obstructive sleep apnoea (osa) predicts microvascular complications in type 2 diabetes

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

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Heart attack Chest pain Coronaryheart

disease

Congestiveheart failure

Stroke Chronickidneydisease

Footproblems

Eye damage

Perc

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ions

Diagnosed diabetesNormal blood sugar levels

Prevalence of diabetes macrovascular and microvascular complications

Macrovascular Microvascular

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.

*†

‡

*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.

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.

Multiple metabolic pathways may contribute to diabetic microvascular complications

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

C-11 HEDFLOW

C-11 HED

DistalShort Axis

ProximalShort Axis

VerticalLong Axis

HorizontalLong Axis

N-13 Ammonia Blood Flow

Stevens et al Circulation 1999

OSA is associated with CAN

OSA+ OSA- P value

Cardiac autonomic neuropathy (Spectral analysis, >= 3 abnormalities

69.9% 54.3% 0.034

Effect of OSA on skin structure

Diabetes: Mild OSA Diabetes: Severe OSA

Diabetes: No OSA Non-diabetic

Diabetes microvascular complications

• Neuropathy• Nephropathy• Retinopathy

Approximately 40% of patients with type 2 diabetes show signs of CKD1

* 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 Stage 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

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%) 0.002

Tahrani A et al, Diabetes Care 2013; 36:3718-25

OSA and diabetic nephropathy: Cross-sectional multivariable analysis

Model R2 OR 95% CI P valueUnadjusted 0.09 3.12 1.70-5.75 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

A

CB

Diabetic Retinopathy

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)

Sight threatening retinopathy

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)

Tahrani AA et al AM J Respir Crit Care Med 2012Tahrani AA et al Diabetes Care 2013Tahrani AA et al Eur J Ophthalmol 2013

The postulated mechanisms linking OSA and microvascular complications

HyperglycaemiaOSA/ Intermittent

Hypoxia ROS/ RNS

Polyolpathway

Hexosaminepathway

AGE pathway

PKCpathway

HTN

ET-1PAI-1VEGFTGF-BNF-KB

NO

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

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