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diabete 2 article .pdf

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Titre: Aiding sleep in type 2 diabetes: therapeutic considerations
Auteur: Xiao Tan PhD

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Aiding sleep in type 2 diabetes: therapeutic considerations
Xiao Tan, Lieve van Egmond, Colin D Chapman, Jonathan Cedernaes, Christian Benedict
Lancet Diabetes Endocrinol
2018; 6: 60–68
Published Online
August 24, 2017
Department of Neuroscience,
Uppsala University, Uppsala,
Sweden (X Tan PhD,
L van Egmond MSc,
C D Chapman MSc,
J Cedernaes MD, C Benedict PhD)
Correspondence to:
Dr Xiao Tan, Department of
Neuroscience, Uppsala
University, SE-751 24 Uppsala,

Insomnia and obstructive sleep apnoea (OSA) are more prevalent in patients with type 2 diabetes than in the general
population. Both insomnia and OSA have been linked to cardiometabolic alterations (eg, hypertension, increased
activity of the sympathetic nervous system, and systemic insulin resistance) that can exacerbate the pathophysiology
of type 2 diabetes. Improvement of sleep in patients with diabetes could therefore aid the treatment of diabetes. To
help health practitioners choose the best clinical tool to improve their patients’ sleep without detrimentally affecting
glucose regulation, this Review critically analyses the effects of common treatments for insomnia and OSA on both
sleep and glucose metabolism in patients with type 2 diabetes. These treatments include pharmaceutical sleep aids
(eg, benzodiazepine receptor agonists, melatonin) and cognitive behavioural therapy for insomnia, continuous
positive airway pressure for OSA, and lifestyle interventions.

Patient care requires attention to detail and consideration
of all the available and relevant information. The presence
of different comorbidities can substantially affect the
choice of treatment. A substantial and underappreciated
proportion of patients with type 2 diabetes also have
problems with sleep. A study1 of 7239 patients with type 2
diabetes found that about 77% regularly have symptoms of
insomnia, such as difficulty in falling and staying asleep
panel 1). Reductions in the total duration of sleep,
fragmentation of sleep, and light sleep—each of which
can occur as part of clinical insomnia—have been linked
to various indices of impaired glucose control in investi­
gations involving healthy individuals.3–7
In addition to the association between insomnia and
type 2 diabetes, studies8–11 showed that around 50–90% of
patients aged 18 years or older with type 2 diabetes have
obstructive sleep apnoea (OSA), which is significantly
higher than the prevalence of OSA in the age-matched
Panel 1: The definition of insomnia according to the
International Classification of Sleep Disorders
(3rd edition) criteria2
• Reports of one or more of the following symptoms:
difficulty falling asleep; difficulty staying asleep; waking too
early; or sleep that is chronically non-restorative or of poor
quality. The symptom occurs at least 3 nights per week and
has been present for at least 3 months, despite adequate
opportunities and circumstances for sleep.
• Reports of at least one of the following forms of daytime
impairment, associated with the night-time sleep
difficulty: fatigue or malaise; attention, concentration,
or memory impairment; social or vocational dysfunction
or poor school performance; mood disturbance or
irritability; daytime sleepiness; reduction in motivation,
energy, or initiative; prone to errors or accidents at work
or when driving; tension, headaches, or gastrointestinal
symptoms in response to loss of sleep; and concerns or
worries about sleep.
• The difficulty in sleeping and waking is not explained by
an unrelated sleep disorder.


general population (10–17% in men, 3–9% in women;
panel 2).14 Partial or total cessation of breathing caused by
OSA impairs the quality of sleep because of arousal and
puts a considerable burden on the cardiometabolic system
because of hypoxia-induced activation of the sympathetic
nervous system (eg, increased cardiac effort, higher
systemic and pulmonary blood pressure, insulin resis­
tance).15 The high prevalence of insomnia and OSA in
patients with type 2 diabetes is important because
nocturnal sleep of sufficient quality and duration is
important for the maintenance of optimal cardio­
meta­bolic health. A meta-analysis16 of 3258 patients with
type 2 diabetes (aged 20–89 years) showed that poor sleep
quality (estimated by the Pittsburgh Sleep Quality Index)
and short sleep duration (<6 h/night) were both associated
with increased HbA1c (weighted mean difference for poor
sleep quality vs normal sleep quality was 0·35%, 95% CI
0·12–0·58, and for short sleep duration vs normal sleep
duration [6–8 h/night] was 0·23%, 0·10–0·36).
Spontaneous sleep extension (for about 80 days, on
average 30·7 min/night, recorded in a sleep diary) in
125 obese adults with short sleep duration (<6·5 h/night)
decreased signs of insulin resistance, reduced the
Panel 2: Definition of apnoea, hypopnoea, and obstructive
sleep apnoea (OSA) in adults2,12
Drop in the peak air flow signal excursion by ≥90% of
pre-event baseline; duration ≥10 s (typically measured by
full polysomnography)
Peak air flow signal excursions drop by ≥30% of pre-event
baseline; duration ≥10 s in association with either
≥3% arterial oxygen desaturation or an arousal by OSA
(typically measured by full polysomnography)
Apnoea-hypopnoea index ≥15 events per h, or
between 5 and <15 events per h with excessive daytime
sleepiness (typically assessed by the Epworth Sleepiness Scale);13
laboured breathing during the apnoea event Vol 6 January 2018


