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Martin J Stevens MD, FRCP, Professor of Medicine

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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
* Macrovascular 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: Accessed April 18, NA. 3

4 Multiple metabolic pathways may contribute to diabetic microvascular complications
PURPOSE OF THE SLIDE To show potential aetiologies of neuropathy associated with diabetes. KEY POINTS A large body of evidence suggesting that multiple metabolic changes may contribute to nerve damage.1,2 Hyperglycemia activates several processes as demonstrated in this slide. Protein kinase C beta (PKC): The activation of PKC leads to multiple pathogenetic consequences including altered expression of endothelial nitric oxide synthetase and vascular endothelial growth factor (VEGF; this was discovered as an endothelial-specific growth factor with a predominant role in angiogenesis. It also has direct effects on neurons and glial cells, stimulating their growth, survival, and axonal outgrowth. It has potential for a dual impact on both the vasculature and neurons and could represent an important therapeutic intervention in diabetic neuropathy). Polyol pathway: The polyol pathway represents an alternative metabolic fate for glucose. Aldose reductase is a key enzyme in this pathway and generates sugar alcohols such as sorbitol. In animal models of diabetes, there is an association between increased flux through the polyol pathway and a reduction in nerve conduction velocity (NCV), both of which can be ameliorated with aldose reductase inhibitors (ARIs). In humans this situation is not clear. Glycation: Glycation involves the non-enzymatic reaction between glucose and amino groups of proteins (forming a covalent attachment via the Amidori reaction). The rate of this reaction is proportional to the ambient concentration of glucose (e.g., the formation of glycosylated hemoglobin, HbA1c). Glycation of proteins may alter their function. There is also evidence for specific receptors for these glycated proteins (termed advanced glycation end products or AGEs). Interaction with these receptors may induce monocytes and endothelial cells to increase the production of cytokines and adhesion molecules. Intervention trials have used aminoguanidine to block the glycation reaction, or have utilised soluble receptors to block the downstream effects of receptor binding. Oxidative stress: There is an increasing body of data to support the role of oxidative stress in the pathogenesis of diabetic neuropathy in animal models. There is emerging evidence that single-nucleotide polymorphisms of the genes for mitochondrial and extracellular superoxide dismutases may confer an increased risk for the development of neuropathy. Many of these mechanisms could have direct effects on the neurons, may directly damage the microvasculature, or could lead to neuropathy through both routes. REFERENCE 1.Boulton AJ, et al. Diabetic somatic neuropathies. Diabetes Care. 2004;27:1458–1486. 2.Vinik A et al. Nat Clin Pract Endocrinol Metab. 2006; 2(5): 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):

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

6 Excess Mortality

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
58% of pts with OSA Tahrani et al Am. J. Resp. Crit. Care Med :434-41

15 The autonomic nervous system regulates many different tissues
The autonomic nervous system regulates the function of many different tissues, including the eye, lungs, liver, pancreas and bowel, kidneys, bladder and heart, and so its dysfunction can result in a wide spectrum of clinical manifestations. The cardiovascular consequences, are the focus of this presentation.

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

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

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

19 Diabetes microvascular complications
Neuropathy Nephropathy Retinopathy

20 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 eGFR (mL/min) No CKD ≥ 90* 1 ≥ 90** 2 60–89 3 30–59 4 15–29 5 < 15 or dialysis Diabetic nephropathy is a leading cause of chronic kidney disease. In fact, diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) cases in the United States. To estimate the prevalence of Chronic Kidney Disease in the United States, the CDC analyzed the most recent data from the National Health and Nutrition Examination Survey (NHANES). The study clearly showed that people with diabetes had a greater prevalence of CKD than healthy individuals. CKD prevalence was greater among persons with diabetes than among those without diabetes (40.2% versus 15.4%). By disease stage, the prevalence for CKD Stages 1, 2 and 3 were below were 5.7%; 5.4%; and 5.4%, respectively in the normal population –lower than the figures shown in the table for diabetes patients. For diabetes patients, the prevalence of late-stage CKD was over 2%, whereas in the normal population the prevalence was 0.4%. In summary, CKD prevalence is high in diabetes patients, with around 40% of all diabetes patients affected by some degree of declining renal function. References Koro CE, et al. Clin Ther. 2009;31:2608–17 Coresh J, et al. JAMA. 2007;298(17): * Normal kidney function, no sign of kidney damage ** Albuminuria – kidney damage Adapted from 1. Koro CE, et al. Clin Ther. 2009;31:2608–2617 and 2. Saydah S, et al. JAMA. 2007;297(16):1767. 20 20

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 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)

22 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 Macroalbuminuria 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 Estimated GFR < 60 ml/min/1.73 m2 5 (6.3%) 32 (22.2%) Tahrani A et al, Diabetes Care 2013; 36:

23 OSA and diabetic nephropathy: Cross-sectional multivariable analysis
Model R2 OR 95% CI P value Unadjusted 0.09 3.12 p<0.001 Adjusted 0.46 2.64 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). There was a stepwise association between OSA severity and DN. Compared to AHI tertile 1 (AHI < 4.8), tertiles 2 (4.8–11.89) (OR 2.79, 95%CI , p=0.004) and 3 (≥ 11.90) (OR 3.11, 95%CI , p=0.001) were associated with DN; this association lost significance following adjustment (OR 2.43, 95%CI , p=0.055 and OR 2.47, 95%CI , p=0.07 for AHI tertiles 2 and 3 respectively). Similar associations were found for DN and nadir nocturnal oxygen saturation (OR 0.96, 95%CI , p=0.004), which became borderline after adjustment as in model 3 (OR 0.96, 95%CI , p=0.05). Tahrani A et al, Diabetes Care 2013; 36:

24 Diabetic nephropathy: natural history
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) in many countries(1) and has significant impact on patients and healthcare systems(2). DN progresses slowly, starting with microalbuminuria, which progresses into overt proteinuria in 20–40% of patients and 20% of patients will have progressed to ESRD within 20 years after onset of overt proteinuria(1). The speed of DN progression is variable and largely dependent on blood pressure (BP), obesity, metabolic control and other factors such male sex and ethnicity(3,4).

25 OSA and eGFR: Longitudinal analysis

26 OSA and eGFR: Longitudinal analysis

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 Diabetic Retinopathy A B C
A normal retina (A) is shown here for comparison with the microaneurysms and associated exudates and venous dilatation (B) that are characteristic of diabetic retinopathy and the hemorrhages (C) of proliferative retinopathy that lead to fibrosis, distortion of the vitreous, and tearing of the retina. Hall R, et al. Diabetes mellitus. In: A Colour Atlas of Endocrinology. 2nd ed. 1990:chap 7. 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 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) Proliferative 4.1% (3) 9.6% (12) Maculopathy 17.6% (13) 44.0% (55)

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 ( ) Neuropathy 4.09 (2.28–7.35) 2.77 (1.36–5.62) Nephropathy 3.12 ( ) 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 OSA/ Intermittent Hypoxia
The postulated mechanisms linking OSA and microvascular complications Hyperglycaemia OSA/ Intermittent Hypoxia ROS/ RNS Polyol pathway Hexosamine AGE PKC HTN ET - 1 PAI 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
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