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PostScript

Obstructive sleep apnoea is


associated with the development
and progression of diabetic
retinopathy, independent of
conventional risk factors and
novel biomarkers for diabetic
retinopathy
Accumulating evidence suggests an association between obstructive sleep apnoea
(OSA) and diabetic retinopathy.1 The mechanism for this is unclear but a previous
study suggested that hypertension and high
body mass index are strongly implicated.2
Increases in serum vascular endothelial
growth factor and other biomarkers35 have
also recently been shown to be independently predictive for retinopathy. Their role
in mediating OSA induced retinopathy,
independent of conventional risk factors, is
not known. We therefore performed an
exploratory study to corroborate the link
between OSA with diabetic retinopathy and
the association of novel serum biomarkers
on OSA induced diabetic retinopathy.
In all, 31 male obese patients with Type 2
diabetes (body mass index 2840; HbA1c
7.0%12.0%) attending a hospital diabetes
obesity clinic on stable medication regimen
with no signicant comorbidities were
recruited. All subjects underwent an inhospital sleep study via the Visilab system. OSA
was diagnosed based on the presence of
apneahypopnea index (AHI) >5 events/h
(mild), 1530 events/h (moderate) and AHI
30 (severe). Indication for continuous positive airway pressure therapy at our unit is
AHI of 514 events/h with excessive daytime
sleepiness or any AHI>15. Assessments
included clinical parameters, lifestyle, food
questionnaire, Epworth Score, HbA1c levels,
fasting glucose, plasma vascular endothelial
growth factor, tumour necrotic factor ,
monocyte chemoattractant-protein 1, matrix
metalloproteinases, highly sensitive-CRP and
interleukin 6 levels. Retinopathy and maculopathy gradings were obtained from the
National diabetic eye screening programme

Table 1

record which involves digital photography of


the retina and systematic image grading by
optometrists and/or ophthalmologist. The
study was approved by the Nottingham
Research Ethics committee and all participants provided written consent.
Mean age was 54.911.3 years, body
mass index 35.34.8 kg/m2, HbA1c level
9.22.4% and diabetes duration 11.08.3
years. All clinical and biochemical parameters were equally matched between OSA
(n=17) and non-OSA patients (n=16)
except for Epworth and the AHI scores
(table 1). Retinopathy score ( p=0.04) but
not maculopathy score ( p=0.15) was signicantly worse in the OSA group. The proportion of patients with proliferative diabetic
retinopathy was signicantly higher in
the OSA group (N=4 vs 0; 2 4.8; p=0.01).
Following stepwise multiple regression analysis to adjust for potential confounders to
include novel serum biomarkers for diabetic
retinopathy and inammation, only OSA is
an independent signicant predictor of the
total retinopathy scores ( p=0.008) and
remained in the regression model after stepwise forced exclusion of covariates which did
not inuence the prediction for diabetic retinopathy progression.
The present study supports recent observation between OSA and diabetic retinopathy. The new observation here is that this
association persists even after adjustment for
novel biomarkers for diabetic retinopathy. In
addition, there appears to be an association
between OSA and severity of retinopathy.
Severity of OSA however did not predict
total retinopathy score. Novel serum biomarkers previously linked with retinopathy progression did not appear to independently
drive the association between OSA and diabetic retinopathy. OSA induced neovascularisation of diabetic retinopathy at least in this
study appears to be driven by local angiogenesis (ie, cellular expression and vitreous level
of inammatory marker) rather than systemic vasculogenesis.6 The lack of association between OSA and maculopathy
however is surprising, given the putative
mechanism thought to explain the association between OSA and diabetic retinopathy.

Non-OSA (N=17)

OSA (N=16)

p Value

55.8
8.9
9.9
6.8
3.1
4.0
132.3
80.0
34.2

54.1
10.0
12.3
11.0
23.4
3.0
138.8
80.4
36.4

0.67
0.09
0.43
0.008
<0.001
0.57
0.34
0.91
0.18

BP, blood pressure; OSA, obstructive sleep apnoea.

