Diabetologia (2021) 64:2367–2377

https://doi.org/10.1007/s00125-021-05541-0

REVIEW

Sleep disorders in people with type 2 diabetes and associated health

outcomes: a review of the literature
Samantha B. J. Schipper 1,2 & Maaike M. Van Veen 3,4 & Petra J. M. Elders 2,5 & Annemieke van Straten 2,6 &
Ysbrand D. Van Der Werf 7,8 & Kristen L. Knutson 9 & Femke Rutters
1

Received: 31 March 2021 / Accepted: 25 May 2021 / Published online: 16 August 2021
# The Author(s) 2021

Abstract
Sleep disorders are linked to development of type 2 diabetes and increase the risk of developing diabetes complications. Treating sleep
disorders might therefore play an important role in the prevention of diabetes progression. However, the detection and treatment of
sleep disorders are not part of standardised care for people with type 2 diabetes. To highlight the importance of sleep disorders in people
with type 2 diabetes, we provide a review of the literature on the prevalence of sleep disorders in type 2 diabetes and the association
between sleep disorders and health outcomes, such as glycaemic control, microvascular and macrovascular complications, depression,
mortality and quality of life. Additionally, we examine the extent to which treating sleep disorders in people with type 2 diabetes
improves these health outcomes. We performed a literature search in PubMed from inception until January 2021, using search terms for
sleep disorders, type 2 diabetes, prevalence, treatment and health outcomes. Both observational and experimental studies were included
in the review. We found that insomnia (39% [95% CI 34, 44]), obstructive sleep apnoea (55–86%) and restless legs syndrome (8–45%)
were more prevalent in people with type 2 diabetes, compared with the general population. No studies reported prevalence rates for
circadian rhythm sleep–wake disorders, central disorders of hypersomnolence or parasomnias. Additionally, several cross-sectional and
prospective studies showed that sleep disorders negatively affect health outcomes in at least one diabetes domain, especially glycaemic
control. For example, insomnia is associated with increased HbA1c levels (2.51 mmol/mol [95% CI 1.1, 4.4]; 0.23% [95% CI 0.1, 0.4]).
Finally, randomised controlled trials that investigate the effect of treating sleep disorders in people with type 2 diabetes are scarce, based
on a small number of participants and sometimes inconclusive. Conventional therapies such as weight loss, sleep education and
cognitive behavioural therapy seem to be effective in improving sleep and health outcomes in people with type 2 diabetes. We
conclude that sleep disorders are highly prevalent in people with type 2 diabetes, negatively affecting health outcomes. Since treatment
of the sleep disorder could prevent diabetes progression, efforts should be made to diagnose and treat sleep disorders in type 2 diabetes
in order to ultimately improve health and therefore quality of life.

Keywords Health outcomes . Prevalence . Review . Sleep disorders . Type 2 diabetes

Abbreviations CBT-I Cognitive behavioural therapy insomnia

BLT Bright light therapy CPAP Continuous positive airway pressure

* Femke Rutters 5
Department of General Practice, Amsterdam UMC, location VUmc,
[email protected] Amsterdam, the Netherlands
6
1
Faculty of Behavioural and Movement Sciences, Vrije Universiteit,
Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
location VUmc, Amsterdam, the Netherlands 7
2
Department of Anatomy & Neurosciences, Amsterdam UMC,
Amsterdam Public Health Research Institute, Amsterdam, the Amsterdam, the Netherlands
Netherlands 8
3
Amsterdam Neuroscience, Amsterdam, the Netherlands
Centre of Expertise on Sleep and Psychiatry, GGZ Drenthe Mental 9
Health Institute, Assen, the Netherlands Department of Medicine, University of Chicago, Chicago, IL, USA
4
Centre of Expertise on Sleep and Psychiatry, GGZ Drenthe Mental
Health Institute, Assen, the Netherlands
2368 Diabetologia (2021) 64:2367–2377

CRSWD Circadian rhythm sleep–wake disorder diagnosis and treatment of sleep disorders in people with type
OSA Obstructive sleep apnoea 2 diabetes.
PLMD Periodic limbic movement disorder
QoL Quality of life
REM Rapid eye movement
RLS Restless legs syndrome Methods

