To the best of our knowledge, a meta-analysis of prospective studies on sleep quality and duration, and blood lipids in the general population without diagnosed sleep disorders has not yet been published. We set out to systematically evaluate prospective studies for an association between sleep duration and quality, and blood lipids in the general population and to pool the evidence in a meta-analysis.

Systematic reviews of observational studies suggest a lack of consistency in the association between sleep duration and lipid profiles, with a large heterogeneity in the classification of exposure and outcome and the type of analysis. Furthermore, these were mainly based on cross-sectional evidence—hence unable to establish a temporal relationship between exposure and outcome—and did not evaluate sleep quality as a potential exposure of interest. 15 16 In recent years, new prospective studies that include measures on sleep and blood lipids have emerged. Nadeem et al 17 performed a meta-analysis of 64 observational studies involving 18 116 patients on obstructive sleep apnoea (OSA) and the blood lipid profile. They found that OSA was associated with a significantly higher risk of dyslipidaemia, for example, high TC and LDL-C, high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C). However, this meta-analysis was performed in a specific patient group, did not include sleep duration as an exposure and was based on cross-sectional studies.

U-shaped relationships between duration of sleep and risk factors for CVD, such as hypertension and metabolic syndrome have been observed. 8 9 For obesity, the longitudinal association is most clear in paediatric populations, in which shorter sleep is associated with an increased risk of obesity. 10 Fewer studies have been performed on sleep quality, but poor sleep quality has also been associated with an increased risk of hypertension, 11 metabolic syndrome 12 and diabetes. 2

Research into sleep and its effects on health has increased in recent years. This has been accompanied by public health concerns about the declining quality and quantity of sleep in modern society. 1 Both short and long sleep duration are consistently associated with mortality and serious chronic diseases, such as diabetes and cardiovascular disease (CVD). 2–4 Similarly, poor sleep quality has been associated with mortality and CVD. 4 5 CVD is the leading cause of non-communicable disease deaths globally and deaths by CVD have risen by 12.5% between 2005 and 2015. 6 There is still debate about whether the association between sleep and CVD is causal or whether sleep disturbances are merely symptoms or risk markers of disease. 7 Understanding the possible mechanisms through which sleep affects CVD can provide important supportive evidence for a causative link.

A random effects model with inverse-variance weighting was used to pool HRs, ORs and RRs into RRs for developing high TC, low HDL-C, TC/HDL-C ratio ≥5 and high TG in short sleepers and long sleepers compared with the reference category. Ratio measures and standard errors were transformed into natural logarithms for analysis. For a detailed overview and examples of data transformations performed, see online supplementary appendix table A2 . Changes in lipid levels over time were meta-analysed using a random effects model when at least two cohorts with a similar exposure and outcome measurement were available. Due to heterogeneity in sleep quality aspects and types of outcomes reported, we were unable to meta-analyse the studies on sleep quality. Publication bias was assessed with examination of funnel plot symmetry and Egger’s regression test for small study effects when the number of cohorts available was greater than 2. Heterogeneity was investigated with Q test statistic and quantified by I 2 statistics. The following thresholds for I 2 interpretation from Cochrane Reviews were used: ‘0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity’. 20 The influence of individual studies was investigated by excluding one study at a time. A two-tailed P value <0.05 was considered statistically significant. Statistical analyses were performed with Stata V.14 (StataCorp, College Station, Texas, USA).

Data from each study was extracted independently by two investigators (MK and FPC). Extracted data included: first author, year of publication, country of origin of the population, recruitment year of cohort, age (at sleep assessment), sex, duration of follow-up, number of participants included, methods of assessment of both exposure and outcome, definitions of sleep categories, relative risks (RR), HR, OR, regression coefficients (β) representing changes in lipid levels, 95% CI, SE and adjustment for covariates. SEs were derived from CI if not reported (online supplementary appendix table A1 ). The most adjusted estimates were used for analysis. When data were reported for men and women separately, they were entered for analysis as two separate cohorts. When data from the same cohort was published in separate papers, only one estimate was used (usually the longer follow-up or the largest dataset). Differences in extracted information were resolved by discussion and consensus among two of the investigators.

