Obstrukční spánková apnoe a metabolické poruchy. Jan Polák 2. interní klinika FN Královské Vinohrady a 3.LFUK Ústav patofyziologie 3.

Obstrukční spánková apnoe a metabolické poruchy Jan Polák 2. interní klinika FN Královské Vinohrady a 3.LFUK Ústav patofyziologie 3.LFUK Brno, ResMed Akademie 2018 1

Katecholaminy Antidiuretický hormon, BNP Kortizol GIT hormony OSA Růstový hormon Štítnice

Kardiovaskulární choroby Diabetes mellitus 2.typu

December 18, 2018 5

Kompletní kruh kauzality? Možné mechanismy Randomizované studie CPAP Průřezové studie Prospektivní studie December 18, 2018 6

Inzulínová citlivost Sekrece inzulínu Intermitentní hypoxie indukuje dysfunkci β-buněk u zdravých dobrovolníků Trvání expozice: 5 hodin Louis, 2009, J Appl Physiol, 1538-1544

December 18, 2018 8 Jun et. al, JCEM, June 2017

Zvířecí modely: Intermitentní hypoxie (IH) Kontrola (vzduch) Samci C57/B-6J Intermit. Hypoxie Vzduch 7 dní 7 dní FiO 2 21% - 6.5 % 60 cyklů/hod 12 hod /den 14 dnů 9

Expozice intermitentní hypoxii Procesor časovač Průtokoměr O 2 N 2 Tagaito et.al., J Appl Physiol. 2001 Dec;91(6):2758-66. December 18, 2018 10

Hyperglykémie po intermitentní hypoxii Glykémie

Intraperitoneální glukózový toleranční test Peak insulin measurements December 18, 2018 12

Inzulínová rezistence indukovaná IH je částečně zlepšena při přerušení Insulin effect Contraregulatory response

Glukóza v médiu Intermitentní hypoxie zvyšuje jaterní výdej glukózy a glukoneogenezu PEPCK mrna PEPCK protein December 18, 2018 14

OSA zhoršuje sekreci inzulínu u T2DM December 18, 2018 15

Kompletní kruh kauzality? Možné mechanismy Randomizované studie CPAP Průřezové studie Prospektivní studie December 18, 2018 16

Prevalence OSA u T2 DM

First Author Year Study Design Study Sample Ayas Sample Size Dependent Variable 2003 Longitudinal Nurses 70026 Incident Diabetes Gottlieb 2005 Cross-sectional Community 1486 Glucose intolerance diabetes Confounders Assessed BMI, age, activity, smoking, depression, hypertension, shift work, snoring Waist, age, sex, race, AHI + - Bjoirkelund 2005 Longitudinal Population 1462 Incident Diabetes BMI, waist-to-hip ratio, age, subscapular skin folds - Yaggi 2006 Longitudinal Population 1139 Incident diabetes Waist, age, smoking, education, hypertension + Chaput 2007 Cross-sectional Healthy adults 740 Glucose tolerance and prevalent diabetes Waist, age, sex, activity, alcohol, hypertension, coffee + Glucose tolerance and BMI, age, sleep apnea, smoking, activity, medication Tuomilehto 2007 Cross-sectional Population 2770 + prevalent diabetes use Santos 2007 Cross-sectional Population 14/18 2164 Metabolic syndrome Age, sex, alcohol, education level - Gangwisch 2007 Longitudinal Population 8992 Incident diabetes BMI, age, activity, depression, alcohol, education + Hayashino 2007 Longitudinal Population 6509 Incident diabetes BMI, age, sex, smoking, hypertension, cholesterol - Fasting glucose levels Age, sex, obesity, blood pressure, HDL level, Nakajima 2008 Cross-sectional Rural sample 1062 + and HbA1c triglyceride level, medication use BMI, age, sex, alcohol, smoking, exercise, family Choi 2008 Cross-sectional Population 4222 Metabolic syndrome + history of hypertension or diabetes Age, sex, race, education, smoking, activity, LDL level, Hall 2008 Cross-sectional Community 1214 + Metabolic syndrome depression BMI, age, sex, glucose tolerance, hypertension, family Beihl 2009 Cross sectional Community 900 Incident Diabetes + history, smoking, educaiton Chaput 2009 Cross Sectional Community 276 Glucose Tolerance BMI, waist circumference, % body fat + Kim 2009 Crosssectional Population 1652 Incident Diabetes Xu 2010 Longitudinal NIH- AARP 10413 Incident Diabetes Rafalson 2010 Longitudinal Community 1455 Fasting glucose Cappuccio 2010 Systematic review Mixed 107756 Risk of type 2 diabetes Age, smoking, drinking, exercise, education, income, hypertension, obesity, triglyceride, HDL, cholesterol BMI, age, sex, education, smoking, coffee, alcohol, activity, marital status, family history Sex, race, age, abdominal height, weight change, family history, smoking, hypertension, depression Sex, BMI, activity, diet + + + +

