https://orcid.org/0009-0004-4891-9742
Figures & data
Table 1 Pharmacokinetic Properties of Metformin
Figure 1 Papers published for the period 1974–2023 that include terms for metformin and atrial fibrillation.
Note: Created with BioRender.com.
Figure 2 Putative pathways for activation of AMPK by metformin.
Notes: Putative mechanisms for the activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin. One pathway is via the inhibition of mitochondrial complex I of the electron transport chain (see El-Mir et al 2000; Owen et al 2000Citation95,Citation96). Inhibition of complex 1 results in an increase in the ratio of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which in turn results in the activation of AMPK. Some studies indicate a role for the upstream candidate serine/threonine kinase 11 (STK11) (also known as liver kinase B1 (LKB1)). Metformin effects via LKB1, a tumor suppressor, and the DNA-damage sensor, ATM (Ataxia Telangiectasia Mutated gene), which encodes for phosphatidylinositol 3/phosphatidylinositol 4 (PI3/PI4)-kinases, may contribute to the putative beneficial effects of metformin to reduce the risk of a number of cancers.Citation11,Citation77,Citation85–90 Another alternative pathway is activation of AMPK via a mechanism dependent on the expression of the Nuclear Receptor Subfamily 4 Group A Member 1, NR4A1 (also referred to Nur77), and subsequent activation of the STK11/AMPK signaling cascade.Citation94 Created with BioRender.com.
Figure 3 Downstream effects of metformin on metabolism.
Notes: Conflicting evidence suggests that metformin activates adenosine monophosphate-activated protein kinase (AMPK) either directly, or indirectly via the upstream serine-threonine liver kinase B1 (LKB1), or via ataxia telangiectasia mutated (ATM). AMPK, sometimes referred to as the “fuel gauge” of the cell, in addition to reducing hepatic gluconeogenesis also induces fatty acid β-oxidation, insulin signalling and mitochondrial biogenesis, and inhibits the synthesis of triglycerides, fatty acids and cholesterol. High levels of metformin may also reduce the expression of CYP3A4. Additionally, via its anti-hyperglycemic actions metformin protects against diabetic cardiomyopathy. In skeletal muscle, AMPK actions result in the increased translocation of Glucose Transporter Type 4 (GLUT4) to the plasma membrane, thereby increasing glucose uptake.Citation105 Created with BioRender.com.
Table 2 Search Strategy Used on Embase. The Search Was Based on “Metformin and AF and Diabetes and (Clinical Trials or Reviews)”. Total Number of Studies Used Was = 196 After Removing Duplicates (n = 3)
Table 3 Summary of clinical studies evaluating the effects of metformin in patients with AF.
Figure 4 Putative sites of action of metformin that contribute to its protective action against AF.
Notes: (A) (Endothelial function): Metformin, via activation of adenosine monophosphate-activated protein kinase (AMPK) increases the bioactivity of endothelial nitric oxide synthase (eNOS) thereby increasing the generation of nitric oxide (NO). Metformin also reduces hypercoagulability and facilitates fibrinolysis by decreasing plasminogen activator inhibitor-1 (PAI-1) and increasing Tissue Plasminogen Activator (TPA). Additionally, metformin reduces endothelial dysfunction by inhibiting the production of Reactive Oxygen Species (ROS) and Advanced Glycation End-Products (AGE), as well as endothelial lipotoxicity. Lastly, metformin, in part via its vascular protective effects, reduces the risk of stroke. (B) (Connexins): Metformin activation AMPK which results not only in beneficial effects on glucose regulation and insulin resistance but also results in increase in the expression of Zonula Occludens-1 (ZO-1) and its interaction with and expression of connexin 43 (Cx43). (C) (Cardiac Dysmetabolism): Metformin, via its activation of AMPK, increases fatty acid and glucose uptake and fatty acid β-oxidation, while improving calcium homeostasis. Metformin also activates Peroxisome Proliferator-Activated Receptor α (PPARα) either directly or through AMPK, to increase fatty acid β-oxidation by increasing the activity of Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD). In addition, metformin reduces triglyceride and fatty acid levels in the body and inhibits the accumulation of lipids in the left atrial (LA) appendage and the infiltration of lipids in the diabetic heart. (D) (Ion Channels): Metformin activation of AMPK results in the inhibition of the opening of ATP-sensitive potassium (KATP) channels, and it also increases the expression of voltage-gated sodium channels (Nav1.5) by activating serine/threonine kinase 11 (STK11/LKB11) (also known as liver kinase B1 (LKB1)), either through AMPK activation or its direct effect on Nav1.5 expression.Citation35 (E) (Adenosine): Metformin activation of AMPK leads to an increase in intracellular adenosine which has cardioprotective effects via the adenosine A1 receptor. (F) (Oxidative Stress, Inflammation and Apoptosis): Metformin activation of AMPK via the STK11/LKB1 pathway results in the activation of eNOS, and increased production of catalase and superoxide dismutase which reduces ROS, and inhibits apoptosis. Metformin also decreases the generation of pro-inflammatory cytokines and inflammatory including Tumor Necrosis Factor-α (TNF- α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), C-Reactive Protein (CRP), Monocyte Chemoattractant Protein-1 (MCP-1), and Nuclear Factor-κB (NF-κB) and induces the polarization of macrophages towards anti-inflammatory M2 subtype over the pro-inflammatory M1 subtype).Citation35,Citation105,Citation175 Created with BioRender.com.
