyltransferases and histone deacetylases. However, their anti-arrhythmic effects remain as yet unexplored.…”

Metformin in the management of patients with diabetes and advanced heart failure (HFrEF): a propensity score-matched analysis

“…(46) A direct antiarrhythmic effect of MET has been postulated as well. (47) Although QoL was independent of DM status in our study, we have observed a better QoL in MET-treated DM patients and MET was signi cantly associated with QoL also in multivariable linear regression suggesting its independent effect on QoL. To our best knowledge, this is the rst study that analyzed the QoL with respect to MET treatment using a validated tool.…”

Pathophysiological aspects of insulin resistance in Atrial Fibrillation: novel therapeutic approaches

“…Metformin has many benefits in the case of cardiovascular protection such as left ventricular mass, myocardial infarction, cardiovascular death, reduction in blood pressure, heart failure, stroke, and all-cause mortality [39]. It also increases ketone body metabolism, promotes fatty acid oxidation, reduces lipid accumulation, induces the expression of glucose transporter in cardiomyocytes, all of which happened due to the activation of 5′-adenosine monophosphate-activated protein kinase, and it also facilitated efficient energy use with reduction of metabolic stress [40,41].…”

“…To decrease the incidence of AF in diabetic patients with and without myocardial infarction, metformin was associated to prevent the structural and electrical remodeling of the left atrium through improving calcium homeostasis, attenuating inflammation, activating 5′ adenosine monophosphate-activated protein kinase, increasing connexin-43 gap junction expression, attenuating intracellular reactive oxygen species, restoring small conductance calcium-activated potassium channels current [39]. Metformin is recommended for the treatment of type 2 diabetes mellitus and exerts an insulin-sensitizing effect [42] and might have anticancer, anti-inflammatory and antimicrobial and antiaging effects [43][44][45][46].…”