After title and abstract scanning, full-text articles were retrieved. Prospective articles were evaluated for inclusion by two of three investigators (MK, WR and FPC) according to the following criteria set a priori: (A) original published article, (B) observational prospective design, (C) a baseline assessment of exposures (sleep duration or sleep quality) and (D) one of the following outcomes: (1) a change in serum lipids over time or (2) a relative risk of developing dyslipidaemia in short or long sleepers compared with the reference sleep category. Studies were excluded if (A) exposure was napping or shift work, (B) population had a diagnosed sleep disorder like OSAS or pre-existing cardiovascular or metabolic disease, (C) it was a case–control study. No sample size, age or duration of follow-up restriction was applied. Disagreement on inclusion was resolved by discussion and consensus among the three investigators. Authors were contacted for additional data.

The electronic databases, PubMed (from 1996) and EMBASE (from 1947), were searched on 9 September 2017 using keywords related to exposure (sleep duration and quality), outcome (blood lipids) and design (prospective). Abbreviations, plural forms and alternate spellings (American-English) of keywords were searched. The search was restricted to human research and published journal articles. No language restriction was applied. In addition, a manual check of reference lists was performed using (1) previous review articles on the subject, (2) relevant review articles identified in the search and (3) articles included in the present study. Additional searches were performed into the studies that measured lipids at baseline and follow-up, but did not report on lipids, to see if additional publications were available which did report on the outcome of interest.

There were too few studies to draw any meaningful conclusions from this analysis. ( table 2 ). An increase in sleep duration was not associated with a change in HDL cholesterol. Furthermore, Yang et al 32 report changes in lipid levels in short and long sleepers compared with a 7–8 hours reference group. None of these associations reached significance, except for an 0.085 mmol/L (95% CI 0.014–0.156, P unreported) increase in TG for those sleeping ≥10 hours compared with those sleeping 7–<8 hours.

Meta-analyses of long sleep duration by different lipid fractions are shown in figure 3 . In an overall pooled analysis, the risk of any dyslipidaemia among long sleepers was 0.98 (95% CI 0.87 to 1.10), with heterogeneity (I 2 =63%, P<0.001) and no significant publication bias (P=0.248). There were not enough observations to perform an Egger’s test for the risk of TC/HDL-C ratio≥5, there was no evidence for publication bias for the remaining lipid types (see online supplementary appendix figure A1 d-f ).

The quality of studies included in the meta-analyses ranged from 12 to 18 out of a maximum score of 20 (see online supplementary appendix table A4 ). All studies scored high on items of reporting and bias. Studies scored less well on items of external validity and confounding. All studies lacked in adequate confounder adjustment by not adjusting for at least one of the following factors: baseline lipid levels, dyslipidaemia medication, other sleep variables or depression. Meta-analyses included three cohorts with high TC (21 453 participants), four cohorts with low HDL-C (11 851 participants), two cohorts with high TC/HDL-C ratio (503 participants) and five cohorts with high TG (11 450 participants). Meta-analyses of short sleep duration by different lipids fractions are shown in figure 2 . In an overall pooled analysis of sleep duration (6 studies, 16 cohort samples; 30 033 participants; follow-up 2.6–10 years), short sleep was associated with a risk of 1.01 (95% CI 0.93 to 1.10) of developing any dyslipidaemia, with moderate heterogeneity (I 2 =56%, P=0.003) and publication bias (P=0.035). Short sleep was associated with a non-significant increased risk of developing high TC (RR=1.10; 95% CI 0.99 to 1.22; P=0.07; no heterogeneity and publication bias). There were not enough observations to perform an Egger’s test for the risk of TC/HDL-C ratio ≥5, there was no evidence for publication bias for the remaining lipid types (see online supplementary appendix figures A1 a–c ).

In online supplementary appendix table A3 , an overview of the results reported in the individual studies for sleep quality is given. In general, studies reported both favourable and unfavourable associations of poor sleep quality with blood lipids. The associations reported differed by lipid type and aspects of sleep quality assessed. Only Haaramo et al 34 reported significant associations. Those occasionally or frequently suffering from insomnia symptoms had a significantly increased risk of dyslipidaemia medication compared with those without insomnia symptoms.