proportion of participants with abnormal fasting glucose
concentrations, and improved subjective sleep quality as
assessed by the Pittsburgh Sleep Quality Index.17 In 16 nonobese healthy adults with short sleep duration (around
6·5 h/night on weekdays), a 6-week sleep extension
(on average 44–54 min on weekdays, confirmed by wrist
actigraphy) improved fasting insulin sensitivity (r=–0·66
for correlation between changes in actigraphic measures
of sleep time and changes in morning insulin-to-glucose
ratio).18 In adults aged 55 years or older with chronic
insomnia (n=70), 4 months of cognitive behavioural
therapy (CBT) successfully improved their Pittsburgh
Sleep Quality Index score and reduced their risk of
developing type 2 diabetes.19 In individuals with OSA,
treatment approaches, such as continuous positive airway
pressure (CPAP), have been found to improve glycaemic
control, particularly in those with type 2 diabetes.15
These findings provide strong support for the hypothesis
that interventions to improve sleep could enhance manage­
ment of type 2 diabetes. However, it is crucial to choose
sleep interventions that do not detrimentally affect glucose
regulation. With this consideration in mind, this Review
evaluates and discusses the effects of commonly used
treatments for insomnia and OSA on both sleep and
glucose metabolism in patients with type 2 diabetes.

Pharmacological treatments

Benzodiazepine receptor agonists and benzodiazepines
Benzodiazepine receptor agonists (so-called Z drugs) and
benzodiazepines, positive allosteric modulators of
γ-aminobutyric-acid receptor A, are prescribed for the
treatment of insomnia. In a meta-analysis20 of 4378 patients
taking Z drugs (eszopiclone 1–3 mg/day, zaleplon
5–20 mg/day, or zolpidem 6·25–15 mg/day, for 34 days on
average), insomnia was improved by shortening the
latency of sleep onset (weighted mean difference
vs placebo –22 min, 95% CI –33 to –11, measured by
polysomnography). A meta-analysis21 (n=2672) of patients
taking benzodiazepines (brotizolam 0·25 mg/day,
estazolam 2 mg/day, flurazepam 15 or 30 mg/day,
midazolam 15 mg/day, quazepam 15 mg/day, temazepam
30 mg/day, or triazolam 0·5 mg/day, for 17 days on
average) also showed reduced latency of sleep onset
(weighted mean difference vs placebo –14·3 min, 95% CI
–18·0 to –10·6, measured by subjective estimation) as well
as prolonged sleep duration (weighted mean difference
vs placebo 48·4 min, 39·6–57·1, subjective estimation).21
Because Z drugs have shorter half-lives and
reduced risks of next day side-effects (eg, drowsiness)
compared with benzodiazepines,22 they are the most
widely prescribed class of medication for insomnia.20
Nevertheless, benzodiazepines are frequently prescribed
to treat conditions such as anxiety that often co-exist with
type 2 diabetes or sleep disturbances.23,24 Patients with
type 2 diabetes show signs of insomnia more frequently
than the general population,25,26 so the prescription of
Z drugs and benzodiazepines to alleviate insomnia Vol 6 January 2018

might be more common in this patient group. A Dutch
study27 of 7016 patients with type 2 diabetes showed
that 10·1% were prescribed hypnotics or anxiolytics, or
both (most commonly Z drugs and benzodiazepines).28
In addition to the numerous side-effects—such as
cognitive impairment, daytime somnolence, dizziness,
fatigue, and withdrawal symptoms20,21—some studies
have suggested that both Z drugs and benzodiazepines
might impair glucose metabolism. In healthy adults
(n=12, aged 38·3 years, SD 8·1), 15-day oral administration
of zolpidem (10 mg/day at 22:00 h) or brotizolam
(0·25 mg/day) enlarged the glucose delta area under
curve response to oral glucose tolerance testing (OGTT,
75 g, done between 08:30 and 09:00 on day 16) by
about 86% and 122%, respectively, while the insulin
response to OGTT remained unchanged.29 Moreover,
zolpidem use has been linked to a 45% increased
incidence of type 2 diabetes in a longitudinal cohort
of around 45 000 adults in Taiwan followed up bet­
ween 1997 and 2011.30 One explanation for these findings
could be that Z drugs, such as zolpidem, reduce slowwave activity during non-rapid-eye movement (REM)
sleep.31 Such alterations in sleep have previously been
linked to reduced daytime insulin sensitivity.3,32 Although
further research is warranted to investigate the effects of
Z drugs and benzodiazepines on glucose metabolism in
patients with type 2 diabetes and insomnia, current
findings nonetheless suggest that these patients require
more frequent monitoring of glucometabolic measures.

