In this population-based case-control study, people receiving pharmacologic treatment for diabetes had 40% higher risk of developing atrial fibrillation than people without diabetes. Risk was higher with longer duration of treated diabetes, and there was a suggestion of higher risk with worse glycemic control.
Prior studies examining risk of atrial fibrillation in relation to diabetes or impaired glucose metabolism have yielded conflicting results.3,9,11–27
Our results are similar to those reported by several prospective studies,12,14,18
including the Framingham Heart Study,14
all of which reported ORs in the range of 1.4 to 1.6. Other studies found an association between higher blood glucose and increased risk of atrial fibrillation.9,17
However, numerous studies did not observe an association between diabetes and atrial fibrillation,11,20–27
and one study observed an association in women but not men (adjusted OR 1.26 [1.08-1.46] for women and 1.09 [0.96-1.24] for men).13
The discrepant findings may reflect methodologic differences including sample size, leading to low power in some studies, as well as the definition and method of ascertaining diabetes and atrial fibrillation. Unlike many prior studies, our primary focus was on the diabetes-atrial fibrillation relationship, and so we designed our statistical analyses accordingly. Unlike most prior studies, we adjusted for BMI, and so our findings support an independent association of diabetes with atrial fibrillation beyond the known association with obesity.20,28,29
A large proportion (39%) of our cases had “transitory” atrial fibrillation, defined as a single episode lasting 7 days or less without recurring in the ensuing 6 months. Many prior studies did not report information about duration or persistence of atrial fibrillation11,13,14,16,17,19,20,25–27
or used a classification scheme not directly comparable to ours.9,12,22
Based on their methods, some prior studies would have been more likely to detect permanent than paroxysmal atrial fibrillation.12,19,25,27
If diabetes conveys increased risk of paroxysmal atrial fibrillation and these cases were classified as not having atrial fibrillation in other studies, then our risk estimates may be higher than those from studies with such misclassification. We found that people with diabetes were at increased risk for all subtypes of atrial fibrillation, regardless of its duration or persistence.
Our study is the first to examine risk of atrial fibrillation in relation to diabetes duration and glycemic control. We observed higher risk with longer duration of pharmacologic treatment for diabetes (used as a surrogate for diabetes duration) and worse glycemic control. This pattern supports a dose-response effect, with greater exposure to hyperglycemia conferring increased risk. A dose-response effect is considered to support causality. Our risk estimates suggest higher atrial fibrillation risk for people with treated diabetes for more than 5 years or average hemoglobin A1c above 7.0. These findings could indicate a threshold effect, which is further supported by our finding that risk was not elevated among people with diabetes who were not receiving pharmacologic treatment (OR 1.04, 95% CI 0.75-1.45). Within GH, people with diabetes who are not receiving pharmacologic treatment probably are earlier in the course of diabetes or have milder disease than those receiving treatment. GH laboratory data confirm that the average hemoglobin A1c in the untreated group was lower than in the treated group. Still, our risk estimates have wide confidence limits, and we cannot rule out a clinically meaningful elevated risk for atrial fibrillation in people with diabetes who are not receiving pharmacologic treatment or have short duration of diabetes or excellent glycemic control.
In subgroup analyses, we observed an association between diabetes and risk of atrial fibrillation for people who were obese but no association in those who were not obese. This result should be interpreted cautiously because it was unexpected and arose from analyses examining many subgroups. It is possible that the physiology of diabetes differs by body mass index, with obese individuals having higher levels of insulin resistance and perhaps altered levels of some hormones compared to non-obese individuals. Further investigation of this potential interaction is warranted because it could shed light on the mechanism by which diabetes may lead to atrial fibrillation.
Several physiologic mechanisms could underlie a causal relationship between diabetes and atrial fibrillation.37
People with diabetes have higher levels of C-reactive protein,3–6
a marker of systemic inflammation, which may promote myocardial fibrosis and diastolic dysfunction. Diabetes is associated with left atrial enlargement2
which is thought to allow the development and propagation of reentrant electrical circuits. Diabetes also causes neural remodeling in the atria, including parasympathetic denervation and heterogeneous sympathetic denervation.38
People with diabetes are at higher risk of coronary artery disease and congestive heart failure, which may contribute to the development of atrial fibrillation. Finally, after accounting for obesity, people with diabetes have higher prevalence of obstructive sleep apnea,39
which may lead to atrial fibrillation.40
Our study has limitations. Our population consists of post- and perimenopausal women and hypertensive men and is predominantly white, which may limit generalizability. Because diabetes was identified in the course of routine clinical care, some people in the study probably had unrecognized diabetes. We identified only atrial fibrillation that came to clinical attention, so some transitory or asymptomatic cases may have been missed. It is possible that people with diabetes were more likely to have their atrial fibrillation recognized than people without diabetes, which could have resulted in bias. We lacked information about actual duration of diabetes and so we examined as a surrogate measure the duration of pharmacologic treatment for diabetes. Many people have diabetes for years before it is clinically detected. These factors may have led to misclassification of diabetes duration. We lacked information about some characteristics (e.g. physical activity and thyroid disease) and so there may be residual confounding.
In conclusion, we observed that pharmacologically treated diabetes was associated with a 40% increased risk of developing atrial fibrillation, and that risk was higher in people with longer duration of diabetes and worse glycemic control, providing support for a causal association. These results may increase understanding of the spectrum of cardiovascular disease associated with diabetes. Our findings suggest clinicians should have heightened suspicion for atrial fibrillation in people with diabetes, particularly those presenting with relevant symptoms. It may also be useful to screen for diabetes in people newly diagnosed with atrial fibrillation. In addition, given the high and rising prevalence of diabetes, our results have important implications for the future health burden of atrial fibrillation. Future research should investigate treatment approaches to reduce the risk of atrial fibrillation among people with diabetes.