Introduction
Worldwide, diabetes affected 451 million people (8.4% of the world’s population) in 2017, and this number might dramatically rise to 693 million (9.9%) by 2045 [
1]. Patients with type 2 diabetes are at increased risk of several chronic diseases and associated clinical complications, such as heart disease [
2], which, in turn, is associated with cerebral vascular disease, dementia, disability and premature mortality [
3].
Coronary heart disease, heart failure and cardiac arrhythmias are the common types of heart disease [
3]. Thus far, population-based longitudinal studies have consistently shown that type 2 diabetes is associated with the risk of total CVD, mainly including coronary heart disease and stroke [
2,
4‐
7]. However, the associations between type 2 diabetes and certain subtypes of heart disease independently remain unclear. Several cohort studies examined the relationship between type 2 diabetes and atrial fibrillation and flutter, and showed inconsistent results [
8‐
12]. Discrepancies in previous findings can be attributed to the different study populations, follow-up times and sample size, and lack of consideration of possible confounders.
Although type 2 diabetes may be linked to heart disease through several biologically plausible pathways, our understanding of the mechanisms for such an association is still limited. Both type 2 diabetes and heart disease are complex genetic and lifestyle-related disorders [
3]. Genetic and early-life familial environmental factors may contribute to the development of type 2 diabetes [
13] and heart disease [
14]. However, their role in the association between type 2 diabetes and heart disease is uncertain. Twins are generally reared together and share genetic background. Thus, twin studies provide the possibility to assess whether genetic and/or early familial environmental factors play a role in a given association [
15]. In addition, previous studies have suggested that an individual healthy lifestyle factor (such as maintaining a normal weight, being a non-smoker, non-heavy drinking or regular exercise) was associated with lower risk of both type 2 diabetes and CVD in the general population [
3,
16]. Currently, accumulating evidence has shown that adopting an overall and combined healthy lifestyle can be a more effective prevention strategy for patients with type 2 diabetes to reduce the risk of cardiovascular complications (such as cause-specific mortality rate) [
17,
18]. However, the question remains whether and to what extent a combined healthy lifestyle may counteract the risk of heart disease associated with type 2 diabetes.
In the current study, we sought to: (1) examine the association between type 2 diabetes and the risk of heart disease including its major subtypes; (2) explore whether genetic and early-life familial environmental factors play a role in this association; and (3) investigate whether and to what extent a healthy lifestyle could mitigate the risk of heart disease related to type 2 diabetes.
Discussion
In this large-scale, nationwide, genetically informative sample of Swedish twins, we found that type 2 diabetes was independently associated with increased risk of heart disease and its major types, specifically angina pectoris, acute myocardial infarction, chronic ischaemic heart disease, atrial fibrillation and flutter, and heart failure. The association remained significant, even after controlling for genetic and early-life familial environmental factors. However, a healthy lifestyle might significantly mitigate the risk of heart disease related to type 2 diabetes compared with an unfavourable lifestyle.
In recent decades, many epidemiologic studies have shown that type 2 diabetes is associated with a two- to sixfold increased risk of total CVD and coronary heart disease [
2,
4‐
6]. However, the association between type 2 diabetes and atrial fibrillation has been addressed in a number of epidemiologic studies with inconclusive results. Some studies showed an increased risk of atrial fibrillation among people with type 2 diabetes [
8,
9,
12], but others indicated no clear association [
10,
11]. In a recent meta-analysis of 32 cohort studies, type 2 diabetes was associated with a modest 30% increased atrial fibrillation risk [
26]. In the present study, we found that type 2 diabetes conferred a more than fourfold greater risk of coronary heart disease and a doubled atrial fibrillation risk. Several studies have shown that type 2 diabetes is positively associated with heart failure, but in most of these the influences of other subtypes of heart disease were not taken into account [
2,
27,
28]. As the onset and progression of angina pectoris, acute myocardial infarction and atrial fibrillation may also contribute to heart failure, we looked at the first onset of heart failure with no previous coronary heart disease and cardiac arrhythmias and found that the higher risk of heart failure with type 2 diabetes was independent of other specific subtypes of heart disease.
Accumulating evidence has shown that molecular defects, intrauterine environment and socioeconomic factors are associated with the development of type 2 diabetes, and also contribute to an increased risk of heart disease [
13,
29]. Twins are generally raised together and share the same genetic background as well as intrauterine, childhood and adolescent environments. Twin studies provide us with an opportunity to investigate whether the association between type 2 diabetes and heart disease is potentially confounded by genetic and/or early-life familial environmental backgrounds. In the present study, results of co-twin control analyses implicate that type 2 diabetes is still associated with an increased risk of heart disease, even after fully controlling for genetic and early-life familial environmental backgrounds.
