Introduction
A suggested novel risk factor for incident diabetes mellitus is sleep duration; insufficient or excessive amounts of sleep may contribute to the development of diabetes, with prospective studies reporting that short but not long sleep duration [
1‐
4], or both short and long sleep duration, are associated with incident diabetes [
5‐
7]. Meta-analyses support a U-shaped association between sleep duration and incident type 2 diabetes [
8,
9]. Furthermore, sleep duration predicts cardiovascular outcomes [
10], and both short [
11‐
14] and long [
14,
15] sleep time is associated with incident CHD in prospective studies. The importance of sleep for cardiovascular health has prompted the American Heart Association to recently release a scientific statement outlining clinical recommendations and future research directions on sleep behaviour [
16].
Any positive association between excessive or insufficient sleep duration and incident CHD must, however, be considered in the context of diabetes as a major risk factor for CHD [
17]. Cardiometabolic risk factors, including prevalent type 2 diabetes, have been discussed as possible mediators for the association between sleep duration and CHD [
11,
14], with prospective studies adjusting for prevalent baseline cases of diabetes in their analyses [
11‐
15]. This may be insufficient as the same studies do not take into account the incident cases of diabetes occurring during follow-up. Incident diabetes may represent a change in the risk of developing future CHD, yet no study to date has been able to conclusively demonstrate or refute whether only those who are diagnosed with incident diabetes during follow-up constitute a specific group in which short and long sleep duration are associated with incident CHD.
Sex-stratified analyses are already an established method in cardiovascular research. However, there is emerging evidence of the importance of sex-stratification in research involving diabetes-related risk factors [
18,
19] and outcomes [
17,
20]. Sex-stratified analyses are thus called for to identify sex-specific diabetes and CHD risk factors and their mechanisms [
17]. Sleep duration may be one such important sex-specific lifestyle-related risk factor [
21].
The primary objective of the present study was thus to investigate, in sex-specific analyses, the role of incident diabetes as the possible biological mechanism for the reported association between short/long sleep duration and incident CHD. Such a crucial role of incident diabetes can be confirmed in four steps: (1) if an association between sleep duration and incident diabetes is established, and (2) an association between sleep duration and incident CHD is confirmed, it is possible to investigate whether the latter association persists when considering (3) only cases of incident CHD occurring prior to incident diabetes, and (4) only cases of incident CHD occurring after incident diabetes, respectively.
We hypothesised that any association between sleep duration and incident CHD would be significant only in individuals who, during follow-up, were diagnosed with diabetes before CHD. In accordance with this hypothesis, we expected no association between sleep duration and incident CHD occurring before incident diabetes, but an increased risk of incident CHD occurring after incident diabetes. In order to address the possibility of sex-specific risks, all analyses were conducted separately for men and women.
Methods
The Malmö Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmö, Sweden, whose details have been described elsewhere [
22]. In brief, men and women between the ages of 45 and 73 years were randomly selected and recruited for a baseline examination between the years 1991 and 1996. Participants’ anthropometric data and blood samples were gathered, in addition to responses to a detailed questionnaire on heredity, socioeconomic variables, social network, occupation, physical activity, alcohol consumption, smoking, diseases and medication.
At baseline, 30,447 individuals were identified in the study population (see electronic supplementary material [ESM] Fig.
1). Participants of the present study were excluded if they had a history of prevalent diabetes (
n = 1340) or CHD (
n = 670), provided incomplete information on sleep duration (
n = 12,048) or provided a sleep duration that represented an outlier value of more than three interquartile ranges below or above the first and fourth quartiles respectively (
n = 45). A total of 6966 men and 9378 women were included in the analyses. Participants were followed from the starting point until 31 December 2010, with person-years calculated from the starting point to the date of the incident event, loss to follow-up or the end of the follow-up period, whichever came first.
The MDC study was approved by the ethics committee at Lund University, and all participants provided written informed consent.