Melatonin and melatonin receptor agonists
The sleep-promoting hormone melatonin is secreted by
the pineal gland, regulates circadian rhythms, and its
production is controlled by light and retinohypothalamic
tract.33 Melatonin is available as an over-the-counter
medication in many countries (eg, the USA and several
European countries) for alleviating the symptoms of jet
lag.34 According to a survey35 in 2012, about 1·3% of the US
population (3·1 million) reported regular melatonin use to
facilitate sleep onset, but very few studies have assessed the
efficacy of exogenous melatonin in the treatment of
insomnia. A meta-analysis36 focusing on adults and
children with primary sleep disorders (including insomnia,
delayed sleep phase syndrome, and REM sleep behaviour
disorder, n=1683) showed that oral treatment with
melatonin versus placebo shortens the latency of sleep
onset (weighted mean difference 7·06 min, 95% CI
4·37–9·75) and prolongs total sleep duration (8·25 min,
1·74–14·75), but the treatment dose (0·1–5 mg/day),
treatment period (7–182 days), participant age, and sleep
disorders included were highly heterogeneous, which
made evaluation of the effects of exogenous melatonin on
the treatment of insomnia impossible. Furthermore,
mistimed exposure to natural light (which can phase shift
the endogenous circadian rhythm), unscheduled sleep
times, and the timing of melatonin treatment have all been
proposed to alter the efficacy of oral melatonin in sleep


difficulties.37 The American Academy of Sleep Medicine
does not recommend melatonin for treatment of insomnia
in anyone,38 and existing knowledge is insufficient to
support a definitive conclusion on the efficacy of oral
melatonin to ease insomnia in patients with type 2
In addition to the ambiguous effects of exogenous
melatonin on sleep, data conflict about its effect on glucose
metabolism. In a study39 of healthy young adults (n=36),
oral administration of 5 mg melatonin versus rice flour
placebo scheduled 5·75 h before habitual bedtime induced
an advance of dim light (night) melatonin onset, as
measured by salivary melatonin. A meta-analysis40 based
on nine placebo-controlled studies of exogenous melatonin
in delayed sleep phase disorder showed that administration
of exogenous melatonin advances endo­genous melatonin
onset and sleep onset in children and adults, rendering
melatonin a chronotherapeutic option in the treatment of
sleep onset disturbances. In a cross-sectional study41 in
1014 non-shift working adults with prediabetes (mean
age 62·4 [SD 8·7] years), late chronotype—ie, a condition
in which an individual’s sleep onset shifts towards
eveningness—has been associated with higher HbA1c
concentrations. Melatonin-induced earlier sleep onset
might therefore improve glycaemic control in patients
with type 2 diabetes. In the Nurses’ Health Study,42 a casecontrolled study in 370 women who developed type 2
diabetes from 2000–12 versus matched 370 controls with
risk-set sampling (64·4 vs 64·2 years), low melatonin
secretion was associated with an increased risk of type 2
diabetes development compared with high melatonin
secretion. However, evidence also suggests that exogenous
melatonin could detrimentally affect glucose control in
human beings. For instance, in a study43 of 21 healthy
women, 5 mg oral melatonin versus placebo administered
either in the morning (08:45) or evening (20:45) increased
the incremental area under the curve of plasma glucose
following OGTT (morning 186%; evening 54%). In a
study44 of 45 adults without diabetes, 3 months of treatment
with 4 mg oral melatonin taken at bedtime reduced
first-phase glucose-induced insulin secretion in OGTT
(around 22% compared with baseline), particularly in
carriers of a risk variant in the melatonin receptor 1 b gene
(MTNR1B), which is present in around 30% of the general
Ramelteon, a selective melatonin receptor agonist, has
been approved in the USA and Japan for the treatment of
sleep-onset insomnia.45 The safety of ramelteon in patients
with insomnia has been examined—the only substantial
adverse effect is daytime somnolence.46 The most recent
meta-analysis involving placebo-controlled trials of ramel­
teon (including both published and unpublished data)
showed that oral administration of this melatonin receptor
agonist (4–32 mg/day for 6–180 days) shortened subjective
latency of sleep onset (weighted mean difference vs placebo
–4·30 min, 95% CI –7·01 to –1·58), in adults with
symptoms of insomnia (n=5812).46 However, these

improvements are small and oral administration of
ramelteon does not significantly improve insomnia with
difficulty in sleep maintenance. The effects of ramelteon
on glucose metabolism have been studied in 32 Japanese
patients with type 2 diabetes. After a 3-month intervention
with ramelteon (8 mg/day, taken at night), no significant
changes in HbA1c concentrations were observed.47
Because melatonin is available as an over-the-counter
drug in countries such as the USA, the fact that some
patients might self-medicate with a higher than
recommended dose or at unfavourable times in the
circadian rhythm (eg, morning) cannot be ruled out, and
this could increase their risk for disturbed glucose
metabolism. Given that the existing evidence on the effects
of melatonin and melatonin receptor agonists on sleep
and glucose metabolism is still controversial, more
research is warranted to shed light on the safety profile of
these medications in patients with type 2 diabetes and

