Antiarrhythmic effects of metformin

Abstract

Atrial fibrillation/flutter (AF) is a major public health problem and is associated with stroke, heart failure, dementia, and death. It is estimated that 20%-30% of Americans will develop AF at some point in their life. Current medications to prevent AF have limited efficacy and significant adverse effects. Newer and safer therapies to prevent AF are needed. Ventricular arrhythmias are less prevalent than AF but may have significant consequences including sudden cardiac death. Metformin is the most prescribed, first-line medication for treatment of diabetes mellitus (DM). It decreases hepatic glucose production but also reduces inflammation and oxidative stress. Experimental studies have shown that metformin improves metabolic, electrical, and histologic risk factors associated with AF and ventricular arrhythmias. Furthermore, in large clinical observational studies, metformin has been associated with a reduced risk of AF in people with DM. These data suggest that metformin may have antiarrhythmic properties and may be a candidate to be repurposed as a medication to prevent cardiac arrhythmias. In this article, we review the clinical observational and experimental evidence for the association between metformin and cardiac arrhythmias. We also discuss the potential antiarrhythmic mechanisms underlying this association. Repurposing a well-tolerated, safe, and inexpensive medication to prevent cardiac arrhythmias has significant positive public health implications.

Keywords: Arrhythmia; Atrial fibrillation; Metformin; Prediabetes; Ventricular fibrillation; Ventricular tachycardia.

Figure 1

Putative antiarrhythmic benefits of metformin. AMPK = adenosine monophosphate-activated protein kinase; IL-6 = interleukin 6; NFκB = nuclear factor kappa-B; PPARγ = peroxisome proliferator-activated receptor-gamma; SERCA2a = sarco(endo)plasmic reticulum Ca²⁺ adenosine triphosphatase; TGF-β = transforming growth factor-beta; TNF-α = tumor necrosis factor-alpha. Created with BioRender.com.

Figure 2

Pharmacoepidemiologic validation of metformin in reducing atrial fibrillation (AF) occurrence odds ratio (OR) and 95% confidence interval (CI) for metformin vs combination of the 4 drug groups (all: dipeptidyl peptidase-4 sulfonylurea [DPP4], thiazolidinedione [TZD], sulfonylurea, and glucagon-like peptide 1 receptor agonist [GLP1RA]) (n = 3578) (A), DPP4 (n = 1244) (B), sulfonylurea (n = 2352) (C), and TZD (n = 288) (D). For each of the 4 comparisons, the results for comparisons between subgroups (including female, male, Black, and White) are also shown. Patient groups were matched using propensity score matching with the variables age, gender, race, and comorbidities for the overall group comparisons. For the subgroup of male and female, the matching variables excluded gender, and for the subgroup Black and White, the matching variables excluded race. Logistic regression models were used for statistical inference of the AF ORs. Subgroup analyses were performed in females (orange), males (green), Black Americans (dark green), and White Americans (blue).P <.05. (Lal et al. Reprinted with permission.)

Figure 3

Association of metformin monotherapy with arrhythmias compared to other medications for treatment of diabetes mellitus. Abbreviations as in Figure 2. (Ostropolets et al. Reprinted with permission.)

Figure 4

Kaplan-Meier survival curves of ventricular arrhythmias and sudden cardiac death associated with metformin vs sulfonylurea. CI = confidence interval; HR = hazard ratio; SCD = sudden cardiac death; VA = ventricular arrhythmia. (Lee et al. Reprinted with permission.)