Results
Compared with those who did not provide information on sleep duration, the group that was included in all analyses had a higher proportion of men (42.6% vs 32.4%). Moreover, compared with those who were included (mean age and SD for both men and women, 57.3 ± 6.0 years), men who did not provide information on sleep duration were older (61.3 ± 7.8 years), whereas women were slightly younger (57.0 ± 9.6 years).
Mean sleep duration for men and women was 7.3 h (SD ± 0.9 h). Table
1 summarises baseline characteristics stratified according to sex. The largest proportion of men (42.9%) and women (40.9%) had a sleep duration of 7–8 h. Compared with those with short (< 6 h) and long (≥ 9 h) sleep durations, men and women in the reference category (7–8 h) were less likely to be obese, do high levels of physical activity or shift work, and smoke more than 20 cigarettes/day, and more likely to be married and report low levels of psychological stress. Men who reported 7–8 h of sleep were also less likely to be hypertensive and less likely to use lipid-lowering medication.
Table 1
Baseline characteristics for men and women according to sleep duration
Number of individuals | 305 | 1484 | 2988 | 1897 | 292 | | 460 | 1819 | 3835 | 2843 | 421 | |
Proportion of population (%) | 4.4 | 21.3 | 42.9 | 27.2 | 4.2 | | 4.9 | 19.4 | 40.9 | 30.3 | 4.5 | |
Age (mean years ± SD) | 57.0 ± 5.9 | 56.6 ± 5.7 | 56.7 ± 5.9 | 58.4 ± 6.1 | 59.7 ± 5.9 | < 0.001 | 58.3 ± 6.0 | 57.2 ± 6.0 | 56.6 ± 5.9 | 57.9 ± 6.1 | 58.4 ± 6.2 | < 0.001 |
Socioeconomic index (%) | | | | | | < 0.001 | | | | | | < 0.001 |
Manual worker | 43.9 | 33.6 | 29.5 | 33.6 | 37.0 | | 43.0 | 39.3 | 33.7 | 37.9 | 42.8 | |
Lower and intermediate non-manual worker | 21.6 | 33.4 | 35.7 | 31.9 | 28.1 | | 39.4 | 45.0 | 48.5 | 44.0 | 33.5 | |
Higher non-manual worker | 10.2 | 11.0 | 13.4 | 9.1 | 6.5 | | 4.8 | 5.8 | 7.0 | 5.3 | 4.3 | |
Other (self-employed and farmers) | 17.4 | 15.9 | 15.9 | 18.5 | 21.9 | | 7.0 | 5.2 | 6.2 | 6.7 | 9.5 | |
Unemployed | 5.6 | 5.8 | 5.4 | 6.7 | 6.2 | | 3.5 | 3.6 | 3.8 | 4.9 | 7.1 | |
Missing information | 1.3 | 0.4 | 0.2 | 0.3 | 0.3 | | 2.4 | 1.2 | 0.8 | 1.2 | 2.9 | |
Smoking status (%) | | | | | | 0.02 | | | | | | < 0.001 |
Never | 29.2 | 27.9 | 30.9 | 28.5 | 20.9 | | 41.7 | 42.3 | 46.2 | 47.9 | 40.9 | |
Past | 37.1 | 40.4 | 40.6 | 42.2 | 40.8 | | 30.0 | 26.2 | 26.1 | 26.0 | 27.6 | |
Current < 20 cigarettes/day | 11.2 | 11.1 | 10.8 | 10.5 | 14.0 | | 13.7 | 18.1 | 17.0 | 15.2 | 18.5 | |
Current ≥ 20 cigarettes/day | 22.6 | 20.6 | 17.7 | 18.8 | 24.3 | | 14.6 | 13.5 | 10.7 | 10.8 | 13.1 | |
Missing information | 0.0 | 0.1 | 0.0 | 0.1 | 0.0 | | 0.0 | 0.0 | 0.0 | 0.1 | 0.0 | |
Alcohol consumption (%) | | | | | | < 0.001 | | | | | | < 0.001 |
