Sleep, Heart, Brain: What Promotes and How to Reduce Cardiovascular Risk in Patients With Narcolepsy

Phyllis C. Zee, MD, PhD, Barbara Hutchinson, MD, PhD, FACC, and Michael Grandner, PhD, MTR, DBSM, discuss narcolepsy in this CME activity titled "Sleep, Heart, Brain: What Promotes and How to Reduce Cardiovascular Risk in Patients With Narcolepsy." For the full presentation, please visit us at www.peervoice.com/RHA870.

1. PeerVoice

Sleep, Heart, Brain: What Promotes and How to Reduce Cardiovascular
Risk in Patients With Narcolepsy

Learning Objectives

Describe the pathophysiology of narcolepsy in the context of
cardiovascular (CV) effects

Differentiate between narcolepsy medications regarding their impact on
CV risk factors

Identify medications used for common comorbidities associated with
narcolepsy that have the potential to increase CV risk

Propose strategies to manage CV risk in patients with narcolepsy

ice.com/RHA870

2. PeerVoice

Part 1 of 4: Narcolepsy and Cardiovascular Disease: The Pathophysiological Link

Phyllis C. Zee, MD, PhD

Benjamin and Virginia T. Boshes Professor in Neurology
Northwestern University Feinberg School of Medicine
Director, Center for Circadian and Sleep Medicine
Northwestern Medicine

Chicago, Illinois

Barbara Hutchinson, MD, PhD, FACC
Adjunct Instructor

University of Maryland Baltimore
Baltimore, Maryland

Cardiologist

Chesapeake Cardiac Care

Bowie, Maryland

Michael Grandner, PhD, MTR, DBSM
Associate Professor of Psychiatry
University of Arizona

Director, Behavioral Sleep Medicine Clinic
Banner-University Medical Center
Tucson, Arizona

Copyright © 2010-2024, PeerVoice

3. PeerVoice

Phyllis C. Zee, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for CVS Caremark; Eisai Co, Ltd; and Idorsia Pharmaceuticals Ltd.
Grant/Research Support from Vanda Pharmaceuticals Inc. (relationship ended).

Stock Shareholder in Teva Pharmaceutical Industries Ltd.

Advisory Board or Panel for Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and Takeda
Pharmaceutical Company Limited.

Barbara Hutchinson, MD, PhD, FACC, has a financial interest/relationship or affiliation in the
form of:

Honoraria from advisory board work for Cytokinetics, Incorporated; Jazz Pharmaceuticals Inc;
and Novartis AG.

Michael Grandner, PhD, MTR, DBSM, has a financial interest/relationship or affiliation in the
form of:

Consultant for Fitbit; Idorsia Pharmaceuticals Ltd; Natrol, LLC; Pharmavite; and SmartyPants
Vitamins.

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4. PeerVoice

Introduction

- Sleep paralysis

Elevated presence of

Hypnagogic/

obesity, dyslipidemia,

hypnopompic hallucinations iiyeererclan

aa Increased risk of new-onset
pis stroke, AF, HF, MACE, CVD
Orexin deficiency

AF: atrial fibration: CVD: cardiovascular (CV) disease; HF: heart failure; MACE: major adverse CV events.
Courtesy of Phylis C. Zee, MD, PhD:

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Relationship Between Orexin and Narcolepsy

Wakefulness

700
q 600
E [1 A L | Monoaminergic f
5 Orexin neurons
& 500 Negative neurons
: .
5 400 | feedback
3 H E

SL soma mm
& H i ae Orexin level
= intermedi (10-200 pg/mL)
fra ‘2 "Intermediate range (10-200 pg/mi
8 100 Imbalance of

8 Low range sleep/wakefulness
3 (10 pg/mL)
Control Narcolepsy Narcoleps
a Narcolepsy

cataplexy cataplexy

CSF: cerebrospinal fluid
Wang C et al Front Mol Neurosci. 2018:1:220. Crocker A et al. Neurology. 2005:65:184-1188,

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Narcolepsy and Cardiovascular Disease: BOND Study

Individuals

‘Comorbid Conditions, %

nec ° 10 20 30 20 50 60 70 80 90 10

Hypertension, NOS

Narcolepsy (n = 9,312)
Benign hypertension HControis (n = 46,559)
Coronary atherosclerosis

Congestive heart disease

Nonhypertensive acute Ml

Sleep Disorders
Sleep apnea
Periodic RLS
Limb movement REM

Behavior disorder

Others
Headache/migraine

Mood disorders
Diabetes

Mk myocardial infarction; NOS: not otherwise specified; REM: rapid eye movement; RLS: restless leg syndrome.
Black J et al Sleep Medicine. 2017.33:3-18.