A literature search was performed in PubMed from inception

until January 2021, using MeSH and tiab search terms indi-
Introduction cating sleep disorders (e.g. ‘sleep disorders’, ‘sleep wake
disorders’, ‘sleep deprivation’, ‘circadian’, ‘sleep arousal’,
Diabetes is a severe public health problem, negatively affect- ‘insomnia’, ‘obstructive sleep apnea’ and ‘restless legs
ing a person’s quality of life (QoL) and health, through syndrome’) and type 2 diabetes mellitus (e.g. ‘diabetes
increasing the risk of microvascular and macrovascular mellitus 2’ and ‘non-insulin dependent’). Additionally, search
complications, depression and mortality. An important but terms for prevalence, treatment and health outcomes were
less-known risk factor for the development of type 2 diabetes used (e.g. ‘morbidity’, ‘prevalence’, ‘depressive disorder’,
is having a sleep disorder. Sleep disorders negatively affect ‘sleep drug’, ‘sleep medication’ and ‘health status’). See
sleep quality and duration, causing detrimental effects on Electronic supplementary material Table 1 for the full list of
glucose metabolism and weight regulation [1]. For example, search terms. All relevant English or Dutch language original
a sleep duration of <5 h and poor sleep quality are associated and review studies were read by two authors (SS and FR) and
with developing type 2 diabetes (RR 1.48 [95% CI 1.25, 1.76] summarised. Observational (cross-sectional and longitudinal)
and RR 1.40 [95% CI 1.21, 1.63], respectively) [1], and and experimental studies were included. No quality assess-
insomnia and obstructive sleep apnoea (OSA) have been asso- ment or risk of bias assessment were made.
ciated with developing type 2 diabetes (OR 1.07 [95% CI
1.02, 1.11] and OR 2.02 [95% CI 1.57, 2.61], respectively)
[1, 2]. Managing and treating sleep disorders could therefore
play an important role in the prevention of type 2 diabetes. Prevalence and health outcomes of sleep
According to the of the International Classification of Sleep disorders in type 2 diabetes
Disorders, third edition (ICSD-3) [3], sleep disorders can be
divided into six main groups: insomnia; sleep-related breathing In this section, we discuss the evidence on prevalence and asso-
disorders; central disorders of hypersomnolence; circadian ciations of sleep disorders with health outcomes (see also Fig.
rhythm sleep–wake disorders (CRSWDs); parasomnias; and 1). No or limited literature was found for hypersomnolence,
sleep-related movement disorders (see detailed descriptions in parasomnias and several movement disorders. A review by
Table 1). Sleep disorders typically cause disturbances in the qual- Mohammadi et al. identified several papers that elaborate on
ity, amount and timing of sleep, resulting in impaired daytime mechanisms by which narcolepsy, a very specific disorder,
functioning and distress. Several sleep disorders are highly prev- increases the risk of development of type 2 diabetes [4].
alent in the general population (Table 1). Considering the asso- However, no papers on prevalence of hypersomnolence and
ciation between sleep disorders and development of type 2 diabe- associated health outcomes in people with type 2 diabetes were
tes, the prevalence of sleep disorders in people with type 2 diabe- identified. Only case reports were found for parasomnias (i.e.
tes is probably higher compared with the general population. abnormal nocturnal behaviour [5] and rapid eye movement
Sleep disorders may also result in faster diabetes progres- (REM) sleep behaviour disorder [6]), which will not be
sion and thus play an important role in diabetes management. discussed here. For movement disorders other than restless legs
However, detection and treatment of sleep disorders are not syndrome (RLS) and periodic limbic movement disorder
part of standardised care for people with type 2 diabetes. To (PLMD), some were identified as a risk factor for the develop-
start addressing the gap between current knowledge and clin- ment of type 2 diabetes (i.e. bruxism [7]). Further research is
ical care, we provide a review of the literature on the preva- needed to investigate the prevalence of the aforementioned
lence of sleep disorders in people with type 2 diabetes and the sleep disorders and associated health outcomes in type 2 diabe-
association with the following health outcomes: glycaemic tes. Finally, data on the prevalence of having multiple sleep
control, microvascular and macrovascular complications, disorders simultaneously in those with diabetes is lacking.
depression, mortality and QoL. We also explore the extent This is important as OSA and insomnia frequently co-occur
to which treating sleep disorders in people with type 2 diabetes in the general population and this co-occurrence is associated
improves the above-mentioned health outcomes. With this with increased comorbidities, including diabetes [8].
review, we aim to highlight the importance of targeted
Diabetologia (2021) 64:2367–2377 2369