Kompletní kruh kauzality? Možné mechanismy Randomizované studie CPAP Průřezové studie Prospektivní studie December 18, 2018 19

Zlepšuje CPAP inzulínovou senzitivitu? ANO December 18, 2018 20

Zlepšuje CPAP HbA1C? ASI NE < 4 hod CPAP / noc 25% léčeno inzulínem Malý počet subjektů Labarca, Clin Respir J. 2018 Aug;12(8) December 18, 2018 21

Zlepšuje CPAP HbA1C? MOŽNÁ ANO Vynikající kompenzace vstupně 30-60% léčeno inzulínem Spíše střední závažnost OSA Labarca, Clin Respir J. 2018 Aug;12(8)

CPAP terapie u PREDIABETU! Observační studie smíšené výsledky (spíše negativní) Randomizované studie není efekt CPAP na HbA1c Meta analýza není efekt CPAP na glykémii, insulin a HbA1c (HOMA?) ANO! Sleep. 2012 May 1;35(5):617-625B AJRCCM. 2015 July

Kompletní kruh kauzality? Možné mechanismy Randomizované studie CPAP Průřezové studie Prospektivní studie December 18, 2018 24

Therapie OSA redukuje mortalitu Severe OSA Moderate OSA CPAP treatment Control (mild OSA) December 18, 2018 25

Sleep Heart Health Study mortalita diabetiků Roky AHI < 15 AHI >=15

Poděkování MUDr. Kateřina Westlake MUDr. Martin Pretl, PhD MUDr. Andrea Plíhalová RNDr. František Horka MUDr. Jan Brož MUDr. Mgr. Sylive Špitálníková prof. MUDr. Michal Anděl, CSc. AZV, GAČR, Univerzita Karlova, AASM, PROGRES, Hlávkova nadace Nadání Děkuji za pozornost... December 18, 2018 27

Děkuji za pozornost...

Nalezení vhodných skríninkových metod OSA Kapacita spánkových specialistů v ČR Hodnocení nákladů, efektivity, přínosu December 18, 2018 29

Kompletní kruh kauzality? Navrhované mechanismy RCT on CPAP treatment Průřezové studie Prospective studies December 18, 2018 30

Mortality reduction with ACE-I and Studie Advance statins

OSA increases morbidity and mortality Hypertension Stroke Heart failure Sudden death Myocardial infarction Atrial fibrilation Type 2 diabetes 32 mellitus

Intermittent hypoxia impaired glucose metabolism in helathy individuals Duration of exposure: 5 hours Louis, 2009, J Appl Physiol, 1538-1544

All animals do sleep December 18, 2018 34

Mortality in patients with OSA 35 Young et al, SLEEP, 2008

NORMAL SLEEP ARCHITECTURE

Pathogenesis of OSA December 18, 2018 37

Obstructive Sleep Apnea Syndrome Intermittent hypoxia in tissues (fat,liver, muscle, pancreas) Sympathetic activation Sleep fragmentation December 18, 2018 38

Life-span of patients with T2DM Shorter by 20 years in T1 DM Shorter by 10 years in T2DM Diabetes in the UK 2010: Key statistics on diabetes March 2010 December 18, 2018 39

Obesity as a risk factor for OSA Fat deposition in parapharyngeal and tongue regions Lower lung volume Lower pharyngeal muscle tonus Leptin resistance December 18, 2018 40

December 18, 2018 41

% OSA Age as a risk factor for OSA 35 30 25 20 15 10 Women Men 5 0 30-39 yrs 40-49 yrs 50-60 yrs December 18, 2018 2006 American Academy of Young Sleep medicine T et 42al. N Engl J Med 1993;328.

