Obstructive Sleep Apnoea (OSA)
Predicts Microvascular
Complications in Type 2 Diabetes
Martin J Stevens MD, FRCP,
Professor of Medicine
University of Birmingham, UK
Objectives
• To understand the prevalence of OSA in
diabetes
• To describe the mechanisms whereby OSA
may exacerbate diabetes complications
• To understand the association of OSA with the
microvascular complications of diabetes
Prevalence of diabetes macrovascular and
microvascular complications
Percentage with complications
30
27.8
Diagnosed diabetes
Normal blood sugar levels
22.9
18.9
20
10
9.8
9.5
1.8
9.1
1.7
10
7.9
2.1
6.6
1.1
6.1
1.8
0
Heart attack Chest pain
Coronary
heart
disease
Congestive
heart failure
Macrovascular
Stroke
Chronic
kidney
disease *
Eye damage
Foot
†
problems
Microvascular
*In NHANES, “chronic kidney disease" refers to people with microalbuminuria (albumin:creatinine ratio >30 µg/mg).
†In the NHANES analysis, "foot problems" includes foot/toe amputations, foot lesions, and numbness in the feet.
‡"Eye damage" includes a positive response by NHANES participants to the question, "Have you been told diabetes has affected your
eyes/had retinopathy?" Retinopathy is damage to the eye's retina. In NHANES, people without diagnosed diabetes were not asked this
question, therefore, prevalence information for nondiabetics is not available.
American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report.
Available at: http://www.aace.com/newsroom/press/2007/images/DiabetesComplicationsReport_FINAL.pdf.
Accessed April 18, 2007 14 NA.
‡
Multiple metabolic pathways may contribute
to diabetic microvascular complications
UKCYM01503b February 2013
Adapted from: Boulton AJM, et al. Diabetes Care. 2004; 27:1548–1586 and Vinik A, et al. Nat Clin Pract Endocrinol Metab. 2006; 2(5):269-281.
OSA: Background
• Obstructive sleep apnea is a common medical disorder
that affects at least 4% of men and 2% of women.
• It is characterized by instability of the upper airway
during sleep, which results in markedly reduced
(hypopnea) or absent (apnea) airflow.
• Apnea/hypopnea episodes are usually accompanied
with cyclical oxygen desaturations and cyclical changes
in blood pressure and heart rate.
• OSA and type 2 diabetes (T2DM) share common risk
factors such as age and obesity
Methods
• Subjects were recruited randomly from the diabetes out-patient clinics of
a tertiary centre in the UK
•
DPN was diagnosed using the Michigan Neuropathy Screening
Instrument (MNSI). Retinopathy was graded using retinal photography.
Nephropathy was assessed using eGFR and urine albumin/creatinine
ratios
•
OSA was assessed by an unattended home-based portable multi-channel
respiratory device (Alice PDX, Philips Respironics, USA)
•
An apnea-hypopnea index (AHI) ≥ 5 events/hour was the cut off to
diagnose OSA. AHI ≥ 15 considered to be consistent with moderate to
severe OSA
OSA prevalence
Tahrani et al Am. J. Resp. Crit. Care Med. 2012 186:434-41
An example of a sleep study from a patient with type 2 diabetes and OSA.
The top row shows air flow followed by thoracic and abdominal movements followed by
oxygen saturations. Red areas represent apnoeas, pink areas represent hypopneas and
green areas represent oxygen desaturations
Diabetes microvascular
complications
• Neuropathy
• Nephropathy
• Retinopathy
Diabetes microvascular
complications
• Neuropathy
• Nephropathy
• Retinopathy
Infection of the Chronic Charcot Foot
Skin (intraepidermal) nerve fibres are
reduced in diabetes
Non Diabetic
Diabetes
Tahrani A, Stevens MJ et al. Diabetes Care 2012; 35:1913-8
Prevalence of DPN in relation to OSA status
Tahrani et al Am. J. Resp. Crit. Care Med. 2012 186:434-41
The autonomic nervous system regulates many
different tissues
Advanced cardiac sympathetic dysinnervation
in diabetes
N-13 Ammonia Blood Flow
Distal
Proximal Vertical Horizontal
Short Axis Short Axis Long Axis Long Axis
FLOW
C-11 HED
Stevens et al Circulation 1999
C-11 HED
OSA is associated with CAN
Cardiac autonomic
neuropathy
(Spectral analysis,
>= 3 abnormalities
OSA+
OSA-
P value
69.9%
54.3%
0.034
Effect of OSA on skin structure
Non-diabetic
Diabetes: Mild OSA
Diabetes: No OSA
Diabetes: Severe OSA
Diabetes microvascular
complications
• Neuropathy
• Nephropathy
• Retinopathy
Approximately 40% of patients with type 2 diabetes
show signs of CKD1
CKD prevalence was greater among people with diabetes than among those without
diabetes (40.2% versus 15.4%)†
CKD Stage
* Normal kidney function, no sign of kidney damage
** Albuminuria – kidney damage
eGFR (mL/min)
No CKD
≥ 90*
1
≥ 90**
2
60–89
3
30–59
4
15–29
5
< 15 or dialysis
Adapted from 1. Koro CE, et al. Clin Ther. 2009;31:2608–2617 and 2. Saydah S, et al. JAMA. 2007;297(16):1767.