Table 1 Definitions based on

ICSD-3 and prevalence of sleep Sleep problem Definition of sleep disorder based on ICSD-3 Prevalence in general
disorders in the general population (%)a
population
Insomnia Disorder characterised by a dissatisfaction in quality or 10
quantity of sleep resulting in significant daytime distress.
Insomnia is associated with problems initiating or
maintaining sleep, frequent awakenings and the inability to
return back to sleep. These complaints occur despite
adequate opportunity and circumstances to sleep.
Sleep-related Group of disorders characterised by symptoms such as 3–7
breathing snoring, fatigue, insomnia or subjective respiratory
disorders disturbances, or associated medical or psychiatric disorders
in combination with ≥5 predominantly obstructive
respiratory events per h of sleep, or ≥15 obstructive
respiratory event per h (even in absence of symptoms). This
diagnosis can be further subdivided into OSA disorders,
central sleep apnoea syndromes, sleep-related
hypoventilation disorders and idiopathic central alveolar
hypoventilation.
Central disorders of Group of disorders characterised by subjective excessive 0.02–0.18
hypersomnolence daytime sleepiness that cannot be explained as a result of
another sleep–wake disorder, resulting in daily occurrences
of an insuppressible need to sleep or daytime lapses into
sleep. This disorder group includes narcolepsy, idiopathic
hypersomnia, insufficient sleep syndrome, and
hypersomnias due to medical disorders, medication or
substance and psychiatric disorder
CRSWDs The disorders belonging to this group include delayed and 7–16
advanced sleep–wake phase disorder, irregular sleep–wake
rhythm disorder, non-24 h sleep–wake rhythm disorder,
shift-work disorder, jet-lag disorder and circadian
sleep–wake disorders not otherwise specified. The disorders
are characterised by a chronic or recurrent pattern of
sleep-disruption primarily caused by a change in the
endogenous circadian timing system or misalignments
between the endogenous circadian rhythm and the socially
desired rhythm, resulting in insomnia or excessive
sleepiness. It is associated with distress or functional
impairment over a period of at least 3 months (except for
jet-lag disorder).
Parasomnias Parasomnias can be divided into NREM-related parasomnias, 3–17
REM-related parasomnias and other parasomnias.
NREM-related disorders include recurrent episodes of
incomplete awakening, with abnormal responsiveness,
limited or no memory or dream report, and at least partial
amnesia for the episode. REM-related parasomnias occur as
a consequence of state dissociation between REM sleep and
being awake.
Sleep-related Group of disorders characterised by simple, often repeated 5–10
movement movements during sleep. Diagnoses include RLS, PLMD,
disorders REM sleep behaviour disorder and others
a
Data from [79]
ICSD-3, International Classification of Sleep Disorders, third edition; NREM, non-rapid eye movement

Insomnia population. The prevalence was even higher with increasing

age (44%) or with comorbidities present (60%). However,
Insomnia is characterised by difficulty initiating and maintain- these numbers should be interpreted cautiously, due to the
ing sleep or by waking up earlier than desired despite adequate high heterogeneity of the studies included.
opportunity to sleep. A meta-analysis of 71 studies from our The meta-analysed data [9] also revealed associations
group [9] showed that the prevalence of insomnia and insom- between insomnia and poorer health outcomes, such as poorer
nia symptoms in people with type 2 diabetes is 39% (95% CI control of HbA1c (2.51 mmol/mol [95% CI 1.1, 4.4]; 0.23%
34, 44), which is four times higher than in the general [95% CI 0.1, 0.4]) and fasting glucose (0.4 mmol/l [95% CI
2370 Diabetologia (2021) 64:2367–2377

HbA1c Retinopathy Nephropathy Neuropathy Macrovascular Depression Mortality Quality of Life

Sleep
problem

Insomnia

? ? ?
OSA

?
RLS

?
CRSWDs

? ?
Fig. 1 Summary of the literature to date on association between sleep evidence based on large study sample or multiple studies; non-bold black
disorders, health outcomes and QoL in people with type 2 diabetes. ↑, arrows, medium strength evidence; grey arrows, evidence based on small
increased risk or higher levels; ↓, decreased risk or lower levels; =, no sample or subgroup. This figure is available as part of a downloadable
change in risk or levels; ?, no data available. Bold black arrows, strong slideset