Suvorexant, an anti-insomnia drug released in Japan and
the USA between 2014 and 2015, antagonises signalling
of the hypothalamic neuropeptide orexin (also known as
hypocretin), which acts on the brain to increase wake­
fulness.48 Two randomised placebo-­
controlled trials48,49
found that suvorexant improved sleep, particularly sleep
maintenance, in insomniacs without type 2 diabetes.
In a 4-week phase 2 trial48 of patients receiving suvorexant,
at the dose recommended by the US Food and Drug
Administration (10 mg/day, n=62), and who underwent
graphy, sleep efficiency (percent of in-bed
time asleep) was improved by 4·7% (95% CI 1·6–7·8)
and wake period after sleep onset was reduced
by 21·4 min (8·7–34·2), compared with placebo (n=249).
In a 1-year phase 3 trial,49 suvorexant (40 mg/day, aged
<65 years; 30 mg/day, aged ≥65 years, n=522; placebo,
n=259), was associated with extended subjective sleep
duration (difference vs placebo 22·7 min, 95% CI
16·4 to 29·0) and decreased subjective latency of sleep
onset (–9·5 min, –14·6 to –4·5) during the first month
of treatment.49 However, the recommended dose of
suvorexant (10–20 mg) is not superior to conventional
hypnotics (eg, Z drugs) in terms of efficacy of treatment;
higher than recommended doses of suvorexant (40 mg)
might induce daytime somnolence and narcolepsy-like
symptoms.50 Suvorexant has been found to improve
glucose metabolism in a mouse model of type 2 diabetes.51
If these effects on glycaemic control are shown in human
trials, suvorexant could be a promising treatment for
insomnia in patients with type 2 diabetes.

CBT for insomnia
CBT for insomnia (CBT-I) includes five core techniques:
(1) cognitive therapy, which offers education to target
dysfunctional beliefs and attitudes about sleep and
insomnia; (2) stimulus control, which aims to restrict the Vol 6 January 2018


use of bed for sleeping only, and limit the association
between bed and stimulating behaviour; (3) sleep
restriction, which controls the time spent in bed on the
basis of the individual’s sleep efficiency in order to
restore the homoeostatic drive to sleep; (4) sleep hygiene,
which advises on the environmental factors, physiological
factors, behaviour, and habits that promote sleep; and
(5) relaxation, which limits cognitive arousal and reduces
muscular tension to facilitate sleep.52 CBT-I is the firstline treatment for insomnia because of its high treatment
efficacy and safety. In patients with persistent insomnia
(n=80), a 6-week CBT-I treatment (90 min/session, one
session per week) successfully reduced the subjective
latency of sleep onset by 19·9 min (95% CI 3·6–26·1),
decreased the subjective time of being awake after sleep
onset by 68·7 min (57·8–79·7), and increased subjective
sleep efficiency by 14·4% (11·8–16·9).53 These results
were supported by a meta-analysis54 of 20 studies (n=2411)
that examined the effect of self-administered CBT-I on
insomnia, which suggested that CBT-I is effective
in shortening the latency of subjective sleep onset
(Hedges’s g –0·66, 95% CI –1·0 to –0·4), reducing the
time awake after sleep onset (–0·55, –0·9 to –0·2),
increasing the efficiency of sleep (0·80, 0·4 to 12), and
prolonging the duration of sleep (0·24, 0·0 to 0·5).54
CBT-I also showed improvements in the metabolic
profiles of elderly patients with insomnia.19 A 4-month
programme of one 2 h session of CBT-I per week in
patients with high metabolic risk (defined as having four
or more biomarkers in the abnormal laboratory range,
including HbA1c ≥6·0%) was associated with reduced
insomnia severity as assessed by the Pittsburgh Sleep
Quality Index (mean global sleep quality score at 16 months
vs baseline for CBT-I was 5·6 [SD 3·0] vs 10·4 [2·9] and for
sleep seminar control intervention was 8·2 [3·4] vs 11·1
[2·9]; p<0·01; Cohen’s d=0·44) and reduced odds of
remaining in the high metabolic risk group (odds ratio 0·06,
95% CI 0·005–0·669 vs sleep seminar control intervention)
at 16 months after initiation of the behavioural
intervention.19 However, whether CBT-I is similarly
effective in optimising metabolic profiles in patients with
type 2 diabetes requires further investigation. This
research question is particularly relevant given that some
components of CBT-I, such as sleep restriction, have been
shown to compromise glucose control in healthy
individuals.55,56 Notwithstanding this caveat, evidence
generally supports the introduction of CBT-I as a primary
treatment for insomnia in patients with type 2 diabetes.
First, both the efficacy of treatment and the sustainability
of CBT-I are high, and side-effects are minor compared
with those of pharmaceutical interventions such as
Z drugs and benzodiazepines. Second, in addition to
improving the initiation and maintenance of sleep, CBT-I
has been shown to improve slow-wave sleep.57 This finding
is important because prolonged and consolidated sleep
might benefit daytime glucose control.3,32 However, the fact
that attrition and suboptimal adherence could diminish Vol 6 January 2018