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7. PeerVoice

Narcolepsy and Car

3
25

2

5

&

82

3 dé 17

1 u
Stroke M Coronary

revascularization

Black Jet al. Sleep Medicine. 2017:33:15.

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vascular Disease: BOND Study (Co

26

HF

Cardiac
arrest

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8. PeerVoice

Nocturnal Blood Pressure and Cardiovascular Risk

+ Nondippers or reverse dippers/risers BP profile associated with worse renal and CV
outcomes than dippers
- CV morbidity appears to be linked with nocturnal hypertension and nighttime BP
has been described as a robust predictor of CV mortality

+ Salt excess and volume overload have been involved in the nondipping BP profile
- Patients with salt-sensitive hypertension are more frequently nondippers and
excess sodium intake in those with normal renal function is probably one of the
main factors causing nondipping in essential hypertension

BP: blood pressure.
Huart J et al Hypertension. 2023:80:719-729,

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9. PeerVoice

24-Hour Blood Pressure in Patients With Narcolepsy

Time

O narcolepsy (= 10)

—@- contre 2) €
Ss

HERD

DBP: diastolic BP: SBP: systolic BP.
1 Grimaldi D et al Sleep. 2012:35:519-528. 2. Chavda V et al Brain Sci. 2022121473,

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uo]

A study using 24-hour BP
monitoring showed nocturnal
nondipping status in one third of
patients with untreated
narcolepsy-cataplexy vs 5% in
controls?

Nondipping diastolic BP status
was significantly associated
with narcolepsy-cataplexy (OR
= 12) and with percentage of
time in REM sleep?

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Narcolepsy and Metabolic Disease Risk

* Obesity is common in adults and
children with narcolepsy

+ Obesity can predispose to
cardiometabolic abnormalities and OSA

* Obesity is most obvious in children and
weight increase may occur at time of

NA y ,
more commonly occurs) u 7 a E

narcolepsy onset (precocious puberty
Cohen 2018 Black 2017 Back 2017 Jennum 2012

» Patients with narcolepsy are at Ei Diebetes
increased risk for diabetes

(Odds Ratio

OSA: obstructive sleep apnea.
Nordstrand SEH et al. Sleep. 2020;43(5}2s2277. Cohen A et al. Sleep Med. 2018;43:14-18, Poli F et al Sleep. 2013:36:175-181 Jehan S et al. Sleep Med Disord,
2018:252-58. Jehan S et al. Sleep Med Disord. 2017.100019. Tsuneki H et al Diabetologia. 2008:51657-867. Tsuneki H et al. Diabetes. 2015:64:459-470. Jennum P
et al. Sleep. 2013:36:835-840. Black J etal. Sleep Medicine. 2017;3316.

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11. PeerVoice

Cardiovascular Disorders in Narcolepsy

Narcolepsy > DNS/EDS
= Per
Neural Increased CV Risk
Effects (eg MI stroke, HF)
CV Effects >

(eg, increased BP, increased Systemic Inflammation

heart rate, nondipping BP)

Vascular Inflammation
(eg, endothelial function,
atherosclerosis)

(eg, psychiatric, OSA, smoking)

Narcolepsy Medications

NS: disturbed nocturnal sleep: EDS: excessive daytime sleepiness,
Jennum PJ et al. Sleep Med Rev. 202158101440,

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Slee d Cardiovascular Heal
+ SLEEP is one of the American Heart
Association (AHA)’s Life's Essential 8
factors impacting CV health

Life's

SES Poor habitual sleep has been identified

as a risk factor for all-cause mortality

$ 5 + Insufficient sleep duration is associated
with coronary heart disease

National Institute of Neurological Disorders and Stroke. Narcolepsy Fact Sheet. https://www.ninds.nih gov/narcolepsy-fact-sheet. Krahn LE et al Adv Ther.
2022;39:221-243. St-Onge MP et al. Circulation. 2016:134(18):e367-6386. Lloyd-Jones DM et al. Circulation. 202248(5):18-e43,

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13. PeerVoice

Part 2 of 4: Can Narcolepsy Treatment Impact Cardiovascular Risk?

