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Sleep Apnea and Type 2 Diabetes:

More Than Just a Sleepless Night!

Kim Kelly, PharmD, BCPS, FCCPKelly Diabetes Associates, LLC | Cupertino, CA

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• Affects ~ 2 to 4% of the adult population

• High risk patients include those with:

• Obesity

• Congestive heart failure

• Atrial fibrillation

• Treatment refractory hypertension

• Type 2 diabetes

• Stroke

• Nocturnal dysrhythmias

• Pulmonary hypertension

• High-risk driving populations

• Bariatric surgery candidates

Obstructive Sleep Apnea (OSA)

J Clin Sleep Med; 2009;5:264

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Nighttime Symptoms• Snoring

• Observed apneas

• Choking, gasping

• Restless sleep

• Sweating during sleep

• Nocturia

• Gastroesophageal reflux

• Bruxism (grinding of teeth)

• Decreased libido, impotence

Obstructive Sleep Apnea: Symptoms

Daytime Symptoms• Sleepiness

• Fatigue

• Morning headaches

• Poor concentration

• Decreased attention

• Forgetfulness

• Depressions

• Personality changes

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Obstructive sleep apnea (OSA) is a breathing disorder during sleep in which a person frequently stops breathing during his or her sleep and has implications beyond disrupted sleep …

Obstructive Sleep ApneaDefinition

Mayo Clin Proc. 2011;86:549

J Clin Sleep Med; 2009;5:263

J Amer Coll Card 2008;52:686

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Signs and Symptoms of OSA

The presence of sleep related symptoms: • Loud snoring

• Witnessed breathing interruptions due gasping or choking

• Obesity and/or enlarged neck size

• Excessive daytime sleepiness

Other signs and symptoms• Increased blood pressure

• Morning headaches

• Sexual dysfunction

• Crowded-appearing pharyngeal airway

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ECG --

Airflow --

Thor. Effort --

Abd. Effort --

SAO2 --

What Happens in OSAObstructive Apnea

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• Screening questionnaires

• Sleep history

• Physical examination

• Objective testing

• In-laboratory polysomnography

-- Full night

-- Split night

• Home testing with a portable monitor (PM)

Diagnosis of OSA

J Clin Sleep Med; 2009;5:264

Screening for Obstructive Sleep Apnea

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Daytime Sleepiness

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• Epworth Sleepiness Scale

• Berlin Questionnaire

• G.A.S.P. (self administered)

• STOP-BANG Questionnaire

Screening Tools

http://sleepmedicine.com/content.cfm?article=26

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Diagnostic Tests for Obstructive Sleep Apnea

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Diagnosis is accomplished by measuring the Apnea-Hypopnea Index (AHI) which is the number of apneas (breathing ceases for at least 10 seconds) and hypopneas (airflow decreases by at least 50% for a breath) per hour of sleep.

Diagnosing OSA: Polysomnography

No OSA AHI < 5

Mild OSA AHI > 5 and < 15

Moderate OSA AHI > 15 and < 30

Severe OSA AHI > 30

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• Over 2 dozen manufacturers and devices available to test for OSA at home

• Home Sleep Testing can be covered by Medicare and other payers, payment relates to type of device (channels used)

• Home Sleep Testing can be used as documentation of OSA to show medical necessity for Continuous Positive Airflow Pressure devices

Home Sleep Testing

Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG. Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med.2017;13(3):479–504.

https://aasm.org/clinical-resources/coding-reimbursement/coding-faq/

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A. 1%

B. 5%

C. 30%

D. 50%

E. 60%

Polling Question:What percentage of people with type 2 diabetes have OSA?

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Prevalence of OSAin People with Type 2 Diabetes

sdfvfvEinhorn D, et al Endo Pract 2007;13:355 | Foster GD, et al. Diab Care 2009;32:1017 | Laaban JP, et al. Diabetes Metab 2009;35:372 | Aronsohn RS, et al. Am J Resp Crit Care Med 2010;181:507 | Grimaldi D, et al Diab Care 2014;37:355 | Hanis CL, et al. Cardiovasc Diabetol 2016;15:86, | Siwasaranond N, et al Sleep Breath 201620:569gwd

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Einhorn (2007) Foster (2009) Laaban (2009) Aronsohn (2010) Grimaldi (2014) Hanis (2016) Siwasaranond(2016)

Total Mild Moderate Severe

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• OSA is more common in men than in women ~2:1

• OSA is roughly as prevalent in men and postmenopausal women

• OSA severity is higher in men than in women

OSA in Very Obese Men and Women

Fredheim JM et al. Cardiovascular Diabetology 2011, 10:84

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Estimated 12% increase in risk for each unit increase in BMI. (5)

Childhood Obesity and OSA

(1) Silvestri JM, et al. Pediatr Pulmonology 1993;16:124

(2) Marcus CL, et al. Pediatr Pulmonology 1996;21:176

(3) Kalra M, et al. Obes Res 2005;13:1175

(4) Verhulst SL, et al. Sleep Med Rev 2008;12:339

(5) Redline S, et al. Am J Resp Crit Care Med 1999;159:1527

0%

10%

20%

30%

40%

50%

60%

70%

Ref 1 Ref 2 Ref 3 Ref 4

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Why Obstructive Sleep Apnea is Important

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“Unfortunately…OSA remains the ‘elephant in the [cardiovascular] room’ and often is ignored even in high-risk patients.”