the efficacy of CBT-I should be acknowledged. Additionally,
the time and economic costs of traditional CBT-I
(conducted face-to-face by a therapist) might further
restrict its avail­ability to individuals with type 2 diabetes
and insomnia.58

CPAP is the most widely used therapy for OSA and has
high treatment efficacy.59 The therapy consists of a nasal or
oral-nasal mask that is attached to a flow generator set to a
specific pressure to maintain airway patency and overcome
respiratory disturbance. This technique reduces or pre­
vents the occurrence of apnoeas and hypopnoeas, and
eases sleep fragmentation.59 Numerous studies have
investigated the effects of CPAP on glucose metabolism in
the past two decades. A meta-analysis focusing on patients
without diabetes with moderate to severe OSA (apnoeahypopnoea index [AHI] ≥15 events per h, n=317) showed
that 3–24 weeks of CPAP therapy (>4 h/day) was associated
with a 0·55 lower homoeostatic model assessment insulin
resistance value.60 Evidence suggests that CPAP, especially
long-term (≥3 months) use for at least 4 h/night, improves
clinical measures of glycaemic control in patients with
type 2 diabetes.15,61 A randomised controlled trial62 com­
paring the effects of CPAP (≥4 h/night) for 6 months with
no CPAP intervention on glucose metabolism in patients
with type 2 diabetes and OSA (AHI ≥5 events per h, n=50)
showed that CPAP resulted in a reduction in HbA1c
(treatment difference –0·4%, 95% CI –0·7 to –0·1, adjusted
for baseline HbA1c). In a subgroup of the same study (n=29),
the reduction in HbA1c following CPAP treatment
remained despite treatment with oral antidiabetic drugs
(treatment difference –0·6%, 95% CI –1·0 to –0·2). These
preliminary findings suggest that treatment with CPAP
for patients with OSA and type 2 diabetes has similar
glucose-lowering effects to the major classes of oral
antidiabetic agents (typically averaging a 1–2% reduction
in HbA1c).63 More studies are warranted to investigate
whether CPAP treatment for patients with type 2 diabetes
and OSA could increase their responsive­
ness to anti­
diabetic medication. In a study of 33 patients with resistant
hypertension, patients (n=12, mean age 56 years) with
resistant hypertension receiving CPAP therapy were more
responsive to antihypertensive treatment, whereas patients
(n=21, 54 years) who did not receive CPAP continued to
have refractory hypertension,64 supporting the hypothesis
that CPAP could change patients’ responses to medication.
Traditional 4-h CPAP treatment only covers around 40%
of REM sleep, during which the risk of apnoeas is
considerably increased (as a result of motor inhibition)
and glucose concentrations are elevated compared with
other stages of sleep.65 Extended treatment time covering
most REM sleep might be necessary to improve glycaemic
control in the long term. One study66 of patients with OSA
and prediabetes (n=39) compared a 2-week 8-h nightly
CPAP treatment with oral placebo (ie, a placebo capsule
taken before bedtime, which patients were told was


intended to ease the symptoms of OSA). This study
showed a greater reduction in the glucose delta area under
the curve response to OGTT following CPAP treatment
than oral placebo (treatment difference –1276·9, 95% CI
–2392·4 to –161·5, adjusted for age, BMI, and ethnicitybased diabetes risk), which indicated improved glucose
metabolism.66 However, this study did not compare the
effect of 8-h CPAP with 4-h CPAP on glucose metabolism.
In a separate study, a 1-week 8-h nightly treatment with
CPAP for patients with OSA and type 2 diabetes (n=19)
was effective in reducing their 24-h glucose concentrations
compared with sham CPAP treatment (mean change in
glucose for CPAP vs baseline was –13·7 mg/dL, SEM 3·6
[–0·76 mmol/L, SEM 0·2], and for sham CPAP vs baseline
was –2·9 mg/dL, SEM 1·4 [–0·16 mmol/L, SEM 0·08]).67
These results might partly explain why an earlier study68
(n=42) investigating the effect of CPAP for less than
4 h/night (for over 3 months) did not find improvements
in glycaemic control (change in HbA1c for CPAP vs baseline
was –0·02% [SD 1·5] and for sham CPAP vs baseline was
0·1% [0·7]; 95% CI between groups –0·6 to 0·9).68
Although the use of CPAP has been recommended as
soon as OSA is detected in patients with type 2 diabetes,15
several questions remain. First, the effects of CPAP on
glycaemic control in type 2 diabetes need to be verified