Phyllis C. Zee, MD, PhD

Benjamin and Virginia T. Boshes Professor in Neurology
Northwestern University Feinberg School of Medicine
Director, Center for Circadian and Sleep Medicine
Northwestern Medicine

Chicago, Illinois

Barbara Hutchinson, MD, PhD, FACC
Adjunct Instructor

University of Maryland Baltimore
Baltimore, Maryland

Cardiologist

Chesapeake Cardiac Care

Bowie, Maryland

Michael Grandner, PhD, MTR, DBSM
Associate Professor of Psychiatry
University of Arizona

Director, Behavioral Sleep Medicine Clinic
Banner-University Medical Center
Tucson, Arizona

Copyright © 2010-2024, PeerVoice

14. PeerVoice

Phyllis C. Zee, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for CVS Caremark; Eisai Co, Ltd; and Idorsia Pharmaceuticals Ltd.
Grant/Research Support from Vanda Pharmaceuticals Inc. (relationship ended).

Stock Shareholder in Teva Pharmaceutical Industries Ltd.

Advisory Board or Panel for Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and Takeda
Pharmaceutical Company Limited.

Barbara Hutchinson, MD, PhD, FACC, has a financial interest/relationship or affiliation in the
form of:

Honoraria from advisory board work for Cytokinetics, Incorporated; Jazz Pharmaceuticals Inc;
and Novartis AG.

Michael Grandner, PhD, MTR, DBSM, has a financial interest/relationship or affiliation in the
form of:

Consultant for Fitbit; Idorsia Pharmaceuticals Ltd; Natrol, LLC; Pharmavite; and SmartyPants
Vitamins.

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15. PeerVoice

Increased Cardiovascular Comorbidity in Patients With

Narcolepsy

Stroke
Increased risk in

patients with
narcolepsy
(vs controls)

Heart diseases

Hypertension

Black J et al. Sleep Med. 2017;33:13-18, Ohayon MM. Sleep Med. 2013:14:488-492.

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16. PeerVoice

Cardiovascular Risk Assessment in Narcolepsy

+ Currently there are no guidelines specific to assessment of CV risk in patients with
narcolepsy; recommendations for the general populations may be applied

Traditional Risk Factors Nontraditional Risk Factors
The metabolic syndrome
HIV

Autoimmune disease
Systemic autoinflammatory
process

Depression

Anxiety

Social support
Socioeconomic status
Radiation therapy

Treatable Nontreatable
» Hypertension * Age

+ Dyslipidemia + Family

+ Diabetes history

» Obesity

+ Smoking

+ Physical

activity

Sleep disruption

Jennum PJ et al. Sleep Med Rev. 202158:101440. Khambhati J et al. Clin Cardiol. 2018:41677-684; erratum: Clin Cardiol, 2018:4tmM.

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iovascular Risk Assessment

( Assess for traditional risk factors ]

Base risk estimation via population-based risk score

Consider nontraditional risk rs, biomarkers, noninvasive
measures

Develop personal ri

Khambhati J et al. Clin Cardiol. 2018:41677-684; erratum: Clin Cardio. 2018;

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Impact of Pharmacologic Therapy for Narcolepsy on

Cardiovascular Risk

In the setting of excessive daytime sleepiness

+Cataploxy + Cataploxy + DNS

Matota A-M et al NeuroSci. 2023;4263-279.

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Impact of Nonpharmacologic Therapy for Narcolepsy on

Cardiovascular Risk

Scheduled naps

Regular sleep patterns/sleep hygiene
Avoidance of stimulants

Balanced diet

Physical activity

Cognitive behavioral therapy

Stress management

Adjustments to employment/work

Matota A-M et al NeuroSci. 2023:4:263-279.