Clinical signs of OSA: Night symptoms: 1. Snoring 2. Witnessed apneas 3. Choking, gasping (awakening) 4. Insomnia (difficulties maintain sleep) December 18, 2018 43

Clinical signs of OSA: Day symptoms 1. Excessive daytime sleepiness Subjective assessment: Epworth Sleepiness Scale Objective assessment: Multiple Sleep Latency Test 2. Tiredness 3. Cognitive deficit, personality changes 4. Morning headache, nausea 5. Depression December 18, 2018 44

Clinical signs of OSA DO YOU SNORE? + ARE YOU TIRED? December 18, 2018 45

Screening for OSA in T2DM ADA, IDF recommendations do it!? HOW? Questionnaire -> Home screening device December 18, 2018 46

Questionnaire OSA Screening in T2DM Low OSA risk in questionnaires 21% 39% 40% No OSA Mild OSA Moderate/severe OSA December 18, 2018 47

Systematic screening of OSA in T2DM patients using home sleep monitoring devices Sleep Med. 2016 Oct;26:71-76

Switzerland Iceland Norway France Belgium Portugal Austria Ireland Netherlands Sweden Germany Estonia Great Britain Denmark Slovenia Italy Romania Slovakia Latvia Greece Czech Republic Finland Turkey Poland Hungary Russia Armenia Serbia Number of Citizens per Sleep Center 0.0 500.0 1000.0 1500.0 2000.0 2500.0 Počet obyvatel (tisíce)

CPAP Therapy December 18, 2018 50

SUMMARY OSA is prevalent in T2DM -30% need treatment OSA increases mortality (2-3 fold) Treatment of OSA reduces mortality Screen T2DM patients for OSA December 18, 2018 51

Thank you as. prof. MUDr. Jan Brož MUDr. Kateřina Westlake MUDr. Andrea Havlová MUDr. Zuzana Lattová, PhD Mgr. Martin Weiszenstein, PhD Eva Bajaníková Ivana Brabcová Funding: AZV, GAČR, AASM, GAUK, SVV December 18, 2018 52

OSA jako (kauzální?) faktor hypertenze Pacienti s OSA mají cca 3x vyšší riziko rozvoje hypertenze během 4 let Wisconsin Sleep Cohort Study Peppard PE et al. NEJM 2000

Prevalence Prevalence OSA u pacientů se stabilním srdečním selháním 60% 57% 50% 40% 30% 57% 57% 20% 36% 43% 43% 48% 30% 10% 57% Oldenburg 2007 Schulz 2007 Khayat 2009 Bitter 2009 Macdonalad 2008 Paulino 2009 0% 1 2 3 4 5 6 7

Arytmie při OSA Mehra R et al. Am J Respir Crit Care Med 2006

OSA zvyšuje riziko CMP Marshal, J Clin 56 Sleep Med, 2014

Intermitentní hypoxie vede k rozvoji aterosklerózy Rozvoj aterosklerotických lézí u ApoE - / - myší po 4 týdenní expozici intermitentní hypoxii AHI = 60 FiO 2 21-7 % á 30s 12 hodin denně v průběhu spánku Jun et al, Atherosclerosis. Apr 2010; 209(2): 381 386.

Doba přežití u pacientů s OSA Young 58 et al, SLEEP, 2008

Terapie CPAP snižuje KV mortalitu Závažná OSA bez léčby Střední OSA bez léčby OSA s léčbou Kontrola (mírná OSA) December 18, 2018 59

First Author Year Study Design Study Sample Ayas Sample Size Dependent Variable 2003 Longitudinal Nurses 70026 Incident Diabetes Gottlieb 2005 Cross-sectional Community 1486 Glucose intolerance diabetes Confounders Assessed BMI, age, activity, smoking, depression, hypertension, shift work, snoring Waist, age, sex, race, AHI + - Bjoirkelund 2005 Longitudinal Population 1462 Incident Diabetes BMI, waist-to-hip ratio, age, subscapular skin folds - Yaggi 2006 Longitudinal Population 1139 Incident diabetes Waist, age, smoking, education, hypertension + Chaput 2007 Cross-sectional Healthy adults 740 Glucose tolerance and prevalent diabetes Waist, age, sex, activity, alcohol, hypertension, coffee + Glucose tolerance and BMI, age, sleep apnea, smoking, activity, medication Tuomilehto 2007 Cross-sectional Population 2770 + prevalent diabetes use Santos 2007 Cross-sectional Population 14/18 2164 Metabolic syndrome Age, sex, alcohol, education level - Gangwisch 2007 Longitudinal Population 8992 Incident diabetes BMI, age, activity, depression, alcohol, education + Hayashino 2007 Longitudinal Population 6509 Incident diabetes BMI, age, sex, smoking, hypertension, cholesterol - Fasting glucose levels Age, sex, obesity, blood pressure, HDL level, Nakajima 2008 Cross-sectional Rural sample 1062 + and HbA1c triglyceride level, medication use BMI, age, sex, alcohol, smoking, exercise, family Choi 2008 Cross-sectional Population 4222 Metabolic syndrome + history of hypertension or diabetes Age, sex, race, education, smoking, activity, LDL level, Hall 2008 Cross-sectional Community 1214 + Metabolic syndrome depression BMI, age, sex, glucose tolerance, hypertension, family Beihl 2009 Cross sectional Community 900 Incident Diabetes + history, smoking, educaiton Chaput 2009 Cross Sectional Community 276 Glucose Tolerance BMI, waist circumference, % body fat + Kim 2009 Crosssectional Population 1652 Incident Diabetes Xu 2010 Longitudinal NIH- AARP 10413 Incident Diabetes Rafalson 2010 Longitudinal Community 1455 Fasting glucose Cappuccio 2010 Systematic review Mixed 107756 Risk of type 2 diabetes Age, smoking, drinking, exercise, education, income, hypertension, obesity, triglyceride, HDL, cholesterol BMI, age, sex, education, smoking, coffee, alcohol, activity, marital status, family history Sex, race, age, abdominal height, weight change, family history, smoking, hypertension, depression Sex, BMI, activity, diet + + + +