In the original protocol submission to PROSPERO (CRD42016045242), the Outcome(s) section reads Primary outcomes: we expect most studies will have measured cholesterol. The expected primary outcomes are therefore changes in TC or the risk of developing hypercholesterolaemia. Secondary outcomes: the following outcomes will also be assessed: changes in serum levels HDL-C, LDL-C and TGs and the risk of developing dyslipidaemia (this can be hypercholesterolaemia, hypertriglyceridaemia, etc). The submission reflects the ‘a priori’ uncertainty on how the outcomes in prospective studies would look like. After the search, it became apparent that the most common form of outcome in prospective studies was indeed ‘incidence of dyslipidaemia’. We report all outcomes originally planned to avoid the risk of selective outcome reporting.

Searches yielded 1594 titles ( figure 1 ). After title and abstract scanning, 157 full-text articles were retrieved. Twelve studies were identified in the search, seven concerned only sleep duration, one concerned only sleep quality and one concerned both. Searching the references of included studies yielded one additional study regarding sleep quality, yielding a total of 13 studies. Four authors were contacted 21–24 for additional data of whom one could provide data.

Discussion

To our knowledge, this is the first systematic review and meta-analysis of the current prospective evidence on the relation between sleep quality, sleep duration and blood lipids in the general population. The results were not influenced by age, study quality, follow-up duration, gender or sleep assessment method. The analysis was carried out by separate lipid fractions. The risk of the development of dyslipidaemia varied among short and long sleepers and by lipid type.

Like Abreu et al,16 we found that studies often adjusted for factors such as diet and body mass index, without exploring potential mediation, while the influence of other sleep variables are ignored. Sleep disordered breathing was not taken into account in any of the included studies, even though it has been associated with an increased risk of dyslipidaemia.18 Another factor that was inconsistently taken into account was stress, which can be a determinant of both poor sleep and increased stress levels. In the Whitehall II study, cortisol secretion was raised in those reporting short sleep duration and high sleep disturbance.35

Polysomnography is the gold standard for objective assessment of sleep quality and quantity, but objective sleep assessment is often not feasible in large cohort studies. Sleep quality and quantity were assessed subjectively by questionnaire or interview in most included studies. Moderate correlation between assessment of sleep duration by self-report and more objective actigraphy assessment have been observed in the Coronary Artery Risk Development in Young Adults study.36 Similarly, the Pittsburgh Sleep Quality Index and Epworth Sleepiness scale, two often used subjective measures of sleep quality, do not correlate well with objective sleep measures.37 In all included studies, a single measurement of sleep was taken at baseline, which may not represent the full sustained effect of sleep duration.

In previous systematic reviews, both long and short sleep duration were strongly associated with health outcomes, including cardiovascular disease.1 4 No such effects were found in this meta-analysis. It is possible that the effects of sleep duration on cardiovascular health are not mediated through blood lipids,38 but through other pathways such as obesity, hypertension and inflammation.10 39–41 However, an effect of sleep duration on blood lipids would be biologically plausible. Sleep restriction is associated with an altered secretion of metabolic and hunger hormones, such as growth hormone, cortisol, leptin and ghrelin.42–44 Furthermore, sleep can influence eating behaviour and physical activity. Short sleep time and non-restorative sleep have been associated with a dietary alterations reflecting a higher intake of energy and fat.45–47 Sleep loss has also been shown to decrease physical activity in free-living conditions,48 and insufficient sleep could undermine dietary efforts to reduce adiposity.49 Several short-term experimental studies also suggest an effect of sleep restriction on blood lipid levels.50 51 Since it is difficult to have people sleep for long periods of time, mechanisms for the effects of long sleep duration on health have been less investigated and remain mostly speculative. It is possible that the observed relationship between long sleep duration and cardiovascular outcomes reflects long sleep duration being a risk marker or symptom of disease rather than a cause.7

Strengths and limitations Strengths of this review include the broad search strategy and in-depth quality assessment of studies. The high heterogeneity of exposure and outcome measurements encountered in this review limited the scope of the meta-analysis. We were unable to perform a meta-analysis for sleep quality. The results can only be representative of published and included studies and the interpretation is limited by the small number of studies and some publication bias. Other limitations include the inability to directly adjust for confounding with study level meta-analysis and the fact that the quality of the meta-analysis cannot go beyond the quality of the included studies.