OSA and diabetic nephropathy prevalence
• Overall OSA prevalence: 64.3% (144/224)
– 38.4% (86/224) mild
– 25.9% (58/224) moderate to severe
• Nephropathy prevalence: 40.2% (90/224)
– Albuminuria 33.0% (74/224)
– eGFR (ml/min/1.73 m2)
≥ 90: 45.5% (102/224)
60-89: 37.9% (85/224)
30-59: 15.2% (32/224)
15 -29:1.3% (3/224)
< 15: 0% (0/224)
OSA and diabetic nephropathy:
Cross-sectional univariable analysis
Total Cohort
OSA- (n=80)
OSA+ (n=144)
P
Diabetic nephropathy
19 (23.8%)
71 (49.3%)
< 0.001
Albuminuria
16 (20.0%)
58 (40.3%)
0.002
4 (5.0%)
19 (13.2%)
0.05
Serum creatinine (µmol/l )
74.4 (23.4)
90.9 (36.8)
<0.001
Estimated GFR (ml/min/1.73 m2)
92.9 (25.1)
82.2 (27.6)
0.005
5 (6.3%)
32 (22.2%)
0.002
Macroalbuminuria
Estimated GFR < 60 ml/min/1.73 m2
Tahrani A et al, Diabetes Care 2013; 36:3718-25
OSA and diabetic nephropathy:
Cross-sectional multivariable analysis
Model
Unadjusted
R2
0.09
OR
3.12
95% CI
1.70-5.75
P value
p<0.001
Adjusted
0.46
2.64
1.13-6.16
p=0.02
Adjusted for gender, ethnicity, age, diabetes duration, BMI, mean
arterial pressure, HbA1c, triglycerides, treatment with insulin, GLP-1
analogues, anti-hypertensives, total cholesterol, HDL, lipid lowering
treatment, anti-platelets, oral anti diabetes agents, alcohol (units per
week), smoking (current or ex smoking vs. none).
Tahrani A et al, Diabetes Care 2013; 36:3718-25
Diabetic nephropathy: natural history
OSA and eGFR: Longitudinal analysis
OSA and eGFR: Longitudinal analysis
Impact of CPAP on eGFR decline (eGFR < 90)
Tahrani A et al, Diabetes Care 2013; 36:3718-25
Diabetes microvascular
complications
• Neuropathy
• Nephropathy
• Retinopathy
Diabetic Retinopathy
A
B
C
Hall R, et al. Diabetes mellitus. In: A Colour Atlas of Endocrinology. 2nd ed. 1990:chap 7.
The relationship between OSA status and sight threatening
diabetic retinopathy, retinopathy and maculopathy
Total cohort
OSA- (n=74)
OSA+ (n=125)
P value
Sight threatening
diabetic
retinopathy
21.6% (16)
48.8% (61)
<0.001
None
40.5% (30)
29.6% (37)
0.006
Background
54.1% (40)
46.4% (58)
<0.01
Pre-proliferative
1.4% (1)
14.4% (18)
<0.001
Proliferative
4.1% (3)
9.6% (12)
<0.01
Maculopathy
17.6% (13)
44.0% (55)
<0.001
Summary: OSA is associated with
microvascular complications
in patients with T2DM
Unadjusted OR (95%CI)
Adjusted OR (95%CI)
3.5 (1.8-6.6)
3.7 (1.6-8.9)
Neuropathy
4.09 (2.28–7.35)
2.77 (1.36–5.62)
Nephropathy
3.12 (1.70-5.75)
2.64 (1.13-6.16)
Sight threatening
retinopathy
Tahrani AA et al AM J Respir Crit Care Med 2012
Tahrani AA et al Diabetes Care 2013
Tahrani AA et al Eur J Ophthalmol 2013
The postulated mechanisms linking OSA and microvascular
complications
OSA/ Intermittent
Hypoxia
ET-1
PAI-1
VEGF
TGF-B
NF-KB
NO
HTN
Hyperglycaemia
ROS/
RNS
PKC
pathway
AGE
pathway
Hexosamine
pathway
Polyol
pathway
Vascular
complications
HTN: hypertension; ROS: reactive oxygen species; RNS: reactive nitrogen species PKC: protein
kinase C; AGE: advance glycation end-products.
Obstructive sleep apnoea predicts
microvascular complications in type 2 diabetes
Thank you!