0.2, 0.7), in people with type 2 diabetes and insomnia (symp- with the overall OSA prevalence ranging from 55% to 86%.
toms), compared with those with type 2 diabetes only. Chew More severe complaints and higher incidence were reported in
et al. [10] showed insomnia to be associated with diabetic men [15]. The prevalence of OSA is 86% in obese populations
retinopathy (OR 1.61 [95% CI 1.01, 2.49) in 1231 people with with type 2 diabetes. The shared association with obesity
diabetes. No studies investigated associations between insom- makes discerning an independent link between OSA and
nia and other microvascular or macrovascular complications. diabetes challenging. In their review, Kent et al. [16] showed
Our meta-analysis [9] did, however, show an association that intermittent hypoxia and sleep deprivation/fragmentation
between insomnia and the predecessor of such complications play a synergistic role in glucose dysfunction and obesity.
(i.e. high cholesterol levels). OSA is a strong predictor of diabetes, with a 49% increase
Several studies have shown insomnia to be associated with in diabetes risk after adjustment for covariates, including BMI
depressive symptoms in type 2 diabetes (OR 1.31 [95% CI [1]. Moreover, the combined occurrence of OSA and insom-
1.16, 1.47]) [11]. Furthermore, in people with diabetes or nia is associated with higher prevalence of cardiometabolic
hypertension, insomnia is associated with an increased mortal- morbidity, including diabetes, irrespective of BMI [8].
ity rate (OR 7.17 [95% CI 1.41, 36.62]) [12]. Finally, in addi- Although highly prevalent, OSA still remains undiagnosed
tion to poorer health outcomes, and perhaps most important in most people with type 2 diabetes managed in primary care,
for patients, insomnia negatively affects QoL, affecting all with only 18% being detected [15]. When diagnosed, OSA is
domains of QoL questionnaires [13, 14], compared with those associated with poorer glycaemic control, with 11 mmol/mol
with type 2 diabetes without insomnia. (1%) difference in HbA1c levels between those with type 2
diabetes in lowest vs highest OSA severity quartiles [17].
OSA People with type 2 diabetes and OSA are also more likely to
develop microvascular complications, with OSA explaining
OSA, a sleep-related breathing disorder, is characterised by 19% of the variance for retinopathy measures (r = 0.2; p =
complaints such as non-restorative sleep, sleepiness or snor- 0.04) [18] and being associated with an increased risk of
ing, accompanied by obstructive respiratory events. A recent diabetic nephropathy (OR 2.64 [95% CI 1.13, 6.16]) [19] as
review of 12 studies, by Reutrakul and Mokhlesi [15], showed well as diabetic neuropathy (OR 3.97 [95% CI 1.80, 8.74])
that OSA is more prevalent in people with type 2 diabetes, [20]. Additionally, people with type 2 diabetes and OSA are
Diabetologia (2021) 64:2367–2377 2371