Bakkar JP, Sharma, B, Mslhotra A. Obstructive Sleep Apnea: The Elephant in the Cardiovascular Room. Chest 2012;141:580

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A. The incidence of OSA is roughly the same in men and women

B. Daytime sleepiness is the hallmark of OSA

C. Diabetes causes OSA

D. OSA causes Hypertension

Polling Question:Which of the following statements is true?

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Metabolic Consequences of Obstructive Sleep Apnea

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Glucose Intolerance andObstructive Sleep Apnea

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Sleep-Disordered Breathing and GlucoseN=2588 individuals without known diabetes(2)

• Cross sectional studies; OSA is associated with impaired glucose tolerance independent of obesity

• Risk strongly associated with severity of nocturnal hypoxia

• Longitudinal cohort studies from America, Europe, and Australia found an overall increased risk of incident diabetes, particularly in moderate to severe OSA

1) Seicean S, et al. Diabetes Care 2008;31:1001–1006

2) Doumit J & Prasad B, Diab Spectrum 2016;29:14-19

0 1 2

OccultDiabetes

IFG + IGT

IFG

IGT

Odds Ratio for Glucose Intolerance

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OSA SeverityAssociated with Poorer Glucose Control in T2DM

Aronsohn RS, et al Am J Resp Crit Care Med. 2010;181:507

5.73

7.227.66

9.42

4.0

5.0

6.0

7.0

8.0

9.0

10.0

11.0

No OSA Mild OSA Moderate OSA Severe OSA

N=60; mean age 57+ 9yrs,

mean BMI 34 + 8 kg/M2

“In patients with type 2 diabetes,

increasing severity of OSA is

associated with poorer glucose

control, independent of adiposity

and other confounders.”

Adju

ste

d A

1C

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• A literature search identified 2727 potential articles based on search terms, 24 trials met the predetermined criteria and were included in the meta-analysis

• A pooled analysis looked at the risk of developing diabetes if you had OSA and vice versa

• The presence of OSA was associated with a 92% increased risk of diabetes, but diabetes was not associated with increased future risk of OSA

• “These results suggest that OSA causes incident diabetes mellitus, but that the reverse is not true”

Meta-Analyses of OSAand Diabetes Relationship

Fujihara K, et al - (Oral Presentation #15)

American Diabetes Association Meeting - June 2012

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• In a study of 12 healthy men, after only 2 days of sleep restriction (only 4 hours each night)

• Daytime profiles of:• Plasma leptin • Ghrelin levels • Ratings of hunger and appetite

• Sleep restriction results:• Anorexigenic (‘satiety’) hormone leptin -- decreased 18%

• Orexigenic (‘hunger’) hormone ghrelin -- increased 28%

• Hunger and appetite -- increased 24%

OSA: Leptin, Ghrelin and Hunger

Spiegel K, et al Ann Intern Med 2004;141:846-850

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OSA and the Vascular System

• OSA was associated with a 2-4 fold increased risk of retinopathy in both T1D and T2D1,2

• Insulin resistance secondary to intermittent hypoxia leads to hyperlipidemia, hypercoagulability2

• OSA and hypoxic stress increases albuminuria and the prevalence of chronic kidney disease2

1. Zhu Z. et al.BioMed Research International 2017, Article ID 4737064

2. Tahrani A. Eur Endocrinol. 2015;11:81-89

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Vicious Cycle of Carotid Body Chemoreflex

• Cells in the carotid body depolarize in response to hypoxia, enhance chemo-receptor activity and a reflex increase in sympathetic nerve activity (SNA)

• Increases sympathetic vasoconstrictor outflow to muscle, splanchnic, and renal beds to elevate arterial pressure resulting in hypertension and eventually increased load on the left ventricle leading to congestive heart failure

Schultz HD, et al. Hypertension 2007;50:6-15

↑ SNA

O2

Hypertension

CHF

↑VR

↓BF

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OSA and Stroke

• “Wake-up stroke” or transient ischemic attack (TIA)

• Occurs most commonly when patients have long obstructions (significant hypoxia) and right-to-left shunting

• Embolic in nature

Dyken ME, Kyoung BI, Chest 2009;136:1668–1677)

Ciccone A., et al. Thorax 2013;68:97-104

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OSA and Ventricular ArrhythmiasDaytime Night

