Association of Metformin With Lower Atrial Fibrillation Risk Among Patients With Type 2 Diabetes Mellitus

A Population-Based Dynamic Cohort and In Vitro Studies

Shang-Hung Chang; Lung-Sheng Wu; Meng-Jiun Chiou; Jia-Rou Liu; Kuang-Hui Yu; Chang-Fu Kuo; Ming-Shien Wen; Wei-Jan Chen; Yung-Hsin Yeh; Lai-Chu See

Disclosures

Cardiovasc Diabetol. 2014;13(123) 

In This Article

Abstract and Introduction

Abstract

Background: Atrial fibrillation (AF), an inflammatory process involving arrhythmia, is associated with severe morbidity and mortality and commonly seen in patients with diabetes mellitus (DM). The effect of metformin, the most commonly used medication for patients with DM, on AF has not been investigated. The primary aim of this study was to examine whether metformin prevented the occurrence of AF in type 2 DM patients by analyzing a nationwide, population-based dynamic cohort. Additionally, we investigated the effect of metformin on tachycardia-induced myolysis and oxidative stress in atrial cells.

Methods: The study population included 645,710 patients with type 2 diabetes and not using other anti-diabetic medication from a subset of the Taiwan National Health Insurance Research Database. Of these patients, those who used metformin were categorized as the user group, and the remaining were classified as the non-user group. The time-dependent Cox's proportional hazard model was used to examine the effect of metformin on AF and the status of metformin use was treated as a time-dependent covariate. HL-1 atrial cells were paced with or without metformin, and then troponin and heavy-chain-myosin were measured as markers of myolysis.

Results: After 13 years of follow-up, 9,983 patients developed AF with an incidence rate of 1.5% (287 per 100,000 person-years). After adjusting for co-morbidities and medications, metformin independently protected the diabetic patients from new-onset AF with a hazard ratio of .81 (95% confidence interval 0.76–0.86, p < 0.0001). Metformin significantly decreased the extent of pacing-induced myolysis and the production of reactive oxygen species.

Conclusion: Metformin use was associated with a decreased risk of AF in patients with type 2 DM who were not using other anti-diabetic medication, probably via attenuation of atrial cell tachycardia-induced myolysis and oxidative stress.

Introduction

Atrial fibrillation (AF) is the most common tachyarrhythmia and is associated with severe morbidity and mortality in clinical practice. The mechanisms underlying AF are extremely complex, and the current strategy for treating and preventing AF is suboptimal.[1,2] Risk factors for AF include old age, male gender, hypertension, valvular disease, congestive heart failure, and diabetes mellitus (DM). Increasingly, evidence has suggested that inflammation is involved with the pathogenesis of AF associated with DM.[3–6] Metformin, the most commonly used first-line anti-diabetic agent, has been shown to attenuate inflammatory responses and oxidative stress in diabetic patients independent of the anti-hyperglycemic effect.[7–14] AF has been shown to increase oxidative stress and induce structural remodeling in atrial myocytes, including degradation of myofibrils and glycogen deposition (also known as myolysis).[15]

We hypothesized that metformin might provide protection against AF. By analyzing data obtained from a representative dynamic cohort of patients with diabetes in Taiwan, the present study aimed to determine whether or not metformin prevented new onset AF. Two of the advantages of a dynamic cohort (where patients can be recruited at different times) are that the number of participants does not decline over time, and that the aging of study participants over time does not weaken the study. The database used in this study contained a large sample size and provided an excellent opportunity to study the association between metformin use and the occurrence of AF. Additionally, we investigated 1) the effect of metformin on the inhibiting of the generation of reactive oxygen species (ROS), and 2) the attenuation of myolysis induced by tachypacing in atrial cells.

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