β-cell Function in a Postprandial State HOMA-β = (360 x insulin)/(glucose-63) December 18, 2018 61 Polak et al., Sleep, 2013

OSA u pacientů s DM 2.typu kauzalita nebo asociace? Mírná OSA Střední a závažná OSA 62

December 18, 2018 63

Skrínink OSA aktivní vyhledávání u rizikových pacientů Berlínský dotazník STOP-BANG Epworthská škála spavosti http://www.spanekadiabetes.cz December 18, 2018 64

Spánkové laboratoře a centra v ČR http://www.sleep-society.cz 16 spánkových center + 12 spánkových laboratoří 10.000 diabetiků pro každé pracoviště 65

Domácí monitoring saturace a dýchání (flow) ve spánku December 18, 2018 66

Redukce mortality po ACE-I a Studie Advance statinech

Sleep, 2008 December 18, 2018 68

December 18, 2018 69

December 18, 2018 70 AJRCCM, 2013

Laboratoř / domácí monitoring December 18, 2018 71

Diagnostika OSA December 18, 2018 72

Mandibular advancement device December 18, 2018 73

Kompletní kruh kauzality u kardiovaskulárních chorob Patogenetický mechanismus Randomizované studie Odstranění příčiny = terapie Průřezové asociativní studie Prospektivní studie December 18, 2018 74

Maxilo-mandibulární advancement December 18, 2018 75

December 18, 2018 76

First Author Year Study Design Study Sample Ayas Sample Size Dependent Variable 2003 Longitudinal Nurses 70026 Incident Diabetes Gottlieb 2005 Cross-sectional Community 1486 Glucose intolerance diabetes Confounders Assessed BMI, age, activity, smoking, depression, hypertension, shift work, snoring Waist, age, sex, race, AHI + - Bjoirkelund 2005 Longitudinal Population 1462 Incident Diabetes BMI, waist-to-hip ratio, age, subscapular skin folds - Yaggi 2006 Longitudinal Population 1139 Incident diabetes Waist, age, smoking, education, hypertension + Chaput 2007 Cross-sectional Healthy adults 740 Glucose tolerance and prevalent diabetes Waist, age, sex, activity, alcohol, hypertension, coffee + Glucose tolerance and BMI, age, sleep apnea, smoking, activity, medication Tuomilehto 2007 Cross-sectional Population 2770 + prevalent diabetes use Santos 2007 Cross-sectional Population 14/18 2164 Metabolic syndrome Age, sex, alcohol, education level - Gangwisch 2007 Longitudinal Population 8992 Incident diabetes BMI, age, activity, depression, alcohol, education + Hayashino 2007 Longitudinal Population 6509 Incident diabetes BMI, age, sex, smoking, hypertension, cholesterol - Fasting glucose levels Age, sex, obesity, blood pressure, HDL level, Nakajima 2008 Cross-sectional Rural sample 1062 + and HbA1c triglyceride level, medication use BMI, age, sex, alcohol, smoking, exercise, family Choi 2008 Cross-sectional Population 4222 Metabolic syndrome + history of hypertension or diabetes Age, sex, race, education, smoking, activity, LDL level, Hall 2008 Cross-sectional Community 1214 + Metabolic syndrome depression BMI, age, sex, glucose tolerance, hypertension, family Beihl 2009 Cross sectional Community 900 Incident Diabetes + history, smoking, educaiton Chaput 2009 Cross Sectional Community 276 Glucose Tolerance BMI, waist circumference, % body fat + Kim 2009 Crosssectional Population 1652 Incident Diabetes Xu 2010 Longitudinal NIH- AARP 10413 Incident Diabetes Rafalson 2010 Longitudinal Community 1455 Fasting glucose Cappuccio 2010 Systematic review Mixed 107756 Risk of type 2 diabetes Age, smoking, drinking, exercise, education, income, hypertension, obesity, triglyceride, HDL, cholesterol BMI, age, sex, education, smoking, coffee, alcohol, activity, marital status, family history Sex, race, age, abdominal height, weight change, family history, smoking, hypertension, depression Sex, BMI, activity, diet + + + +