Namtvedt SK, et al Am J Cardiol 2011;108:1141

0 5 10 15

Complex ventricularectopy

Non-sustained Vtach

VPCs >30/hr

VPCs >5/hr

Without OSA With OSA

0 5 10 15

Complex ventricularectopy

Non-sustained Vtach

VPCs >30/hr

VPCs >5/hr

Without OSA With OSA

N=486; Standard full night polysomnography with daily holter monitor

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Long Term CV Outcomes in Men with OSAIncidence of Events per 100 person-years

Marin JM, et al Lancet 2005;365:1046-53

0

0.5

1

1.5

2

2.5

Healthy Men (264) Simple Snorers (377) Untreated Mild/ModerateOSA (403)

Untreated Severe OSA(235)

OSA using CPAP (372)

Non-fatal CV events Cardiovascular death

Untreated severe OSA was associated with

a 287% increased risk of fatal and non-fatal

CV events compared to controls

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So what are the treatment options?

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• Oral appliances• Mandibular repositioning appliances

(MRA)• Tongue retaining devices

• Treatment of choice for all degrees of OSA is positive airway pressure (PAP)• Can be delivered in a continuous

(CPAP), bi-level (BPAP), or autotitrating (APAP) mode

• Hypoglossal nerve stimulation

• Nasal appliance (EPAP)

• Surgical treatments

Treatment of OSA

Mahmood K, et al. J Clin Sleep Med; 2009;5:268Lorenzi-Filho G, et al . Respirology 2017;22:1500

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A. Laser assisted thyroidectomy

B. Adenotonsillectomy

C. Uvulopalatopharyngoplasty

D. Tracheostomy

E. Bariatric Surgery

Polling Question:Which of the following is not a surgical treatment for OSA?

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• Discomfort with delivery via nasal airway• Heated humidification helps to increase comfort

• Mask discomfort

• Machine not functioning properly

• Machine usage problems

Barriers to CPAP Treatment Adherence

J Clin Sleep Med; 2009;5:271

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• Usually only helpful for mild to moderate cases

• Not as effective as CPAP

• Surgery effectiveness depends on how much of a role tissue excess is playing

Treating Obstructive Sleep Apnea:ENT Surgical and Positional Approaches

Fhttp://www.sleepguide.com/profiles/blogs/cpap-surgery-dental-device-or

http://www.enttoday.org/details/article/531771/Surgery_for_Obstructive_Sleep_Apnea_One_Size_Doesnt_Fit_All.html

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CPAP Adherence: 82 studies spanning 20 years

Rotenberg BW, et al. Journal of Otolaryngology - Head and Neck Surgery (2016) 45:43

0%

10%

20%

30%

40%

50%

60%

Percent non-use

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Putting it all together…

OSAHS Obesity

Oxidative stress

SA

HTN DM Dyslipidaemia

Inflammation

Cardiovascular morbidity

Independent

HTNDMDyslipidaemia

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Effect of CPAP on Blood PressureDecreases in BP with CPAP are Maintained Over Time

Tahrani AA. Diabetes & Vascular Disease Research 2017;14:454-462

-8

-7

-6

-5

-4

-3

-2

-1

0

Systolic BP Diastolic BP

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CPAP Improves Cardiac Functioning

• N=82 patients diagnosed with OSA and treated with CPAP

• Echocardiography for the detection of CPAP related changes in LV/RV function at study initiation and at 6 months

• Changes seen were classed by severity of Apnea-Hypopnea Index (AHI)

• Beneficial effect of CPAP on LV and RV functional parameters predominately in patients with severe OSA

Hammerstingl C, et al, et al. PLosOne 2013;8:e76352

0 -

-10 -

-20 -

-30 -

-40 -

-50 -

80 -

70 -

60 -

50 -

40 -

AHI 5-14 AHI 15-30

AHI Groups

AHI >30

AHI 5-14 AHI 15-30

AHI Groups

AHI >30

P=ns P=0.028 P=<0.0001

P=ns P=0.002 P=<0.0001

2D apical RVSI (%) baseline

2D apical RVSI (%) follow up

LVEF (%)baseline

LVEF (%)follow up

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Mortality with No Treatment by AHI

• N=6294 (53% women)

• Patients followed for 10 years

• AHI of <5 was considered to not have sleep disordered breathing

• Mortality rates per 1,000 person–years in the full cohort varied with the AHI category:• No sleep-disordered breathing=16.8

• Mild disease=21.7

• Moderate disease=28.3

• Severe disease=32.2

Punjabi NM, et al PLoS Medicine 2009;6:e1000132

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• Resolution of daytime drowsiness

• Patient and partner satisfaction

• Adherence to interventions

• Decrease or avoidance of risk factors

• Obtain adequate amount of sleep

• Weight loss

• …Oh, they likely live longer too!

Outcomes of OSA Treatment

J Clin Sleep Med; 2009;5:268

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Thank You! … and sleep well

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