Br J Ophthalmol December 2012 Vol 96 No 12

Supreeth Rudrappa,1 Graham Warren,2


Iskandar Idris1,3
1

Department of Diabetes and Endocrinology, Sherwood


Forest Hospitals Foundation Trust, Nottinghamshire, UK;
2
Trent Research Design Services, University of Nottingham,
Nottinghamshire, UK; 3School of Graduate Entry Medicine,
University of Nottingham, Derby, UK
Correspondence to Dr Iskandar Idris, School of Graduate
Entry Medicine, University of Nottingham, Royal Derby
Hospital, Uttoxeter Road, Derby DE12, UK; iidris@aol.com

Contributors GW assisted in the study analysis. SR


participated in data interpretation and wrote the rst
draft of the paper. II conceived the study, coordinated
the study and obtained ethical approval. All authors
read, contributed towards and approved the nal
manuscript.
Competing interests None.
Patient consent Obtained.
Ethics approval Nottingham Research Ethics
Committee.
Provenance and peer review Not commissioned;
externally peer reviewed.
Accepted 15 September 2012
Published Online First 17 October 2012
Br J Ophthalmol 2012;96:1535.
doi:10.1136/bjophthalmol-2012-301991

REFERENCES
1.

2.

3.

Baseline parameters of patients recruited into the study

Age (years)
HbA1c (%)
Diabetes duration (years)
Epworth score
Apneahypopnea index
Total cholesterol (mmol/l)
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Body mass index (kg/m2)

Some limitations of the study are the relatively small sample size, maximum and
minimum oxygen saturation data on sleep
study not being formally reported, neck size
and exclusive Caucasian population, which
limit the generalisibility of this study.
Nevertheless, this study showed that OSA
may be the most important independent
predictor of retinopathy, but not maculopathy progression independent of conventional
and novel biomarkers for retinopathy progression. Further adequately powered study
is required to clarify the mechanism of OSA
induced diabetic retinopathy progression.

4.

5.

6.

Tahrani AA, Ali A, Begum S, et al. Obstructive


sleep apnoea and sight threatening retinopathy: a
novel association in patients with Type 2 diabetes
P158. Diabet Med 2011;28(S1), Abstracts of the
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Shiba T, Takahashi M, Hori Y, et al. Evaluation of the
relationship between background factors and
sleep-disordered breathing in patients with
proliferative diabetic retinopathy. Jpn J Ophthalmol
2011;55:63842.
Gustavsson C, Agardh E, Bengtsson B, et al.
TNF-alpha is an independent serum marker for
proliferative retinopathy in Type 1 diabetic patients.
Diabetes Complication 2008;22:300916.
Mysliwiec M, Balcerska A, Zorena K, et al. The
role of vascular endothelial growth factor, tumour
necrosis factor alpha and interleukin-6 in
pathogenesis of diabetic retinopathy. Diabetes Res
Clin Pract 2008;79:1416.
Jacqueminet S, Ben Abdesselam O, Chapman MJ,
et al. Elevated circulating levels of matrix
metalloproteinase-9 in Type 1 diabetic patients with and
without retinopathy. Clin Chim Acta 2006;367:1037.
Lee IG, Chae SL, Kim JC. Involvement of circulating
endothelial progenitaor cells and vasculogenic factors
in the pathogenesis of diabetic retinopathy. Eye
2006;20:54652.

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Downloaded from http://bjo.bmj.com/ on November 18, 2014 - Published by group.bmj.com

Obstructive sleep apnoea is associated with


the development and progression of diabetic
retinopathy, independent of conventional risk
factors and novel biomarkers for diabetic
retinopathy
Supreeth Rudrappa, Graham Warren and Iskandar Idris
Br J Ophthalmol 2012 96: 1535 originally published online October 17,
2012

doi: 10.1136/bjophthalmol-2012-301991
Updated information and services can be found at:
http://bjo.bmj.com/content/96/12/1535

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