Type 2 diabetes


Condition Sleep


in randomised trials with larger sample sizes and longer
follow-up periods than previous studies, with and
without treatment with other antidiabetic treatments.
Additionally, further investigations are needed to assess
whether full-night CPAP treatment leads to superior
metabolic improvement than the traditional 4-h treat­
ment protocol, especially for long treatment periods
(eg, ≥3 months). Moreover, a study involving 80 patients
(mean age 58 years) showed that 15% had stopped
CPAP therapy after using it for 10·1 months (SD 15·5),
and 25 of 80 patients (31%) had never commenced
therapy after initial diagnosis and CPAP titration,69 even
though CPAP withdrawal results in the recurrence of
sleep-disordered breathing in patients with mild to
moderate OSA and severe OSA.70 The beneficial effects
of CPAP on glycaemic control, especially following
short-term treatment,66,67 might reverse as soon as the
treatment is stopped. Thus, interventions aiming to
increase patients’ adherence to CPAP, such as CBT,
appear to be important for the success of this inter­
vention.71 Studies should also investigate whether CPAP
combined with other intervention programmes, such as
exercise training or diet-induced weight loss, is superior
to CPAP alone in improving glucose control in patients
with type 2 diabetes and OSA. This research question is

Therapeutic pros

Therapeutic cons


Long-lasting beneficial effects on sleep

Suboptimal adherence; time consuming

GABA A receptor

Acute improvements in the ability to fall and
stay asleep

Impairs SWS; addictive; might impair glucose

Melatonin or melatonin
receptor agonists

Probably facilitates sleep onset and prolongs
total duration of sleep

Possible side-effects on glycaemic control

Orexin receptor antagonist

Prolongs total duration of sleep; reduces
WASO; might improve glucose metabolism

Long-term studies of patients with type 2 diabetes
are lacking

Aerobic exercise

Improves initiation and maintenance of sleep;
beneficial effects on glucose metabolism

Not eligible for patients with, for example,
cardiorespiratory issues and suboptimal adherence

Diet intervention

Might shorten the latency of sleep onset,
improve depth of sleep, and have beneficial
effects on glucose metabolism

Less applicable for patients with specific dietary

CPAP therapy

Reduces cardiometabolic side-effects of
sleep apnoeas; improves glucose metabolism;
restores a normal sleep pattern

Less effective when limited to the first hours of
nocturnal sleep; suboptimal adherence because of
side-effects (eg, dry throat)

Aerobic exercise

Reduces the occurrence of apnoeas; improves
glucose metabolism

Not suitable for some patients with, for example,
cardiorespiratory issues and suboptimal adherence

Diet intervention

Reduces the occurrence of apnoeas following
weight loss; improves glucose metabolism

Less applicable for non-obese patients and patients
with specific dietary restrictions

Figure: Proposed treatment guidelines for patients with type 2 diabetes and insomnia or obstructive sleep apnoea
OSA=obstructive sleep apnoea. CPAP=continuous positive airway pressure. CBT-I=cognitive behavioural therapy for insomnia. GABA=γ-aminobutyric acid.
WASO=wake after sleep onset. SWS=slow-wave sleep.

64 Vol 6 January 2018


particularly relevant since CPAP has not improved other
factors that are closely linked to glucose metabolism,
such as BMI.60
Other treatment options for OSA include oral appliance
therapy, which supports the jaw in a forward position to
maintain an open upper airway,72 which has higher patient
adherence than CPAP although CPAP is more effective in
reducing AHI.73 Upper airway surgeries, including maxillo­
mandibular advancement and pharyn­
geal surgeries,
are additional treatment options to reduce the AHI in
patients with OSA,74 with varied efficacy. For instance,
substantial reductions in AHI have been observed
following maxillomandibular advancement whereas
pharyngeal surgery has shown inconsistent reductions
in AHI.74 Respiration-synchronised electrical stimulation
of the hypoglossal nerve to prevent upper airway collapse
during breathing has been shown to reduce AHI score
(eg, around 68% 1 year after surgery compared with
baseline), which indicates its efficacy in reducing the
severity of OSA.75