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How Does Sodium Intake Affect Cardiovascular Health?

gh soto tao
(nero ROS generen Endotelum
"aire sess sodium chal
ES Endototl aytucion
rnstonce Decreeed ayant of ui te
pS I
Large les ren
| Ataton ot erecta mat Fragmentation of atin ers
Netatopotonases ‘eSumation of len ters

| havea: hows > Tarsı Decreased lstn/colagen ratio

|

| mas |
\ Increased ato! stress
J

ROS: reactive oxygen species.
Grillo A et al. Nutrients. 2019;11970. keda N et al Nutrients. 2022:14:3606.

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Sodium intake is associated
with higher BP

Poor sleep health, including
narcolepsy, is also associated
with higher BP

Reducing salt intake may
decrease risk of CVD

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21. PeerVoice

Reducing Sodium Intake and Blood Pressure

Distribution of Within-Individual 24-Hour Ambulatory BP Response to Dietary Sodium Intake"

10) Change in SBP 30 Change in DBP
Pl ops
ae SE:
» »
SE » E . > 63.3%
85° 85 à
$ 8 [Median change, 7mmHg 5 § - | Median change, 2 mmHg
62%] (op nex} SF 2] (œ-106) an
0 P00 Be P«.001
354 Change in MAP 38 Change in PP
Pe} sos
ES TE >
SE? RE Sh ix
LE» 734% Es E
ES 5 Les
85 © 83 5
5 8 à ]Median change, 4 mmHg 33 3 | Median change, 5 mmHg
52 >] (rows) sal O= (0R.11o 8) 131%
3 P«.001 P<.001

* Calculated from high-sodium diet minus low-sodium diet.

QR: interquartile range; MAP: mean arterial pressure; PP: pulse pressure.
Gupta DK et al. JAMA, 2023;330:2258-2266.

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Hypertension
Heart failure Concerns with
Use of sedatives sodium oxybate

Alcohol consumption

High CV risk Concerns with
stimulants

QTC prolongation or Concerns with
arrhythmias pitolisant

Krahn LE et al Adv Ther. 2022:39:221-243. Jennum PJ et al. Sleep Med Rev. 202158101440. Bosco A et al Neurology. 2018;90(6):0478-e491, Auger RR et al Sleep.
2005:28:667-672.

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Call to Action

+ DO evaluate CV risk in patients with narcolepsy, including
traditional and nontraditional risk factors

+ Consider concomitant medications

+ Include a cardiologist in your care team

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24. PeerVoice

Part 3 of 4: Which Treatments for Common Comorbidities
Associated With Narcolepsy Increase Cardiovascular Risk?

Phyllis C. Zee, MD, PhD

Benjamin and Virginia T. Boshes Professor in Neurology
Northwestern University Feinberg School of Medicine
Director, Center for Circadian and Sleep Medicine
Northwestern Medicine

Chicago, Ilinois

Barbara Hutchinson, MD, PhD, FACC
Adjunct Instructor

University of Maryland Baltimore
Baltimore, Maryland

Cardiologist

Chesapeake Cardiac Care

Bowie, Maryland

Michael Grandner, PhD, MTR, DBSM
Associate Professor of Psychiatry
University of Arizona

Director, Behavioral Sleep Medicine Clinic
Banner-University Medical Center
Tucson, Arizona

Copyright © 2010-2024, Peervoice

25. PeerVoice

Phyllis C. Zee, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for CVS Caremark; Eisai Co, Ltd; and Idorsia Pharmaceuticals Ltd.
Grant/Research Support from Vanda Pharmaceuticals Inc. (relationship ended).

Stock Shareholder in Teva Pharmaceutical Industries Ltd.

Advisory Board or Panel for Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and Takeda
Pharmaceutical Company Limited.

Barbara Hutchinson, MD, PhD, FACC, has a financial interest/relationship or affiliation in the
form of:

Honoraria from advisory board work for Cytokinetics, Incorporated; Jazz Pharmaceuticals Inc;
and Novartis AG.

Michael Grandner, PhD, MTR, DBSM, has a financial interest/relationship or affiliation in the
form of:

Consultant for Fitbit; Idorsia Pharmaceuticals Ltd; Natrol, LLC; Pharmavite; and SmartyPants
Vitamins.

