DIABETICMedicine

DOI: 10.1111/dme.12362

Short Report: Treatment

The relationship between metformin therapy and sleep
quantity and quality in patients with Type 2 diabetes
referred for potential sleep disorders
F. Kajbaf1,2, S. Fendri1, A. Basille-Fantinato3, M. Diouf4, D. Rose3, V. Jounieaux5 and
J.-D. Lalau1,2
1
Service dEndocrinologie et de Nutrition, Centre Hospitalier Universitaire, 2Unite INSERM U-1008, Universite de Picardie Jules Verne, 3Unite de Pathologie du
Sommeil, 4Centre de Recherche Clinique and 5Service de Pneumologie, Centre Hospitalier Universitaire, Amiens, France

Accepted 12 November 2013

Abstract
Aims Given that sleep disorders are known to be related to insulin resistance, and metformin has favourable effects on
insulin resistance and on ventilatory drive, we sought to determine whether metformin therapy was related to sleep
variables in a group of patients with Type 2 diabetes.
Methods We performed a retrospective, observational study of our centres database for patients referred for potential
sleep disorders and then compared metformin-treated patients with those not treated with the drug. All study patients
had undergone the same standard polysomnographic procedure. A multivariate analysis was performed to establish
whether or not there was an independent relationship between metformin use and sleep variables (after adjusting for age,
gender, BMI, neck circumference, cumulated risk factors and insulin use).

We studied 387 patients (mean  SD age: 58.4  10.8 years), of whom 314 had been treated with metformin.
Total sleep time and sleep efficiency were higher in metformin-treated patients than in patients not treated with
metformin [total sleep time: 6 h 39 min vs. 6 h 3 min, respectively (P = 0.002); sleep efficiency: 77.9  12.3 vs.
71.5  17.2%, respectively (P = 0.003)]. These differences persisted after adjustment for covariates and were observed
even although metformin users had a higher BMI than did non-users (median 37.5 vs. 34.8 kg/m2; P = 0.045).

Results

We showed that metformin therapy is associated with a longer sleep duration and better sleep efficiency.
Randomized clinical trials are needed to confirm metformins favourable effect on sleep quality and quantity.

Conclusion

Diabet. Med. 31, 577580 (2014)

Introduction
Sleep disorders are particular frequent in states of insulin
resistance [13]. Given that metformin exerts well-known
effects on insulin resistance in humans [4] and directly
increases ventilatory drive in non-obese rats [5,6], the drug
should (in theory) relieve sleep disorders. Our observations
of a small series of patients referred for sleep disorders
(n = 26) [7] showed that all but one of the patients not
suffering from sleep apnoea syndrome were being treated
with metformin; this finding prompted us to investigate the
putative relationship between metformin and the relief of
sleep disorders in a much larger population.
To this end, we studied patients with Type 2 diabetes
referred for potential sleep disorders in our university
Correspondence to: Jean-Daniel Lalau. E-mail: lalau.jean-daniel@chu-amiens.fr

2013 The Authors.

Diabetic Medicine 2013 Diabetes UK

medical centre and compared metformin-treated and metformin-naive patients in terms of sleep quantity and quality
while taking account of possible confounding factors (BMI,
neck circumference, insulin use, etc.).

Subjects and methods

Subjects

We included consecutive, confirmed outpatients with Type 2

diabetes who had been referred for screening for sleep
apnoea syndrome at Amiens University Hospital (Amiens,
France) because of excessive daytime sleepiness, nocturnal
snoring, disturbed sleep, nycturia or other symptoms. We
excluded patients with unstable or uncontrolled cardiopulmonary diseases, a history of upper airway surgery, uncontrolled thyroid diseases and the sequelae of stroke.

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Metformin and sleep disorders  F. Kajbaf et al.

DIABETICMedicine

Whats new?
We sought to determine whether metformin therapy
was related to sleep variables in a group of patients with
Type 2 diabetes referred for potential sleep disorders.
We observed an association between metformin use on
the one hand and better sleep quality and quantity on
the other.
The observed differences between metformin users and
non-users persisted in a multivariate analysis.
When comparing metformin users and non-users, we
systemically screened for the use of drugs with a sedative
effect (hypnotics, opioids, neuroleptics and antidepressive,
anti-dopaminergic and antihistaminic agents).