Thus far, previous studies have mainly focused on the combined effect of an overall healthy lifestyle and type 2 diabetes on mortality or total CVD (including coronary heart disease, stroke and peripheral vascular disease) risk, but data specific for only heart disease risk are limited. One population-based prospective cohort study of Chinese patients with type 2 diabetes showed that active smoking, physical inactivity, alcohol drinking and high carbohydrate intake increased the risk of all-cause mortality and CVD mortality after a mean follow-up of 4.02 years of follow-up [
17]. Another prospective study including 11,527 participants with type 2 diabetes suggested that an overall healthy lifestyle (diet, smoking status, alcohol consumption and physical activity) was associated with substantially lower risks of CVD incidence (including stroke and coronary heart disease) and CVD mortality during a mean follow-up of 13.3 years of follow-up [
18]. In contrast, at a median follow-up of almost 10 years, a multicentre randomised clinical trial found that an intensive lifestyle intervention (diet modification and increased physical activity) could produce improvements in CVD risk factors (such as blood pressure and high-density lipoprotein cholesterol levels) in individuals with type 2 diabetes, but not reduce CVD events (including stroke and coronary heart disease) [
30]. The discrepancy in findings might reflect differences in follow-up times, lifestyle factors and definitions of outcome. To the best of our knowledge, the current study is the first to provide evidence that a healthy lifestyle consisting of being a non-smoker, no/mild alcohol consumption, regular physical activity and being non-overweight may greatly attenuate the risk of heart disease in type 2 diabetes. In the current study, patients with type 2 diabetes who reported maintaining not only a favourable (four healthy lifestyle factors) but also an intermediate lifestyle (any two or three healthy lifestyle factors) had a significantly lower heart disease risk than those with an unfavourable lifestyle (no or only one healthy lifestyle factor).
The mechanisms responsible for the increased heart disease morbidity attributable to type 2 diabetes are multifactorial and incompletely understood. An important role of metabolic disturbances, such as long-term hyperglycaemia, insulin resistance and dyslipidaemia, has been hypothesised [
31,
32]. Accelerated atherosclerosis and thrombosis in patients with type 2 diabetes principally result from inflammation, reactive oxygen species and endothelial dysfunction combined with coagulation, platelet abnormalities and impaired fibrinolysis [
33]. Type 2 diabetes leads to autonomic dysfunction and structural remodelling of the left atrium in the form of atrial dilatation and interstitial fibrosis, which might contribute to life-threatening arrhythmias [
26]. In addition, how a favourable lifestyle mitigates the risk of heart disease among participants with or without type 2 diabetes may be explained by multiple possible mechanisms—an overall healthy lifestyle can improve glycaemic control, insulin sensitivity, blood pressure, platelet function, lipid profile and body composition [
16,
17,
34].
There are several strengths and limitations in the current study. First, the large, nationwide, population-based twin cohort provided us with a unique opportunity to further examine the effect of type 2 diabetes on heart disease risk while controlling for some unmeasured confounders such as genetic and early-life familial environmental factors. Second, we used GEE modelling, which is more appropriate than logistic regression models in case–control design, since it accounts for the clustering of twins within a pair. Nonetheless, the limitations in our study need to be pointed out. First, blood glucose level was not available in the STR or SALT. Consequently, given the higher prevalence of undiagnosed type 2 diabetes in elderly people [
35], subjects with undiagnosed type 2 diabetes might have been misclassified as type 2 diabetes-free, which might have led to an underestimation of the observed associations. Second, type 2 diabetes and heart disease were associated with mortality risk, which may contribute to under- or over-estimation of the observed associations. In the current study, we repeated the analyses with an additional adjustment for survival status, and the results were not substantially altered. Third, because information on lifestyle factors was obtained at baseline, it is difficult to capture potential variations in lifestyle factors during follow-up, which would result in underestimation for the effect. Fourth, although some lifestyle-related factors such as smoking, alcohol consumption and physical activity were taken into account, information on diet, sleep duration and other lifestyle-related factors was not available. Finally, information bias might have occurred due to self-reported information on lifestyle-related factors. This might have caused non-differential misclassification leading to underestimation for the observed association.
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