Presentation on theme: "Martin J Stevens MD, FRCP, Professor of Medicine"— Presentation transcript:
1Obstructive Sleep Apnoea (OSA) Predicts Microvascular Complications in Type 2 Diabetes Martin J Stevens MD, FRCP, Professor of MedicineUniversity of Birmingham, UK
2Objectives To understand the prevalence of OSA in diabetes To describe the mechanisms whereby OSA may exacerbate diabetes complicationsTo understand the association of OSA with the microvascular complications of diabetes
3Prevalence of diabetes macrovascular and microvascular complications ‡†*MacrovascularMicrovascular*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
4Multiple metabolic pathways may contribute to diabetic microvascular complications PURPOSE OF THE SLIDETo show potential aetiologies of neuropathy associated with diabetes.KEY POINTSA large body of evidence suggesting that multiple metabolic changes may contribute to nerve damage.1,2Hyperglycemia 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.REFERENCE1.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 2013Adapted from: Boulton AJM, et al. Diabetes Care. 2004; 27:1548–1586 and Vinik A, et al. Nat Clin Pract Endocrinol Metab. 2006; 2(5):
5OSA: BackgroundObstructive 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
7MethodsSubjects were recruited randomly from the diabetes out-patient clinics of a tertiary centre in the UKDPN was diagnosed using the Michigan Neuropathy Screening Instrument (MNSI). Retinopathy was graded using retinal photography. Nephropathy was assessed using eGFR and urine albumin/creatinine ratiosOSA 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
8OSA prevalenceTahrani et al Am. J. Resp. Crit. Care Med :434-41
9An 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
13Skin (intraepidermal) nerve fibres are reduced in diabetes Non DiabeticDiabetesTahrani A, Stevens MJ et al. Diabetes Care 2012; 35:1913-8
14Prevalence of DPN in relation to OSA status 58% of pts with OSATahrani et al Am. J. Resp. Crit. Care Med :434-41
15The 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.
16Advanced cardiac sympathetic dysinnervation in diabetes DistalShort AxisProximalVerticalLong AxisHorizontalN-13 Ammonia Blood FlowC-11 HEDFLOWC-11 HEDStevens et al Circulation 1999
17OSA is associated with CAN P valueCardiac autonomic neuropathy (Spectral analysis, >= 3 abnormalities69.9%54.3%0.034
18Effect of OSA on skin structure Non-diabeticDiabetes: No OSADiabetes: Mild OSADiabetes: Severe OSA
20Approximately 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 StageeGFR (mL/min)No CKD≥ 90*1≥ 90**260–89330–59415–295< 15 or dialysisDiabetic 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.ReferencesKoro CE, et al. Clin Ther. 2009;31:2608–17Coresh J, et al. JAMA. 2007;298(17):* Normal kidney function, no sign of kidney damage** Albuminuria – kidney damageAdapted from 1. Koro CE, et al. Clin Ther. 2009;31:2608–2617 and 2. Saydah S, et al. JAMA. 2007;297(16):1767.2020
22OSA and diabetic nephropathy: Cross-sectional univariable analysis Total CohortOSA- (n=80)OSA+ (n=144)PDiabetic nephropathy19 (23.8%)71 (49.3%)< 0.001Albuminuria16 (20.0%)58 (40.3%)0.002Macroalbuminuria4 (5.0%)19 (13.2%)0.05Serum creatinine (µmol/l )74.4 (23.4)90.9 (36.8)<0.001Estimated GFR (ml/min/1.73 m2)92.9 (25.1)82.2 (27.6)0.005Estimated GFR < 60 ml/min/1.73 m25 (6.3%)32 (22.2%)Tahrani A et al, Diabetes Care 2013; 36:
23OSA and diabetic nephropathy: Cross-sectional multivariable analysis ModelR2OR95% CIP valueUnadjusted0.093.12p<0.001Adjusted0.462.64p=0.02Adjusted 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:
24Diabetic 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).
29Diabetic 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.
30The relationship between OSA status and sight threatening diabetic retinopathy, retinopathy and maculopathyTotal cohortOSA- (n=74)OSA+ (n=125)P valueSight threatening diabetic retinopathy21.6% (16)48.8% (61)<0.001None40.5% (30)29.6% (37)0.006Background54.1% (40)46.4% (58)<0.01Pre-proliferative1.4% (1)14.4% (18)Proliferative4.1% (3)9.6% (12)Maculopathy17.6% (13)44.0% (55)
31Summary: OSA is associated with microvascular complications in patients with T2DM Unadjusted OR (95%CI)Adjusted OR (95%CI)Sight threatening retinopathy3.5 ( )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 2012Tahrani AA et al Diabetes Care 2013Tahrani AA et al Eur J Ophthalmol 2013
32OSA/ Intermittent Hypoxia The postulated mechanisms linking OSA and microvascular complicationsHyperglycaemiaOSA/ Intermittent HypoxiaROS/ RNSPolyolpathwayHexosamineAGEPKCHTNET-1PAIVEGFTGFBNFKBNOVascularcomplicationsHTN: hypertension; ROS: reactive oxygen species; RNS: reactive nitrogen species PKC: protein kinase C; AGE: advance glycation end-products.
33Obstructive sleep apnoea predicts microvascular complications in type 2 diabetes Thank you!