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Cited by 228Atrial Fibrillation Management and OutcomesDiabetes Treatment and ManagementMetabolism, Diabetes, and Cancer

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Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies

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Chang, Shang-Hung, Wu, Lung-Sheng, Chiou, Meng-Jiun, Liu, Jia-Rou, Yu, Kuang-Hui, Kuo, Chang-Fu, Wen, Ming-Shien, Chen, Wei-Jan, Yeh, Yung-Hsin, See, Lai-Chu·2014·Cardiovascular Diabetology
DOI 10.1186/s12933-014-0123-xPMC PMC4149273
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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.

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Figure 1 Flowchart of subject selection.
Figure 1 Flowchart of subject selection.CC BY · PubMed Central
Figure 2 Atrial fibrillation (AF) incidence (per 100,000 person-years) vs. DM duration by use of metformin among DM patients, Taiwan 1999–2010.
Figure 2 Atrial fibrillation (AF) incidence (per 100,000 person-years) vs. DM duration by use of metformin among DM patients, Taiwan 1999–2010.CC BY · PubMed Central
Figure 3 AF-free survival rate (n = 645,710) for diabetic patients with and without metformin use. AF = atrial fibrillation. Solid line is for the metformin users and broken line is for the non-users (p < 0.0001).
Figure 3 AF-free survival rate (n = 645,710) for diabetic patients with and without metformin use. AF = atrial fibrillation. Solid line is for the metformin users and broken line is for the non-users (p < 0.0001).CC BY · PubMed Central
Figure 4 HL-1 cells were paced at 4Hz for 24 hours. Figure 4 shows that tachypacing induced intracellular oxidative stress from ROS in atrial myocytes and that metformin reversed this effect. Tachycardia induced myofibril degradation quantified by myosin heavy chain and troponin-I were also rescued by metformin of 1 mM.
Figure 4 HL-1 cells were paced at 4Hz for 24 hours. Figure 4 shows that tachypacing induced intracellular oxidative stress from ROS in atrial myocytes and that metformin reversed this effect. Tachycardia induced myofibril degradation quantified by myosin heavy chain and troponin-I were also rescued by metformin of 1 mM.CC BY · PubMed Central

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Authors
Chang, S.-H., Wu, L.-S., Chiou, M.-J., Liu, J.-R., Yu, K.-H., Kuo, C.-F., Wen, M.-S., Chen, W.-J., Yeh, Y.-H., & See, L.-C.
Affiliations
  • Chang Gung University (TW)
  • Chang Gung Memorial Hospital (TW)
Corresponding author
  • Yeh, Yung-Hsin
  • See, Lai-Chu
ORCID
Venue
Cardiovascular Diabetology
Publisher
Springer Science and Business Media LLC
Published
2014-08-10
Volume
13
Issue
1
Pages
123-123
ISSN
1475-2840 (ISSN-L)
DOI
10.1186/s12933-014-0123-x
PMC
PMC4149273
OpenAlex
W2150052417
Cited by
225
References
31
Citations by year
2026: 11 · 2025: 13 · 2024: 24 · 2023: 22 · 2022: 32 · 2021: 27 · 2020: 27 · 2019: 21 · 2018: 13 · 2017: 14 · 2016: 12 · 2015: 9
FWCI
8.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Cardiovascular Diabetology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Health Research Institutes
  • National Health Insurance Administration
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
metformin, atrial fibrillation, type 2 diabetes, oxidative stress, reactive oxygen species, atrial myocytes, HL-1 cells, antiarrhythmic effect, atrial arrhythmias
MeSH terms
Adult, Aged, Atrial Fibrillation, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Longitudinal Studies, Male, Metformin, Middle Aged, Population Surveillance, Risk Factors, Cohort Studies

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