more likely to develop coronary artery disease (HR 2.2 [95% (50% vs 8%; p < 0.01) in type 2 diabetes, but no other studies
CI 1.2, 3.9]) and heart failure (HR 3.5 [95% CI 1.4, 9.0]) [21]. on health outcomes related to PLMD were found.
No studies have reported on the association between OSA and Overall, these studies on RLS and PLMD show that sleep-
depression in type 2 diabetes. A prospective population-based related movement disorders are highly prevalent in type 2
study did show that people with type 2 diabetes and OSA have diabetes and have negative health outcomes.
a higher risk of cardiovascular mortality (HR 2.37 [95% CI
1.16, 4.82]), compared with people with only type 2 diabetes CRSWDs
or only OSA [22]. Finally, in addition to poorer health
outcomes, OSA affects QoL in people with type 2 diabetes; CRSWDs affect the timing of sleep either through a dysfunc-
those with OSA score lower in all domains of QoL question- tional biological clock system or through a misalignment
naires, compared with people with type 2 diabetes only [23]. between endogenous and exogenous cues. The role of the
disturbance of the circadian clock in type 2 diabetes develop-
RLS and PLMD ment has been studied extensively in animals and sparsely in
humans [37]. To our knowledge, there are no studies on the
RLS is a sleep-related movement disorder that is characterised prevalence or related health outcomes of CRSWDs in people
by the urge to move in response to uncomfortable and with type 2 diabetes. Shift work, however, is a strong predictor
unpleasant sensations in the legs during periods of rest or of CRSWDs. People with type 2 diabetes that perform
inactivity, thus interfering with sleep. The exact pathophysi- (night)shift work are more likely to have insufficient
ology of RLS is not known, but changes in dopaminergic glycaemic control when compared with people with type 2
neurotransmission, related to iron deficiency in specific brain diabetes performing day work: blood glucose levels of
areas, seem to play an important role [24]. Findings from 970 ≤7.2 mmol/l during the last 6 months (84.2% vs 71.7%; p =
participants from several cross-sectional and case–control 0.02) [38]; and higher HbA1c levels [39, 40].
studies [25–32] suggest that the prevalence of RLS in people In addition, these shift workers report poorer mental health
with type 2 diabetes ranges from 8% to 45%, based on the based on the General Health Questionnaire (37.5% vs 14.2%)
International RLS Study Group criteria. No sex differences and more microvascular complications (e.g. higher frequency
were reported. This prevalence might be an overestimation, of diabetic neuropathy [10.5% vs 3.9%; p = 0.005] [39]),
as until recently these study group criteria could not sufficient- compared with people with type 2 diabetes working dayshifts.
ly differentiate RLS from peripheral neuropathy [25, 33]. Studies reporting on macrovascular complications or QoL
With regard to health outcomes, in a population of 872 associated with shift work in people with type 2 diabetes are
people with type 2 diabetes, RLS was associated with a higher lacking. Even though based on only eight deaths, a Swedish
prevalence of retinopathy (OR 1.69 [95% CI 1.15, 2.49]), study in over 18,000 nurses did find a significant association
neuropathy (OR 1.37 [95% CI 1.44, 3.90]) and nephropathy between nightshift work and risk of diabetes-related mortality
(OR 2.19 [95% CI 1.31, 3.68]) [34]. In the same population, a (HR 12.0 [95% CI 3.17, 45.2]) [41]. Overall, research shows
higher prevalence of macrovascular complications was poorer health outcomes in participants with type 2 diabetes
observed, namely coronary heart disease (OR 1.95 [95% CI working shifts.
1.32, 2.89]) and stroke (OR 2.15 [95% CI 1.27, 2.63]),
compared with the prevalence in people with type 2 diabetes
only. No statistically significant increase in HbA1c level [26, Treating sleep disorders in type 2 diabetes
29, 31] was reported in people with type 2 diabetes and RLS,
compared with those without RLS, but they were more likely In this section we discuss the current knowledge on treating
to develop depression (OR 3.21 [95% CI 1.07, 11.23]) [35]. sleep disorders in people with type 2 diabetes and the effect of
Studies on mortality, type 2 diabetes and RLS were not iden- treatment on health outcomes (see also Fig. 2). Sleep disorder
tified. In addition to poorer health outcomes, people with RLS treatments are categorised into pharmacological and non-
and type 2 diabetes have significantly lower QoL (e.g. vitality pharmacological [42].
score 52.3 vs 74.4; p < 0.001) than people with type 2 diabetes
alone [30]. Pharmacological treatment
PLMD is repetitive cramping or jerking of the legs during
sleep. It is the only movement disorder that occurs exclusively In one study, suvorexant, a selective orexin receptor antago-
during sleep and is often linked with RLS, which occurs nist, improved sleep quality and obesity-associated variables
during wakefulness. Rizzi et al. [36] reported that PLMD in people with type 2 diabetes (n = 13) after 14 weeks [43]. In
prevalence was higher in people with type 2 diabetes than in another study in 75 people with type 2 diabetes and insomnia
age-matched healthy volunteers (85% vs 33%). PLMD was receiving dexzopiclone or estazolam for 14 days, sleep was
associated with a higher prevalence of daytime somnolence improved in both groups but only fasting glucose was
2372 Diabetologia (2021) 64:2367–2377

Fig. 2 Summary of the possible

pharmacological and non- Sleep disorder Type of therapy Treatment
pharmacological treatment
options for sleep disorders in
people with type 2 diabetes. Bold Insomnia Orexin receptor antagonist
text, strong evidence based on Low-dose antidepressants
large study sample or multiple Pharmacological
studies; non-bold black text, Antipsychotics
medium strength evidence; grey Melatonin
text, evidence based on small
study sample or subgroup. This
figure is available as part of a Non-pharmacological CBT and sleep education
downloadable slideset

