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.">

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Obstructive Sleep Apnoea (OSA) Predicts Microvascular Complications in Type 2 Diabetes Martin J Stevens MD, FRCP, Professor of Medicine University of Birmingham,

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Presentation on theme: "Obstructive Sleep Apnoea (OSA) Predicts Microvascular Complications in Type 2 Diabetes Martin J Stevens MD, FRCP, Professor of Medicine University of Birmingham,"— Presentation transcript:

1 Obstructive Sleep Apnoea (OSA) Predicts Microvascular Complications in Type 2 Diabetes Martin J Stevens MD, FRCP, Professor of Medicine University of Birmingham, UK

2 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

3 Prevalence of diabetes macrovascular and microvascular complications MacrovascularMicrovascular American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at: Accessed April 18, NA. * † ‡ *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.

4 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): Multiple metabolic pathways may contribute to diabetic microvascular complications

5 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

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7 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

8 OSA prevalence Tahrani et al Am. J. Resp. Crit. Care Med :434-41

9 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

10 Diabetes microvascular complications Neuropathy Nephropathy Retinopathy

11 Diabetes microvascular complications Neuropathy Nephropathy Retinopathy

12 Infection of the Chronic Charcot Foot

13 Skin (intraepidermal) nerve fibres are reduced in diabetes Non Diabetic Diabetes Tahrani A, Stevens MJ et al. Diabetes Care 2012; 35:1913-8

14 Prevalence of DPN in relation to OSA status Tahrani et al Am. J. Resp. Crit. Care Med :434-41

15 The autonomic nervous system regulates many different tissues

16 Advanced cardiac sympathetic dysinnervation in diabetes C-11 HEDFLOW C-11 HED Distal Short Axis Proximal Short Axis Vertical Long Axis Horizontal Long Axis N-13 Ammonia Blood Flow Stevens et al Circulation 1999

17 OSA is associated with CAN OSA+OSA-P value Cardiac autonomic neuropathy (Spectral analysis, >= 3 abnormalities 69.9%54.3%0.034

18 Effect of OSA on skin structure Diabetes: Mild OSA Diabetes: Severe OSA Diabetes: No OSA Non-diabetic

19 Diabetes microvascular complications Neuropathy Nephropathy Retinopathy

20 Approximately 40% of patients with type 2 diabetes show signs of CKD 1 * Normal kidney function, no sign of kidney damage ** Albuminuria – kidney damage CKD prevalence was greater among people with diabetes than among those without diabetes (40.2% versus 15.4%) † CKD StageeGFR (mL/min) No CKD≥ 90* 1≥ 90** 260–89 330–59 415–29 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.

21 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 m 2) ≥ 90: 45.5% (102/224) 60-89: 37.9% (85/224) 30-59: 15.2% (32/224) :1.3% (3/224) < 15: 0% (0/224)

22 OSA and diabetic nephropathy: Cross-sectional univariable analysis Total CohortOSA- (n=80)OSA+ (n=144)P Diabetic nephropathy19 (23.8%)71 (49.3%)< Albuminuria16 (20.0%)58 (40.3%)0.002 Macroalbuminuria4 (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 m 2 )92.9 (25.1)82.2 (27.6)0.005 Estimated GFR < 60 ml/min/1.73 m 2 5 (6.3%)32 (22.2%)0.002 Tahrani A et al, Diabetes Care 2013; 36:

23 OSA and diabetic nephropathy: Cross-sectional multivariable analysis ModelR2R2OR95% CIP value Unadjusted p<0.001 Adjusted 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:

24 Diabetic nephropathy: natural history

25 OSA and eGFR: Longitudinal analysis

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27 Impact of CPAP on eGFR decline (eGFR < 90) Tahrani A et al, Diabetes Care 2013; 36:

28 Diabetes microvascular complications Neuropathy Nephropathy Retinopathy

29 A C B Diabetic Retinopathy Hall R, et al. Diabetes mellitus. In: A Colour Atlas of Endocrinology. 2nd ed. 1990:chap 7.

30 The relationship between OSA status and sight threatening diabetic retinopathy, retinopathy and maculopathy Total cohortOSA- (n=74) OSA+ (n=125)P value Sight threatening diabetic retinopathy 21.6% (16)48.8% (61)<0.001 None40.5% (30)29.6% (37)0.006 Background54.1% (40)46.4% (58)<0.01 Pre-proliferative1.4% (1)14.4% (18)<0.001 Proliferative 4.1% (3)9.6% (12)<0.01 Maculopathy17.6% (13)44.0% (55)<0.001

31 Summary: OSA is associated with microvascular complications in patients with T2DM Unadjusted OR (95%CI)Adjusted OR (95%CI) Sight threatening retinopathy 3.5 ( )3.7 ( ) Neuropathy4.09 (2.28–7.35)2.77 (1.36–5.62) Nephropathy3.12 ( )2.64 ( ) 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

32 The postulated mechanisms linking OSA and microvascular complications Hyperglycaemia OSA/ Intermittent Hypoxia ROS/ RNS Polyol pathway Hexosamine pathway AGE pathway PKC pathway HTN ET-1 PAI-1 VEGF TGF-B NF-KB NO Vascular complications HTN: hypertension; ROS: reactive oxygen species; RNS: reactive nitrogen species PKC: protein kinase C; AGE: advance glycation end-products.

33 Obstructive sleep apnoea predicts microvascular complications in type 2 diabetes Thank you!


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