OSA Diabetes: kauzalita December 18, 2018 78

Vztah mezi inzulínovou rezistencí a sekrecí Inactivity Pregnancy Obesity Aging Disposition index Insulin sensitivity Bergman, J Clin Invest. 1981 Dec;68(6):1456-67. C. Weyer et al.: J Clin Invest 104:787 794, 1999 December 18, 2018 79

Intermittentní hypoxieindukuje dysfunkci β- buněk u zdravých dobrovolníků Duration of exposure: 5 hours Louis, 2009, J Appl Physiol, 1538-1544

Vede léčba CPAP ke zlepšení glukózové homeostázy? Observational studies mixed results (mostly negative) Randomized studies no effect of CPAP on glucose or HbA1c Meta analyses no effect of CPAP on glucose, insulin or HbA1c (HOMA?) Sleep. 2012 May 1;35(5):617-625B

Profil O2 v kleci a v játrech během IH December 18, 2018 82

Intraperitoneální Inzulínový Toleranční Test Insulin single dose 0.5 IU/kg Dynamic test of the whole-body insulin sensitivity (mostly in muscle) December 18, 2018 83

Glucose (mg/dl) Lačná glykémi po expozici IH 180 160 140 120 100 80 60 40 20 0 Control Hypoxia Reversal December 18, 2018 84

Výdej glukózy hepatocyty December 18, 2018 85

Life Is Spent in a Postprandial State Holstrup, EJCNM, Volume 5, Issue 6, 2010, e277 e280 December 18, 2018 86

Intraperitoneal Glucose Tolerance Test Glucose single dose 1g/kg Dynamic test of whole-body glucose tolerance December 18, 2018 87

β-cell Function in a Postprandial State HOMA-β = (360 x insulin)/(glucose-63) December 18, 2018 88

Lipid Peroxidation in Tissues Pancreas Liver Muscle December 18, 2018 89

Summary Intermittent hypoxia in mice induces Insulin resistance partially reversible β-cell dysfunction progressing in normoxic exposure Postprandial glucose homeostasis remains impaired due to compromized insulin secretion December 18, 2018 90

Acknowledgements Menotrs: Naresh M. Punjabi Larissa A. Shimoda Collaborators: Seva Polotsky Luciano F. Drager Mi-Kyung Chin Quaoling Yao Funding: American Academy of Sleep Medicine Fulbright Commision Holly McHugh Clark Undem Julie Maylor December 18, 2018 91

Acknowledgements December 18, 2018 92

Insulin fixed rate Glucose variable rate December 18, 2018 93 Am J Respir Crit Care Med Vol 175. pp 851 857, 2007

December 18, 2018 94

Pathogenesis of OSA Healthy OSA Anatomical predisposition (men) Pharynx tonus during sleep / transitions Arousal treshold Feedback loop stability of resoiratory control Lung volume (caudal traction) December 18, 2018 95

Overview OSA pathogenesis, diagnosis,treatment OSA associated mortality OSA in Type 2 diabets pathogenesis Screening for OSA December 18, 2018 96

Home sleep study

OSA Diagnosis: Home Sleep Study December 18, 2018 98

Apnea/hypopnea index - AHI Events per hour AHI < 5 Normal AHI 5-15 Mild OSA AHI > 15 Moderate OSA AHI > 30 Severe OSA Treatment December 18, 2018 99

Diagnostika: Spánková laboratoř Video-polysomnografie December 18, 2018 100

Terapie PAP přetlak v dýchacích cestách (CPAP, APAP, BPAP, ASV) Indikační kritérium: AHI > 15

Léčba OSA druhá linie Redukce hmotnosti Spánková hygiena Ortodontické preparáty ORL - UPPP, LAUP, RFIT Stomatochirurgie- MMA