OSA
Pharmacological None reported

CPAP
Non-pharmacological Mandibular devices
Weight loss

RLS
Pharmacological Dopamine agonists

Non-pharmacological None reported

CRSWDs
Pharmacological None reported

Non-pharmacological None reported

significantly reduced in the dexzopiclone group. This suggests improved, compared with the placebo, in people with type 2
a direct effect of dexzopiclone on glycaemic control [44]. To diabetes [48], whilst the latter study (n = 42) showed an
date, no studies on the glycaemic effects of other hypnotics in improvement in sleep quality and stopped HbA1c further
type 2 diabetes have been published. This would be important increasing [49]. A meta-analysis on melatonin, also including
as hypnotics are often prescribed to people with type 2 diabe- studies in the general population, supports this finding, show-
tes [45]. Especially considering the frequent off-label use of ing improved glycaemic control through melatonin supple-
low-dose antidepressants or antipsychotics with known meta- mentation [50]. Although this seems promising, the exact role
bolic side-effects as treatment for insomnia [46], special atten- of melatonin in type 2 diabetes is still controversial. Studies
tion is warranted regarding the health effects of such medica- have identified a common variant of melatonin receptor 1B to
tion in people with type 2 diabetes. be associated with impaired insulin secretion in the presence
Although melatonin is generally not recommended for of melatonin. This suggests that melatonin could induce insu-
treatment of insomnia in adults [47], two studies [48, 49] lin insensitivity in the risk allele carriers and thus have adverse
investigated the effect of a melatonin agonist or prolonged- effects [51].
release melatonin in people with type 2 diabetes and insomnia. For RLS, dopamine agonists are the first-line pharmaco-
The former study (n = 36) found that sleep quality and HbA1c logical option [52]. In a study of the RLS population, which
Diabetologia (2021) 64:2367–2377 2373