Procedures

Patients were admitted for standard polysomnography from

19.00 to 08.00 h using the Brainnet System (Medatec,
Brussels, Belgium) coupled to an electroencephalogram, an
electrooculogram, an electromyogram, continuous nasal
airflow measurement, measurement of thoracic and abdominal movements (using strain gauges) and oxygen saturation
measurement with a pulse oximeter (Medatec).

Data analyses

Sleep apnoea syndrome was diagnosed according to the

International Classification of Sleep Disorders criteria [8], on
the basis of an apnoea/hypopnoea index over 15 events/h.
Sleep efficiency was defined as the total sleep time divided by
the total sleep period.
Multivariate analysis was performed to establish whether
or not there was an independent relationship between
metformin use and the prevalence of sleep disorders (after
adjusting for several factors conventionally associated with
disturbed sleep including age, gender, BMI, neck circumference, cumulated cardiovascular risk factors and insulin use).

iable). The independent association between metformin use

and each of the sleep variables was assessed with an analysis
of covariance and backward selection, after controlling for
clinical factors with a univariate P-value < 0.2.
For comparison between metformin users and non-users,
P-values were adjusted with the BonferroniHolm method to
avoid inflation of a type I error. Test results with P-values
0.05 or > 0.05 were considered to be significant and
non-significant, respectively. All statistical analyses were
performed with SAS software (version 9.2; SAS Institute Inc.,
Cary, NC, USA).

Results
Demographic and sleep-related characteristics

Three hundred and eighty-seven patients were included in the

study (mean  SD age: 58.4  10.8 years; male/female
gender ratio: 0.64). Of these, 314 were being treated with
metformin. There was no intergroup difference in demographic characteristics between metformin users and nonusers, with the exception of BMI, number of anti-diabetic
medications and proportion of patients on sulphonylurea
therapy (Table 1). In contrast, the two groups differed
significantly in terms of total sleep time and sleep efficiency
[total sleep time: 6 h 39 min vs. 6 h 3 min for metformin
users and non-users, respectively (P = 0.002); sleep efficacy:
71.5  17.2 vs. 77.9  12.3%, respectively (P = 0.003)]
(Table 1).
The groups of metformin-treated and metformin-naive
patients did not differ significantly in terms of the prevalence
of apnoea or hypopnoea (mainly obstructive; data not
shown), although the BMI was higher in metformin-treated
patients (median 37.5 vs. 34.8 kg/m2, P = 0.045).
Univariate and multivariate analyses

The results of the univariate and multivariate analyses are

presented in Table 1. After adjusting for covariates, the
metformin-treated and metformin-naive groups still differed
significantly in terms of total sleep time and sleep efficiency
(P = 0.0001 and 0.0004, respectively).

Statistical analyses

Data are expressed as either the mean  SD and the median

(interquartile range) (quantitative data) or a percentage
(qualitative data). Quantitative variables were compared
between metformin users and non-users with a Student t-test
or a Wilcoxon test according to the data distribution and a
v2- or Fisher test (as appropriate) were used for the
comparison of qualitative variables between metformin users
and non-users. The univariate association between sleeping
variables (total sleep and sleep efficiency) and clinical factors
were assessed using a Pearson or Spearman correlation
(quantitative variables) or a Student t-test (qualitative var-

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Discussion
Cross-sectional and longitudinal studies have shown a high
prevalence of glucose intolerance, insulin resistance and
diabetes in subjects with sleep disorders [9,10] and, conversely, revealed that sleep disorders are independently
associated with impairments in glucose metabolism [11].
Several mechanistic explanations have been suggested,
including intermittent hypoxia, sleep fragmentation, sleep
deprivation with secondary sympathetic activation, impairments of the hypothalamuspituitary axis, generation of
reactive oxygen species and elevated activity of inflammatory

2013 The Authors.

Diabetic Medicine 2013 Diabetes UK

Research article

DIABETICMedicine

Table 1 The demographic and sleep-related characteristics [quoted as the mean  SD and range%, median (interquartile range) or duration] of the
study subjects, together with the results of the univariate and multivariate analyses
Demographic and sleep-related
characteristics
Metformin-treated
patients n = 314