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26. PeerVoice

Sleep and Mental Health

16 | mSleep mDaytime mPerception

(Odds Ratio

JiX et al Sleep Health, 2019:5:376-381

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27. PeerVoice

Narcolepsy vs General Population

ADHD

Phobias

Generalized Anxiety Disorder
Obsessive-Compulsive Disorder
Social Anxiety Disorder

Panic Disorder

Agoraphobia

PTSD

Bipolar Disorder

Major Depressive Disorder

6.47

1 2 3 4 5 6 $
Odds Ratio

ADHD: attention deficit hyperactivity disorder; PTSD: post-traumatic stress disorder.
‘Ohayon MM. Sleep Med. 2013:14:488-492.

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Mental Health Comorbidities in Patients With Narcolepsy:
BOND Study

Adjustment
disorders

ADHD/ADD

Bipolar disorders

‘Anxiety disorders

Depressive
disorders

10 15 20 25 30 35

40
Patients, %

All comparisons P < 0001.
ADO: attention deficit disorder.
Ruoff CM et a. J Clin Psychiatry. 2017,78:17-176.

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Impact of Narcolepsy and Perceived Stigma

Path Model: Determinants of Functioning in Young Adults
With and Without Narcolepsy?

Narcolepsy

Controls

+ 52% of variance in functioning
was explained by the final
model in the individuals with
narcolepsy vs 41% in those
without narcolepsy

* All paths in the final model were supported by the data (P <.001), with the exception of the path from stigma to Functional Outcomes of Sleep
‘Questionnaire (FOSQ) in controls.

Kapella MC et al PLOS ONE. 2015:10(4):00122478

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30. PeerVoice

d Age Differences Wi ty Disorders and

Individuals With Anxiety Exposure, %
o

LLLE

Male Female Age 12-17 Age 18 and older

Narcolepsy = Control

* Significantly higher comorbidity rates of anxiety disorders in patients with narcolepsy
+ Higher incidence of anxiety disorders in patients aged 12-17 years and female patients

Chen TY et al J Affect Disord, 2020/264:130-137.

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31. PeerVoice

Narcolepsy and Depression

Meta-analysis of 31 studies demonstrated that for patients with
narcolepsy:

| About 32% also present with depression

| Had over tripled risk* of depression |

* Pool of 13 studies that examined a control group.
LIX et al Neuropsychol Rev. 20213189-102

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32. PeerVoice

Treatment for Depression and Cardiovascular Risk

Psychosocial Factors
History of depression Social isolation
Anxiety Bereavement

Personality Other stressors

Demographic Factors
Age
Gender

tT

1

Potential Biologic Mechanisms
‘Autonomic nervous system

Platelet receptors and function
Coagulation factors (eg. fibrinogen, PAI-1)

Pro-inflammatory cytokines
Endothelial function
Genet

Potential Behavioral Mechanisms
Smoking.

Obesity

Inactivity

Poor diet
Poor medication adherence

Perceived Loss (Not Necessarily Actual Loss)
Health

Functional capacity

Immortality/Invincibility

Independence,
Sexual relationships
Employment and financial security

PAI-t plasminogen activator inhibitor-1
Hare DL et al Eur Heart .. 2014:35:1365-1372,

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33. PeerVoice

Antidepressants and Cardiovascular Risk

25
mSSRIS m Other Antidepressant
£
32 199
3 197 186
E
ë
15
134
E A =
E
Diabetes Cardiovascular cHo CVD Mortality
No atidopreasnt letra.

CHO: congestive heart disease; SSR selective serotonin reuptaké
Bansal N et al BJPsych Open. 2022:8(5)e164.