included people with type 2 diabetes, treatment with Weight loss Weight loss is another important intervention for
pramipexole reduced RLS complaint scores (−14.2 ± 0.7 vs OSA. A four-centre RCT [60] found that intense lifestyle
−8.1 ± 0.7) and improved mood, compared with placebo interventions were more effective than the control treatment
[53]. One small Japanese study [27] examined the efficacy in reducing OSA complaints (apnoea–hypopnoea index, −5.4
of pramipexole in eight people diagnosed with type 2 diabe- vs +4.2 events/h; p = 0.000) and HbA1c levels (−7.7 mmol/
tes and RLS. A decrease in RLS scores (−13.6 points [95% mol [−0.7%] vs −2.2 mmol/mol [−0.2%]; p = 0.000) during
CI −15.5, −11.7]) over 12 weeks and a change in HbA1c 1 year. Even after 10 years, the lifestyle intervention group
levels of −3.2 mmol/mol (95% CI −4.4, −2.2) (−0.29% still showed reduced OSA complaints (apnoea–hypopnoea
[95% CI −0.4, −0.2]) was observed. Other pharmacological index, −9.9 vs −5.9 events/h; p = 0.11). In a meta-analysis of
treatments for RLS, such as other dopamine agonists, 136 studies (n = 22,094 individuals) that examined comorbid
opioids, benzodiazepines, anticonvulsants and iron therapy, health outcomes in those who had bariatric surgery for weight
have not been tested in type 2 diabetes for health outcomes loss, 87.9% (1051/1195) and 76.8% (1417/1846) had no more
[54]. OSA and type 2 diabetes, respectively [61].
One study examined the effect of type 2 diabetes medica-
Non-pharmacological treatment tion associated with weight loss on OSA in type 2 diabetes
[62]. This RCT in 36 individuals investigated the effect of
Continuous positive airway pressure and mandibular devices dapagliflozin, a sodium–glucose cotransporter 2 (SGLT2)
Continuous positive airway pressure (CPAP) is the gold stan- inhibitor. No significant reduction in HbA1c levels compared
dard for treating OSA but effects on health outcomes in people with the control group was observed, but significant reduc-
with type 2 diabetes are inconsistent. On the one hand there are tions were observed in OSA severity (−10.17 events/h;
studies showing a significant change in HbA1c (−4.4 mmol/mol p < 0.001), as well as systolic BP (−6.11 mmHg; p = 0.012)
[−0.4%]; p = 0.024) [55], whilst, on the other hand, a meta- and BMI (−1.21 kg/m2; p = 0.004). These results suggest that
analysis including six randomised controlled trials in 518 weight loss, regardless of how the weight loss was induced,
people with type 2 diabetes showed that CPAP did not result could be a successful treatment for OSA and type 2 diabetes.
in a reduction of HbA1c or fasting glucose [56]. These incon-
sistencies might be explained by the following factors: poorer Cognitive behavioural therapy for insomnia and sleep educa-
disease state, with effects being more profound in people with tion An elegant meta-analysis by Kothari et al. [44] identified
higher HbA1c levels; differences in the definition of adherence six studies showing that cognitive behavioural therapy for
to the CPAP intervention; or CPAP use being limited to the first insomnia (CBT-I) and/or sleep education improved sleep
half of the night when non-rapid eye movement (NREM) sleep quality measured by the Pittsburgh Sleep Quality Index
dominates, while specifically REM sleep apnoeas in the latter (−1.31 [95% CI −1.83, −0.80]) and resulted in a non-
half are adversely associated with glycaemic control [17]. significant HbA1c reduction (−3.6 mmol/mol [−0.35%]; p =
Overall, CPAP does seem to positively affect sleep quality, 0.13) in those with sleep disturbances or insomnia, including
blood pressure, QoL and depression [15, 57], which in turn both the general population and people with type 2 diabetes.
could improve type 2 diabetes management and prevent Only two small pilot studies on CBT-I in people with type 2
comorbidities. diabetes have been conducted, reporting a reduction in both
Mandibular advancement devices are another treatment HbA1c levels after 3 weeks (2.8 ± 3.06 mmol/mol [0.26 ±
option for younger people with less-severe OSA. A pilot 0.28%]) [63] and after 7 weeks (4.5 mmol/mol [0.41%]; p =
study from India (n = 24) showed that mandibular devices 0.01) [64], as well as a 4.63 (p = 0.002) decrease in Beck
decreased HbA1c levels (−151 mmol/mol [−14.01%]; p = Depression Inventory measures [65] in the latter cohort. The
0.013) and improved sleep quality (measured by a fact that CBT-I can effectively reduce depressive symptoms
decrease in Epworth Sleepiness Scale of 60.7 points; has been demonstrated previously outside this specific type 2
p = 0.001) over a period of 3 months [58] in people with diabetes population [66].
type 2 diabetes and mild OSA. In people with type 2 With regard to sleep education, two studies analysed the
diabetes, CPAP has not been compared with mandibular effects of sleep education in people with type 2 diabetes,
advancement devices yet. However, in the general popu- although none with diagnosed sleep disorders. One study
lation, CPAP was more effective in reducing the number [67] in people with type 2 diabetes and late sleeping times
of respiratory events, whereas compliance was higher for showed that sleep education improved sleep quality and
mandibular devices [59]. Finally, surgical interventions reduced HbA1c (−1.5 ± 0.55 mmol/mol [−2.29 ± 2.20%] vs
for OSA aimed at correcting underlying anatomical abnor- −1.11 ± 0.47 mmol/mol [−2.25 ± 2.19%]; p < 0.05), compared
malities in the oropharyngeal area and the effect of hypo- with controls. The other study [68] investigating people with
glossal nerve stimulation have not been researched in type type 2 diabetes and abnormal or poor sleep, reported improved
2 diabetes. sleep after sleep education but no change in glycaemic control.
2374 Diabetologia (2021) 64:2367–2377