Patients not
treated with
metformin n = 73

Gender ratio, male:female

BMI, kg/m2

57.9  10.7
(2179)
64.6
37.5 (32.543.3)

Neck circumference, cm

45.0 (42.047.0)

Arterial hypertension,%
Tobacco,%
Hypercholesterolaemia,%
Metabolic syndrome,%
Number of risk factors
Number of
anti-diabetic medications
Metformin therapy
Sulphonylurea therapy,%
Insulin therapy,%
Sedative/hypnotic drugs,%
Total sleep period, h

77.3
62.4
56.7
82.5
4 (45)
1.8  0.8 (15)

60.7  11.4
(3083)
61.6
34.8
(31.241.0)
43.0
(41.047.5)
76.7
58.9
54.8
75.3
4 (45)
1.2  0.5 (03)

28.3
17.3
15.3
8 h 8 min
(4 h 22 min
9 h 55 min)
6 h 39 min
(1 h 51 min
9 h 4 min)
77.9  12.3
(25.099.4)
17.0  23.1
(0112.9)

54.8
15.1
11.0
7 h 58 min
(3 h 34 min
9 h 45 min)
6 h 3 min
(1 h 32 min
8 h 32 min)
71.5  17.2
(16.895.2)
19.9  26.7
(0112)

Age, years

Total sleep time, h

Sleep efficiency,%
Apnoea/hypopnoea index

pathwaysall of which ultimately lead to an insulin-resistant state and worsened glucose tolerance [1214]. In view of
metformins well-known effects on insulin resistance, this
anti-diabetic drug may therefore exert favourable effects on
sleep. Data from animal experiments support this hypothesis
[4,5,15]. However, these preclinical data did not have
clinical counterparts. Here, we present the first evidence of
a favourable, independent association between metformin
therapy and sleep-related characteristics in a fairly large
population.
The present study population was characterized by severe
obesity (with a BMI close to 40 kg/m2 in metformin-treated
patients) and a high cardiovascular risk (with more than four
risk factors present per patient, on average). Most of the
patients had the metabolic syndrome. However, whereas our
study population was characterized by severe obesity, the
mean numbers of apnoea/hypopnoea episodes were suggestive of mild sleep apnoea syndrome. This should be borne in
mind when considering that the metformin-treated and
metformin-naive groups did not differ significantly in terms
of sleep apnoea syndrome.
The two study groups differed significantly in terms of
two important sleep variablesone related to sleep quantity (total sleep time) and the other related to sleep quality

2013 The Authors.

Diabetic Medicine 2013 Diabetes UK

Univariate
analysis P-value

Mutivariate
analysis P-value

Total
sleep time

Sleep
efficiency

Total sleep
time

0.061

0.0024

< 0.0001

0.630
0.045

< 0.0001
0.6325

< 0.0001
0.8372

0.206

0.0431

0.0100

0.0039

< 0.0001

0.7791

0.4252

0.0001

0.0002

0.1892

0.6690

P-value

0.912
0.583
0.769
0.160
0.115
< 0.0001

< 0.0001
0.646
0.344
0.189

Sleep
efficiency
< 0.0001

< 0.0001

< 0.0001

0.0001

0.0004

0.002

0.003
0.397

(sleep efficiency) (P < 0.002 and 0.003, respectively). Our

multivariate analysis provided the most striking finding of
the present study. As expected, we found independent
associations between sleep variables and some demographic variables (but not BMI, surprisingly). It is important to note that, after adjustment for covariates, this
association persisted only for age, gender and metformin
therapyeven although the metformin-treated patients had
a higher BMI than did the metformin-naive patients
(P = 0.045).
Our study had several limitations: (1) some data (such as
the metformin dose, the duration of metformin therapy and
the HbA1c value) were not available; (2) there were relatively
few metformin-naive patients; and (3) the metformin and
metformin-naive study groups differed significantly in terms
of the number of concomitant anti-diabetic medications.
In conclusion, we provide new evidence of an independent
effect of metformin on sleep quantity and quality. Randomized clinical trials are needed to confirm this beneficial
association and to determine whether metformins ability to
lower blood glucose levels might also be related to its effect
on sleep (along with its known mechanisms of action), as
sleep disorders are associated with elevated glycaemia
[2,3,7].

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Funding sources

None.

Competing interests

None declared.

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2013 The Authors.

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