None | 18.0 | 11.5 | 9.4 | 12.3 | 17.5 | | 24.8 | 23.0 | 15.8 | 18.0 | 23.8 | |
0.1–1.6 g ethanol day | 6.2 | 6.7 | 5.1 | 6.1 | 6.2 | | 13.0 | 12.9 | 11.5 | 12.8 | 13.8 | |
1.7–7.2 g ethanol/day | 13.4 | 16.9 | 17.8 | 19.1 | 19.5 | | 26.5 | 25.8 | 30.1 | 29.2 | 30.6 | |
7.3–15.4 g ethanol/day | 18.7 | 22.6 | 26.6 | 24.1 | 21.6 | | 22.4 | 23.1 | 27.6 | 25.6 | 16.6 | |
≥ 15.5 g ethanol/day | 40.0 | 41.2 | 40.0 | 37.1 | 33.2 | | 11.3 | 13.9 | 14.4 | 13.4 | 14.5 | |
Missing information | 3.6 | 1.2 | 1.2 | 1.3 | 2.1 | | 2.0 | 1.3 | 0.7 | 1.0 | 0.7 | |
BMI (%) | | | | | | < 0.001 | | | | | | 0.03 |
< 18.5 kg/m2
| 1.3 | 0.9 | 0.3 | 0.7 | 1.0 | | 2.2 | 1.3 | 1.3 | 1.8 | 1.7 | |
18.5–24.9 kg/m2
| 34.4 | 39.0 | 41.0 | 37.0 | 37.0 | | 49.1 | 51.8 | 54.2 | 52.3 | 48.9 | |
25.0–29.9 kg/m2
| 47.5 | 47.0 | 49.1 | 50.1 | 45.9 | | 31.3 | 33.4 | 33.0 | 32.8 | 33.7 | |
≥ 30.0 kg/m2
| 16.4 | 12.8 | 9.5 | 12.2 | 16.1 | | 17.4 | 13.5 | 11.4 | 13.0 | 15.7 | |
Missing information | 0.3 | 0.3 | 0.1 | 0.1 | 0.0 | | 0.0 | 0.1 | 0.1 | 0.2 | 0.0 | |
Physical activity (%) | | | | | | 0.002 | | | | | | < 0.001 |
Quartile 1 (low physical activity) | 32.5 | 23.9 | 25.2 | 25.1 | 27.4 | | 24.6 | 26.3 | 23.1 | 24.0 | 31.1 | |
Quartile 2 | 21.3 | 24.3 | 25.8 | 23.3 | 20.9 | | 24.1 | 24.9 | 27.6 | 25.3 | 22.3 | |
Quartile 3 | 18.4 | 23.7 | 23.7 | 23.9 | 18.5 | | 24.6 | 23.1 | 26.2 | 25.3 | 19.5 | |
Quartile 4 (high physical activity) | 26.2 | 27.0 | 24.7 | 27.1 | 31.9 | | 25.0 | 24.8 | 22.4 | 24.4 | 25.7 | |
Missing information | 1.6 | 1.2 | 0.5 | 0.7 | 1.4 | | 1.7 | 0.9 | 0.7 | 1.0 | 1.4 | |
Hypertension (%) | 44.6 | 45.6 | 43.5 | 45.8 | 55.1 | 0.004 | 42.0 | 36.0 | 36.1 | 36.9 | 40.1 | NS |
Lipid-lowering medication (%) | 2.6 | 2.1 | 2.1 | 2.8 | 4.8 | 0.04 | 3.0 | 1.4 | 1.5 | 1.4 | 1.9 | NS |
Shift work (%) | 38.0 | 33.7 | 28.7 | 32.0 | 45.6 | < 0.001 | 33.0 | 28.9 | 23.7 | 27.6 | 33.5 | < 0.001 |
Missing information | 3.3 | 0.8 | 0.6 | 0.3 | 1.4 | | 3.5 | 2.1 | 1.5 | 2.4 | 4.0 | |
Marital status (%) | | | | | | 0.002 | | | | | | < 0.001 |
Married | 64.9 | 71.2 | 74.4 | 74.5 | 65.4 | | 55.4 | 59.3 | 64.5 | 64.9 | 61.3 | |
Single | 12.1 | 10.4 | 10.1 | 10.4 | 12.3 | | 7.6 | 9.4 | 7.9 | 7.7 | 8.8 | |
Divorced | 18.4 | 16.0 | 13.6 | 12.4 | 18.5 | | 24.1 | 19.5 | 19.0 | 19.4 | 21.1 | |
Widowed | 4.6 | 2.4 | 2.0 | 2.6 | 3.8 | | 12.8 | 11.8 | 8.6 | 7.8 | 8.6 | |
Missing information | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | 0.0 | 0.1 | 0.1 | 0.1 | 0.2 | |
Psychological stress (%) | | | | | | < 0.001 | | | | | | < 0.001 |
Low | 29.2 | 35.2 | 40.8 | 37.9 | 33.2 | | 18.0 | 25.0 | 30.5 | 30.2 | 21.4 | |
Intermediate | 32.1 | 36.9 | 32.8 | 34.7 | 34.3 | | 41.7 | 37.7 | 35.3 | 34.9 | 35.9 | |
High | 21.0 | 12.7 | 8.2 | 9.8 | 11.3 | | 21.7 | 18.1 | 13.8 | 11.7 | 15.2 | |