Lifestyle interventions

Physical exercise is beneficial for both sleep and glycaemic
control. Mounting evidence from randomised trials
suggests that structured exercise training, especially longterm, regularly performed, moderate-intensity aerobic
exercise (eg, more than three sessions per week,
≥150 min/week), is effective in reducing the symptoms of
insomnia in adults of different ages and with different
BMIs.76–79 A 12-month programme of moderate intensity
aerobic exercise versus health education among 66 adults
aged 55 years and older with sleep complaints, reduced
stage 1 sleep measured by polysomnography (betweengroup difference 2·3% of total sleep time, 95% CI
0·7–4·0), increased time in sleep stage 2 (between-group
difference 3·2% of total sleep time, 0·6–5·7), and
resulted in fewer awakenings during the first third of
the sleep period (between-group difference in number
of awakenings 1·0, 0·39–1·55).77 Another study79
of 45 overweight and obese men with symptoms of
insomnia showed that after a 6-month aerobic exercise
programme had been completed, patients fell asleep
10 min faster compared with baseline (post-exercise
13·7 min, 95% CI 6·7–22·6 vs baseline 23·9 min,
14·0–42·2). For individuals with OSA, a meta-analysis80
(n=129) showed that aerobic exercise or combined aerobic
and resistance exercise for 12 weeks or more could
significantly improve breathing during sleep (pooled
estimate of mean difference vs pre-intervention AHI
–6·27 events per h, 95% CI –8·54 to –3·99) and sleep
efficiency (pooled estimate of mean difference vs preintervention 5·75%, 2·47 to 9·03). Consistent evidence
shows the efficacy of exercise training (aerobic, resistance,
or combined for ≥12 weeks) in reducing HbA1c
concentrations in patients with type 2 diabetes,81 so
structured exercise intervention in patients with type 2 Vol 6 January 2018

diabetes and sleep disorders might prove clinically
important. Studies are needed to address the extent to
which exercise can benefit sleep and glycaemic control in
patients with type 2 diabetes and insomnia or type 2
diabetes and OSA.
Although many forms of exercise have improved
glycaemic control in type 2 diabetes, only aerobic exercise
also mitigates sleep disturbances and sleep disordered
breathing in insomnia and OSA.77–81 The intervention
period should last for at least 12 weeks (≥3 sessions
per week, ≥150 min/week) for patients with OSA and
type 2 diabetes,49 and at least 6 months (≥3 sessions
per week, ≥150 min/week) for patients with type 2
diabetes and symptoms of insomnia.77–79,82 For individuals
with low maximal oxygen uptake or a sedentary lifestyle,
both of which are typical in patients with type 2 diabetes,83
monitoring of exercise intensity with an ambulatory
heart rate monitor is recommended and treatment
should begin at low intensity. To achieve the goal of
regular exercise that exceeds the recommended weekly
minimum, several methods should be considered, such
as continuous behavioural support throughout the
exercise intervention and interventions in a home-based
environment.84 However, few studies have reported on
Panel 3: Practice points
• γ-aminobutyric-acid (GABA) A receptor modulators might adversely affect glycaemic
control and slow-wave activity during non-rapid eye movement (REM) sleep.29–31
The prescription of GABA A receptor modulators to alleviate symptoms of insomnia in
individuals with type 2 diabetes should be done cautiously and their highly addictive
potential should be considered.
• Data conflict on the effect of melatonin on glucose metabolism.39–44 More research is
warranted to determine the safety profile of melatonin and melatonin receptor agonists
in patients with type 2 diabetes and insomnia.
• Treatment with orexin receptor antagonists, such as suvorexant, has been found to
improve sleep in individuals with insomnia.48,49 Some positive effects of orexin receptor
antagonists on glucose metabolism have also been observed in animals.51 Orexin
receptor antagonists might be a promising treatment for the symptoms of insomnia in
patients with type 2 diabetes, but, long-term studies are needed to investigate the
possible effects of this medication on glucose metabolism in patients with type 2
diabetes and insomnia.
• Cognitive behavioural therapy for insomnia (CBT-I) and continuous positive airway
pressure are the first-line choices for treatment of chronic insomnia and obstructive sleep
apnoea (OSA), respectively, in type 2 diabetes15,19,53,54,59,61 because they mitigate the
symptoms of insomnia and sleep-disordered breathing and improve glycaemic control.
Factors that could prevent patients from receiving CBT-I are treatment cost (which could
be circumvented via mobile-based apps),58 features of CBT-I that might have adverse
effects in some patients such as initial sleep restriction, and limited access to treatment
(because of the number of therapists available).
• Aerobic exercise and dietary adjustments are effective and feasible interventions to
improve glucose metabolism in patients with type 2 diabetes. Preliminary
evidence76–82,86–90 suggests that such lifestyle interventions could also improve sleep in
patients with type 2 diabetes who have insomnia or OSA. Exercise training and dietary
interventions should be tailored to individual characteristics, such as patients’
cardiorespiratory capacity and dietary regimens.