Overall, these studies suggest that both CBT-I and sleep 77], compared with matched control participants. Since these
education could contribute to improving sleep and health studies are cross-sectional, no cause–effect relationship can be
outcomes in those with type 2 diabetes and sleep disorders. determined and the relationship may even be bidirectional.
Despite the limited data available, treating sleep disorders This bidirectional relationship may explain the increased prev-
non-pharmacologically in people with type 2 diabetes seems to alence of sleep disorders in people with type 2 diabetes.
have a positive effect on health outcomes. This calls for more In this review, we found that insomnia, OSA and RLS are
extensive research on above-mentioned treatments as well as more prevalent in people with type 2 diabetes than in the
other promising non-pharmacological interventions in those with general population [9, 15, 25–32]. Additionally, we showed
sleep disorders and type 2 diabetes. It is important to focus on that these three sleep disorders as well as (work-related)
non-pharmacological treatment because of the previously disturbances of the circadian rhythm negatively affect health
mentioned negative effects that some pharmacological options outcomes in at least one, and often multiple, diabetes domains,
may have on weight and glycaemic control [46, 69]. One inter- especially glycaemic control. Given their high prevalence and
esting option is bright light therapy (BLT), which is known for its adverse consequences, it is strongly recommended to include
activating and synchronising effects and is used for treatment of active assessment of possible sleep disorders in management
CRSWDs and depression. A study in 83 people with type 2 of type 2 diabetes. Sex differences should be taken into
diabetes and depression, showed that BLT reduced depressive account and special attention should be given to detecting
symptoms (−3.9 [95% CI −9.0, 1.2] Inventory of Depressive OSA, which often remains undiagnosed in type 2 diabetes.
Symptomatology points) and improved insulin sensitivity Additionally, differentiating between RLS and conditions
(0.15 mg/kg × min [95% CI −0.41, 0.70] measured using mimicking RLS commands attention, as this may affect treat-
hyperinsulinaemic–euglycaemic clamp), although neither ment responsiveness [53].
change was statistically significant [70]. In general, improving sleep in people with type 2 diabe-
tes could in turn improve glycaemic control, thus provid-
ing an important aid in preventing type 2 diabetes progres-
sion, and ultimately improve QoL [78]. Studies on the
Possible mechanisms, clinical implications effect of treating sleep disorders specifically in people with
and future research type 2 diabetes are limited, based on small studies, or
absent. Most first-line treatments for sleep disorders seem
Evidence suggests that there is a bidirectional relationship effective in people with type 2 diabetes, comparable with
between sleep disorders and type 2 diabetes, implying a the general population, but with additional positive effects
vicious circle. On the one hand, sleep disorders contribute to on type 2 diabetes and other health outcomes. Of high
progression of type 2 diabetes via hypothetical mechanisms, clinical relevance are people with type 2 diabetes who
such as decreased brain glucose utilisation, altered orexin partake in shift work, who require specific guidance in
response, overactivation of the hypothalamus–pituitary–adre- terms of meal preparation and insulin regimens in order
nal axis [71], suboptimal self-care (i.e. lower medication to achieve optimal glycaemic control.
adherence [72]) and impaired decision-making (i.e. unhealthy This review is the first to summarise the literature on the
diet and sedentary behaviour) [73]. Additionally, despite the prevalence of sleep disorders in type 2 diabetes, its health
fact that no literature on this topic was found, as sleep disor- consequences and effects of treatment of sleep disorders. We
ders disrupt multiple metabolic processes via attenuated sleep could not include information on all sleep disorders and all
quality, sleep quantity or disturbances of the circadian rhythm, treatment options due to gaps in the literature, and some data
it is conceivable that they affect the efficacy of drugs aimed at presented should be interpreted cautiously because they are
lowering HbA1c. On the other hand, type 2 diabetes and asso- based on few participants or specific subgroups, as is indicated
ciated comorbidities, such as obesity, nightly hypoglycaemia, in Figs 1 and 2. A general recommendation for future studies is
increased sympathetic activity, neuropathic pain and nocturia, therefore to further explore the impact of several sleep disorders
may contribute to the development of sleep disorders [74]. and overlap between them, including CRSWDs, central disor-
Medication may play a role as well, with metformin, for exam- ders of hypersomnolence and parasomnias in people with type
ple, causing insomnia in about 1.7% of the people starting this 2 diabetes. Moreover, special research focus is warranted on the
drug [75]. effects of both pharmacological and non-pharmacological treat-
Finally, sleep architecture might differ between people ment options on health outcomes in type 2 diabetes.
with and without diabetes. EEG case–control studies show In conclusion, sleep disorders are highly prevalent in
that people with type 2 diabetes indeed have lower amounts people with type 2 diabetes, negatively affecting health
of slow wave sleep (SWS) or more micro-arousal events [76, outcomes. Since treatment of the sleep disorder could prevent
Diabetologia (2021) 64:2367–2377 2375

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but unedited supplementary material including a slideset of the figures for 3390/jcm8101653
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Funding Work in the authors’ group is supported by Diabetes Foundation
9. Koopman ADM, Beulens JW, Dijkstra T et al (2020) Prevalence of
Netherlands (FR) and the National Institutes of Health (KLK;
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1R01HL141881, 1R01AG059291).
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Endocrinol Metab 105(3):614–643. https://doi.org/10.1210/
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article and revising it critically for important intellectual content. All diabres.2019.107967
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