Figure 5 Metformin reverses pathological remodeling.
Notes: Putative targets for metformin to reverse pathological cardiac remodeling. (A) (Structural Remodeling): Metformin activation of adenosine monophosphate-activated protein kinase (AMPK) results in improved energy balance, improved mitochondrial function, inhibition of fibrosis, and reduced generation of Reactive Oxygen Species (ROS). AMPK also corrects gap junction expression and improves cell-to-cell coupling. Metformin reduces the generation of pro-inflammatory mediators leading to reduction in fibrosis and degradation of myofibrils in the diabetic heart. Lastly, metformin also reduces the production of Advanced Glycation End-Products (AGE) and Receptors for Advanced Glycation End-Products (RAGE) by counteracting hyperglycemia, which also reduces ROS and tissue fibrosis. (B) (Electrical Remodeling): In animal models as well as in humans metformin reduces electrical remodeling by improving ionic homeostasis via the activation of AMPK. (C) (Electromechanical Remodeling): Metformin has direct effects to improve ionic homeostasis and inhibit fibrosis and reduce electromechanical remodeling. (D) (Autonomic Remodeling): Metformin, via its anti-diabetes actions, reduces the risk of autonomic neuropathy thereby reducing remodeling of the heart.Citation116,Citation166,Citation168–170 Created with BioRender.com.
Figure 6 Metformin as a treatment for AF.
Notes: In this schematic metformin is depicted to have multiple beneficial effects that collectively lower the risk of AF and arguably justify its repurposing as an adjunct therapeutic drug for the treatment of atrial fibrillation (AF). A long history of clinical use indicates that metformin, via its antihyperglycemic and insulin sensitizing actions, is a safe drug for the treatment of type 2 diabetes that unlike sulfonylureas and insulin is not associated with the risk of hypoglycemia. These actions as an anti-diabetes agent may entirely explain metformin’s putative benefits in AF including the reduction of oxidative stress, cardiac metabolism dysregulation, inflammation and decreased fibrosis and structural remodeling; however, pleiotropic actions of metformin may also contribute. An accumulation of evidence supports the hypothesis that metformin’s cellular actions are mediated, at least in part, via the activation of 5’ adenosine monophosphate-activated protein kinase (AMPK), either directly or via activation of upstream kinases such as liver kinase B1 (LKB1). AMPK has multiple downstream targets that include: (i) Effects on cardiac connexins and ion channels that can improve electrical conduction in the heart. (ii) Enhanced activity of endothelial nitric oxide synthase (eNOS) and generation of nitric oxide (NO) that has multiple positive effects to improve endothelial function and reduce cardiac and vascular dysfunction that collectively can reduce the risk of AF. (iii) A reduction of oxidative stress in part via its antihyperglycemic actions and beneficial effects on fatty acid uptake and metabolism in the heart as well as also via direct effects on mitochondrial function. (iv) Collectively, these actions result in a reduced inflammation, and beneficial effects to offset atrial remodeling. Created with BioRender.com.