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22

173

All-Cause Mortality

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34. PeerVoice

Treatment for Depression and Weight Gain

16
O other Ml sur
Mirtazapine
e ds O ica SSRI
14
2
3
2
2 A
2 Duloxetine ital
2 Escitalopram Citalopram
2| +
Trazodone Sertraline: Fluoxetine o
Nortriptyline ™ Venlafaxine Amitriptyline
© „Dosulepin
10 Paroxetine
o 5 10 15 20 25 30

All Prescriptions, %

‘SNR serotonin-norepinephrine reuptake inhibitor; TCA: tricyclic antidepressant.
Gafoor R et al. BMJ. 2018:36Hk1951

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Call to Action

+ Treating sleep disorders often improves mental health symptoms

+ Mental health treatments may be very effective and synergistic
with sleep disorders treatment

+ Mental health strategies useful in other chronic illness populations
may be beneficial

+ CV risk should be a motivating factor for diagnosis and
management of narcolepsy

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36. PeerVoice

Part 4 of 4: Protecting the Heart and Brain While Managing Narcolepsy:
What Is and What Should Be Happening in Clinic

Phyllis C. Zee, MD, PhD

Benjamin and Virginia T. Boshes Professor in Neurology
Northwestern University Feinberg School of Medicine
Director, Center for Circadian and Sleep Medicine
Northwestern Medicine

Chicago, Ilinois

Barbara Hutchinson, MD, PhD, FACC
Adjunct Instructor

University of Maryland Baltimore
Baltimore, Maryland

Cardiologist

Chesapeake Cardiac Care

Bowie, Maryland

Michael Grandner, PhD, MTR, DBSM
Associate Professor of Psychiatry
University of Arizona

Director, Behavioral Sleep Medicine Clinic
Banner-University Medical Center
Tucson, Arizona

Copyright © 2010-2024, Peervoice

37. PeerVoice

Phyllis C. Zee, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for CVS Caremark; Eisai Co, Ltd; and Idorsia Pharmaceuticals Ltd.
Grant/Research Support from Vanda Pharmaceuticals Inc. (relationship ended).

Stock Shareholder in Teva Pharmaceutical Industries Ltd.

Advisory Board or Panel for Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and Takeda
Pharmaceutical Company Limited.

Barbara Hutchinson, MD, PhD, FACC, has a financial interest/relationship or affiliation in the
form of:

Honoraria from advisory board work for Cytokinetics, Incorporated; Jazz Pharmaceuticals Inc;
and Novartis AG.

Michael Grandner, PhD, MTR, DBSM, has a financial interest/relationship or affiliation in the
form of:

Consultant for Fitbit; Idorsia Pharmaceuticals Ltd; Natrol, LLC; Pharmavite; and SmartyPants
Vitamins.

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38. PeerVoice

Patient Case

28-year-old woman diagnosed with narcolepsy with mild
cataplexy

+ Currently on short-term disability after falling asleep
repeatedly at work

* Slurring of speech when stressed or excited

+ History: depression, OSA

+ Has been told her blood pressure is high

+ BMI=26

+ She reports a sedentary lifestyle, poor sleep

+ Nonsmoker, has an occasional glass of wine,
no recreational drugs

+ Family history of CVD, stroke, type 2 diabetes,

chronic kidney disease

She has not started therapy for narcolepsy at this point

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39. PeerVoice

CV Risk Is a Continuum

Promote CV health across the life course

en)

Rist-based
NE) prevention with

) | came
Auen 0 red at En EV | | Éd Soa

8 À 4 2 ¢

{ EN ) U Acoisconce —] [> vowmgncinoos ] [mane] [7 orme |]
( DEEE )

(social/behavioral/biologic)

( Dorian CID cf ine |

Khan SS et al. Circulation. 2023:148:1982-2004.

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40. PeerVoice

Consider! able CV Risk Factors

Eat a healthy diet Avoid tobacco smoke
Reduce sodium intake |. | Limit alcohol consumption

Engage in regular
physical activity

Consider impact of
medications on CV risk

Maintain healthy weight Maintain good sleep health

| Appropriately manage mental health |

symptoms (CBT)

CBr: cognitive behavioral therapy.
Whelton PK et al. Hypertension. 2018:7:1269-1324, Errata: Hypertension. 2018:7X6}136-0139; 72(3):033.

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Reducing Treatment-Related Sodium i

Study

Narcolepsy: TENOR

eee a ee 8

8

leTotl Qe 85) anrccepsy Type 1 8) _atwedtepsy Type 2 (n= 40)

Most common reason for

gringas oriong-tarm
Benefits due to lower
content of lew-socium oxybate

PA ne

Husain AM et al Sleep Med. 2024:13:328-337.

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