Missing information | 17.7 | 15.2 | 18.2 | 17.7 | 21.2 | | 18.5 | 19.2 | 20.4 | 23.2 | 27.6 | |
Sleep quality (%) | | | | | | < 0.001 | | | | | | < 0.001 |
Good | 50.8 | 74.4 | 86.1 | 87.8 | 83.2 | | 29.1 | 55.9 | 76.6 | 79.5 | 77.7 | |
Poor | 48.2 | 25.1 | 13.2 | 11.4 | 15.4 | | 70.4 | 43.3 | 22.7 | 19.5 | 20.7 | |
Missing information | 1.0 | 0.5 | 0.7 | 0.7 | 1.4 | | 0.4 | 0.8 | 0.7 | 1.0 | 1.7 | |
Discussion
Our study is the first of its kind to consider incident diabetes on the pathway between self-reported sleep duration and CHD risk. The associations between sleep duration and incident CHD directly reflect the associations between sleep duration and incident diabetes, and when taken together with the strong association between sleep duration and diabetes-CHD, our study convincingly demonstrates that incident diabetes is the most probable explanatory biological mechanism for the positive associations found between sleep duration and CHD.
The association between short sleep duration and incident diabetes in our study is consistent with previous prospective findings [
1‐
7]. Although both BMI and hypertension have been mentioned as possible mediators [
6] for the association between short sleep duration and incident diabetes, the association between short sleep duration and incident diabetes in our study persisted in both men and women despite BMI-stratified analyses and adjustment for a large number of known diabetes risk factors and covariates, including hypertension. Prospective studies with repeated measurements of BMI and blood pressure are, however, urged to investigate the importance of any change in these variables over time for the association between sleep duration, incident diabetes and incident CHD, respectively.
The increased risk of CHD with short sleep duration [
11‐
14] is also consistent with previous prospective studies and could easily have been argued as an increased risk independent of diabetes considering the exclusion of individuals with prevalent diabetes from our analyses. However, we chose to take into account the association between habitually short sleep duration and incident diabetes and opted for an approach that (1) censored cases of incident CHD if these occurred after incident diabetes (non-diabetes CHD), thereby obliterating any significant association between short sleep duration and CHD; and (2) considered only cases of incident CHD that followed incident diabetes (diabetes-CHD), which in turn showed significant positive associations between short sleep duration and CHD despite the low number of cases. This novel approach recognises the important role of incident diabetes as the explanatory mechanism for any association between short sleep duration and incident CHD in both men and women.
