Metformin and Lower AF Risk Among Patients With T2DM
From 1999 to 2010, 645,710 patients who were newly diagnosed type 2 DM, were not using insulin, were older than 18 years, and had not used other oral anti-diabetics were enrolled in this study. The mean follow-up duration was 5.4 years. Within the first year of DM diagnosis, 85,198 (13.2%) patients used metformin and 560,512 patients (86.8%) did not. The mean age of the study population was 58.6 ± 17.1 years, and males accounted for 49.8% of the patients. The demographic characteristics, relevant co-morbidities, and medications used in the first and ≥10th year after the diagnosis of DM are shown in Table 1. During the follow-up period after the diagnosis of DM, the metformin group had higher incidences of hypertension and sleep apnea syndrome, while the non-user group had higher incidences of congestive heart failure, chronic kidney disease, asthma, myocardial infarction, stroke, and peripheral arterial disease. In general, anti-hypertensive drugs were commonly used among the patients with DM, and the proportion increased from 62.8% to 70.7% during the follow-up period. Statins were the second most commonly used drug, with an increase in prevalence from 20.5% to 27.8%. The metformin group took more anti-hypertensives and statins than the non-user group (Additional file 1: Supplement 3 http://www.cardiab.com/content/13/1/123/additional).
The overall AF rate was 287 per 100,000 person-years, and the AF rate for the metformin user group was significantly lower than that of the nonuser group (245 for metformin users and 293 for nonusers, p < 0.0001). From the first to the second year after the diagnosis of DM, the metformin group had significantly lower incidence rates of AF than the non-user group (Figure 2). Figure 3 demonstrates Kaplan-Meier curves of the AF-free survival rates among the diabetic patients who did and did not use metformin. The metformin group had a significantly higher cumulative AF-free rate during the 13 years of follow-up than the non-user group (p < 0.001).
(Enlarge Image)
Figure 2.
Atrial fibrillation (AF) incidence (per 100,000 person-years) vs. DM duration by use of metformin among DM patients, Taiwan 1999–2010.
(Enlarge Image)
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).
Unadjusted and adjusted HRs of AF calculated by Cox multivariate regression analyses are presented in Table 2. After adjusting for age, sex, hypertension, congestive heart failure, chronic kidney disease, asthma, myocardial infarction, ischemic stroke, peripheral arterial disease, the use of anti-hypertensives, and statins, the metformin group had a significantly lower AF occurrence rate with a HR of 0.81 (95% CI 0.76–0.86, p < 0.001).
A large body of evidence suggests that there is a link between oxidative stress and AF. During tachyarrhythmia, substantial oxidative damage and cellular (ionic and structural) remodeling occurs in atrial myocardium that can induce AF. We used MHC and troponin I degradation in cultured HL-1 atrial myocytes to evaluate the effects of metformin on preventing tachycardia-induced oxidative stress and on reducing the extent of cellular remodeling. HL-1 cells were paced at 4 Hz for 24 hours. Figure 4 shows that tachypacing induced intracellular oxidative stress from reactive oxygen species (ROS) in atrial myocytes, and that metformin reversed this effect. Tachycardia-induced myofibril degradation quantified by MHC and troponin-I was also rescued by 1 mM of metformin.
(Enlarge Image)
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.
Results
Cohort Study
From 1999 to 2010, 645,710 patients who were newly diagnosed type 2 DM, were not using insulin, were older than 18 years, and had not used other oral anti-diabetics were enrolled in this study. The mean follow-up duration was 5.4 years. Within the first year of DM diagnosis, 85,198 (13.2%) patients used metformin and 560,512 patients (86.8%) did not. The mean age of the study population was 58.6 ± 17.1 years, and males accounted for 49.8% of the patients. The demographic characteristics, relevant co-morbidities, and medications used in the first and ≥10th year after the diagnosis of DM are shown in Table 1. During the follow-up period after the diagnosis of DM, the metformin group had higher incidences of hypertension and sleep apnea syndrome, while the non-user group had higher incidences of congestive heart failure, chronic kidney disease, asthma, myocardial infarction, stroke, and peripheral arterial disease. In general, anti-hypertensive drugs were commonly used among the patients with DM, and the proportion increased from 62.8% to 70.7% during the follow-up period. Statins were the second most commonly used drug, with an increase in prevalence from 20.5% to 27.8%. The metformin group took more anti-hypertensives and statins than the non-user group (Additional file 1: Supplement 3 http://www.cardiab.com/content/13/1/123/additional).
The overall AF rate was 287 per 100,000 person-years, and the AF rate for the metformin user group was significantly lower than that of the nonuser group (245 for metformin users and 293 for nonusers, p < 0.0001). From the first to the second year after the diagnosis of DM, the metformin group had significantly lower incidence rates of AF than the non-user group (Figure 2). Figure 3 demonstrates Kaplan-Meier curves of the AF-free survival rates among the diabetic patients who did and did not use metformin. The metformin group had a significantly higher cumulative AF-free rate during the 13 years of follow-up than the non-user group (p < 0.001).
(Enlarge Image)
Figure 2.
Atrial fibrillation (AF) incidence (per 100,000 person-years) vs. DM duration by use of metformin among DM patients, Taiwan 1999–2010.
(Enlarge Image)
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).
Unadjusted and adjusted HRs of AF calculated by Cox multivariate regression analyses are presented in Table 2. After adjusting for age, sex, hypertension, congestive heart failure, chronic kidney disease, asthma, myocardial infarction, ischemic stroke, peripheral arterial disease, the use of anti-hypertensives, and statins, the metformin group had a significantly lower AF occurrence rate with a HR of 0.81 (95% CI 0.76–0.86, p < 0.001).
Metformin Attenuated Tachycardia-induced Oxidative Stress and Atrial Remodeling
A large body of evidence suggests that there is a link between oxidative stress and AF. During tachyarrhythmia, substantial oxidative damage and cellular (ionic and structural) remodeling occurs in atrial myocardium that can induce AF. We used MHC and troponin I degradation in cultured HL-1 atrial myocytes to evaluate the effects of metformin on preventing tachycardia-induced oxidative stress and on reducing the extent of cellular remodeling. HL-1 cells were paced at 4 Hz for 24 hours. Figure 4 shows that tachypacing induced intracellular oxidative stress from reactive oxygen species (ROS) in atrial myocytes, and that metformin reversed this effect. Tachycardia-induced myofibril degradation quantified by MHC and troponin-I was also rescued by 1 mM of metformin.
(Enlarge Image)
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.
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