Search strategy and selection criteria
We searched PubMed for peer reviewed articles written in English. The search terms were
‘’pharmaceutical’’, ‘’benzodiazepine’’, “melatonin”, “ramelteon”, ‘’suvoraxent’’, ‘’cognitive
behavioral treatment’’, ‘’continuous positive airway pressure’’, ‘’exercise’’, ‘’diet’’
combined with one or more of the following terms: ‘’glucose’’, ‘’insulin’’, ‘’diabetes’’,
‘’insomnia’’, ‘’sleep’’, ‘’apnea’’. We did not use dates to limit our searches, but most
references were published between Jan 1, 2010, and March 31, 2017.

continuation of exercise after the study has stopped, thus
it remains an open question whether exercise
intervention can lead to a consistently active lifestyle for
the management of sleep and type 2 diabetes.

The association between diet and sleep has been
documented for over 40 years,85 and increasing evidence
suggests that diet can affect night-time sleep in human
beings.86 For example, in a study87 of 26 healthy adults, ad
libitum food intake resulting in a positive energy balance
compared with a controlled diet in which individual
energy requirements were met, was associated with a
decrease in slow-wave sleep (mean 24·6 [SD 12·8] min
for ad libitum vs 29·3 [13·9] min for control diet) and an
increase in the latency of sleep onset (29·2 [23·1] min vs
16·9 [11·1] min). In the same study,87 saturated fat intake
throughout the day was negatively correlated with the
duration of slow-wave sleep at night (regression
coefficient –0·71, SEM 0·32), and daytime fibre intake
was positively associated with the duration of slow-wave
sleep at night (0·26, 0·11).87 In another study involving
49 men who were overweight and obese and had
insomnia, a 6-month generalised calorie reduction
intervention (300–500 less kcal per day) versus no
intervention reduced the latency of sleep-onset by about
10 min.88 These findings suggest that dietary patterns
might alter the aspects of sleep that can be negatively
affected by insomnia.86 Additionally, evidence suggests
that dietary alterations, especially calorie reductions,
might help to mitigate the symptoms of OSA.89
Surprisingly few studies have assessed whether
optimisation of diet improves sleep in patients with type 2
diabetes. In patients with type 2 diabetes, obesity, and OSA
(n=264), a 1-year calorie restricted diet (1200–1800 kcal
per day depending on the patient’s initial bodyweight)
improved their breathing during sleep; relative to the
control group (who received diabetes support and edu­
cation), diet-induced weight loss was associated with an
adjusted decrease in AHI of 9·7 (SEM 2·0) events per h.90
With the substantial evidence for the effect of dietary
interventions on glycaemic control in type 2 diabetes,91,92
further dietary adjustments could be a promising
treatment for patients with insomnia, OSA, and type 2
diabetes. Studies with larger sample sizes and longer
intervention periods than previous studies are needed to
investigate whether alterations in macronutrient ratio and

micronutrients might also change objective measures of
sleep. Consideration of the timing of food intake is
important in dietary intervention because glucometabolic
homoeostasis is under circadian regulation, which has
been shown to control glucose in type 2 diabetes

On the one hand, considerable evidence exists suggesting
that poor sleep conditions—such as fragmented sleep,
short sleep, and sleep with intermittent apnoeas—increase
the risk of developing metabolic diseases including type 2
diabetes.94–97 On the other hand, evidence is growing to
suggest that sleep problems are highly prevalent in those
who have already been diagnosed with type 2 diabetes.98,99
Thus, patients with type 2 diabetes and sleep problems are
likely to be a high-risk group for disease progression and
might have generalised resistance to typical treatments for
type 2 diabetes. Readily available interventions can alleviate
sleep problems and reduce sleep-disordered breathing in
patients with type 2 diabetes, including pharmaceutical
sleep aids, CBT-I, CPAP, and lifestyle interventions such
as aerobic exercise training and dietary interventions
(figure). However, the effects of commonly used sleep
interventions on sleep and glucose control can differ
considerably in patients with type 2 diabetes (panel 3).
XT, LvE, and CB devised the Review. XT, LvE, CDC, JC, and CB did the
literature search. XT, CDC, and CB illustrated the figure. XT, LvE, CDC,
JC, and CB wrote the Review.
Declaration of interests
We declare no competing interests.
No specific funding was received to support preparation of this Review.
Work from the authors’ laboratory is supported by AFA Insurance; Erik,
Karin and Gösta Selanders Foundation; Fredrik and Ingrid Thurings
Foundation, the Lars Hiertas Minne Foundation; Novo Nordisk
Foundation; the Tore Nilson Foundation; the Swedish Society for Medical
Research; the Swedish Society for Medicine; the Swedish Brain Foundation;
the Swedish Research Council; and the Åke Wiberg Foundation.
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