Our study also found that long sleep duration (≥ 9 h) in men is associated with incident diabetes and diabetes-CHD, but not with non-diabetes CHD. Contrary to the situation with short sleep duration, the associations between long sleep duration and incident diabetes and CHD, respectively, have been suggested to result from comorbidity and residual confounding [
5,
10] or from reverse causation bias [
2,
14]. In order to address the problem of reverse causation, our study excluded individuals with prevalent diabetes and CHD, and allowed for sensitivity analyses that further excluded the first 3 years of follow-up. Despite this approach, long sleep duration in men remained significantly positively associated with incident diabetes, incident CHD and incident diabetes-CHD, but not with incident non-diabetes CHD. The main reason for a null finding between long sleep duration and incident CHD in women is most likely due to the lack of any association between long sleep duration and incident diabetes in this group, a finding consistent with one previous report [
1]. We therefore propose for the first time that incident diabetes is also the responsible mechanism for the observed association between long sleep duration and incident CHD in men.
The findings are strong and point toward diabetes as the explanatory biological mechanism for the association between sleep duration and CHD, and the fact that this association may differ between men and women. The significance of this finding is threefold. First, it highlights that sleep duration should be considered an important behavioural risk factor for incident diabetes. Second, the relevance of our findings is not limited to CHD, owing to the importance of diabetes as a major risk factor for micro- and macrovascular disease. Sleep interventions in individuals who are habitually short or long sleepers thus have the potential to greatly impact health outcomes and should be considered on a par with advice on physical exercise. Indeed, the American Heart Association has recently published a scientific statement [
16] outlining clinical recommendations and research priorities on sleep behaviour owing to the strong association between sleep and cardiovascular health. Third, the present results strengthen the need for sex-stratified analyses with regard to diabetes risk factors and CHD complications. The main sex difference that emerges from our study is that long sleep duration is a risk factor for incident diabetes and incident diabetes-CHD in men but not women. Such differences between men and women may be due to underlying biological as well as psychosocial influences [
36], which may determine sex-specific diabetes risk factors [
18]. Indeed, sex differences in the association between sleep duration and incident diabetes have already been reported [
1], and the impact of sleep duration on body composition may differ according to sex [
21]. Mechanistic studies are required to explain the sex-specific effects of sleep duration and their association with incident diabetes and incident CHD, respectively. Future research on this topic is thus highly warranted.
There are a few limitations to this study. First, sleep was assessed through self-reported questionnaires, with possible overestimation of sleep duration. However, any non-differential misclassification of sleep duration among our participants would consequently result in a subsequent underestimation of our study findings. Additionally, when considering the nature and size of our study, no other feasible methods of assessing sleep duration exist. Second, the lack of an association between long sleep duration and the diabetes-CHD endpoint in women could be due to a lack of statistical power because of the small number of individuals involved. Studies with a larger population and longer follow-up times are encouraged to conduct sex-stratified analyses and attempt to replicate our results. Third, the MDC study does not contain information on mental illness, and we were therefore unable to adjust for this in our analyses. Fourth, the group of individuals included in analyses differed in age and sex from those who had not provided information on sleep duration. Those included for analysis included a higher proportion of men, and they were also younger than the excluded men. Conversely, the women included were slightly older than their excluded counterparts. This may have biased our findings. Fifth, the generalisability of results to other populations may be limited. Ethnic differences in the association between sleep duration and incident diabetes have been shown in previous research [
2], and different ethnicities may require different amounts of sleep before such behaviours constitute a health hazard.
Despite such limitations, this study has a number of strengths. First, incident diabetes and incident CHD were established using nationwide registers, with very high accuracy. Second, the MDC questionnaire asks about habitual sleep duration, which would be the question of choice if sleep duration were assessed by healthcare professionals. Third, we have used a population that is highly representative of the Swedish general population, and we adjusted for a large number of covariates associated with incident diabetes and CHD. Finally, we adjusted for sleep quality as poor sleep quality may confound any association between short or long sleep duration and health outcomes. With the exception of one prospective study [
3], sleep quality has not been considered when positive associations have been reported between sleep duration and incident diabetes.
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