Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies

Chair P. Barton Duell, MD, discusses hyperlipidemia in this CME activity titled “Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/3UlwR3J. CME credit will be available until August 15, 2025.

1. Lipid Management Beyond Statins

Early Screening, Prompt Intervention, and Timely
Intensification With PCSK9-Targeted Therapies

P. Barton Duell, MD

Professor of Medicine

Director, Sterol Analysis Laboratory

Director, LDL Apheresis Unit

Oregon Health & Science University

Center for Preventive Cardiology

Knight Cardiovascular Institute

Division of Endocrinology, Diabetes and Clinical Nutrition
Portland, Oregon

Go online to access full CME information, including faculty disclosures.

Copyright © 2000

2. Our Goals for Today

Augment your knowledge of screening and diagnostic guidelines
for patients with hyperlipidemia

Understand the mechanisms of action, administration, efficacy, and
safety of agents targeting the PCSK9 pathway to lower lipid levels

Equip you with the skills to identify appropriate patients who may
benefit from PCSK9-targeting therapy

Suggest ways to collaborate with colleagues across disciplines to
improve patient education and outcomes

Copyright ©

3. The Importance of Early Screening, Prompt Detection,
and Accurate Diagnosis of Hyperlipidemia

Do the Statins are Nonadherence Selecting
basics first often not to lipid- additional
> enough = lowering =» lipid-

therapy lowering
is high therapies

Screen,
treat, and
follow up

Copyright

4. Elevated LDL-C Increases the Risk of Incident
Cardiovascular Events at Any Aget-32b

m 20 mon m 2029 mmon. m 3039 mon. m 40-49 mmol. msnm
<77 mgldL. 77-112 mg/dL. 116-151 mg/dL 155-190 mg/dL. 2193 mg/dL.

Myocardial Infarction ASCVD

a atl a st lll

20-49 50-59 60-69 70-79 80-100 20-49 50-59 6069 70-79 80-100
Age Groups, y Age Groups, y

sa

a

Event Rate Per 1,000 Person-Years

Don't lose

5 t of the importance of lifetime ASCVD risk!
+ The estimated 10-year risk is low in a 25-year-old with LDL-C of 250 mg/dL, but their lifetime risk may be >80%
+ Adelay in treatment increases the long-term risk of ASCVD events

+ Inpatients aged <40 years, statins may be considered for LDL-C levels of 2160 mg/dL or LDL-C 2190 mg/dL?

191.191 naval winout ASCVO or eabees at base and who were not aking statins nro int Copennagen General Popuaten Sud, 2009-2015

LDL ves vo been convened om mma MOI and rod

1. Mrtensen MB, Norcesigentd BC. Lance! 2020396 1644-1652 2. Uoyeones OM et al J Am Col Carol 2022:0: 1366-14183. Grundy SM et Am Cl en

Cardiol 2019.73:0286-0360, PeerView.com

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5. Total Cholesterol, mg/dL.

LDL-C, mg/dL.

1. Aggarwal Reta. JAMA. 2022;328:797-745,

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NHANES 2007-201

3

10

Favorable Trends Observed in US Age-Adjusted
Cholesterol Levels, but There Is More Work to Be Done!

Total Cholesterol

= —

EEE ET TE TETE TETE TETE]
Time, y

LDL-C

pr

HDL-C, mg/dL.

representative survey of US adults aged 220 years

©) HDL-C

EE ME SET MENTESTEMETTETT EEE TETE TT]
Time, y

1G

m Men

10
so Women
a

202 20D Zuın2012 20192014 20152016 20172018
Timo, y

ETES TETE TETE TETE TETE TT

Time, y PeerView.com

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6. Risk Factors for Dyslipidemia’

Familial
hypercholesterolemia

‘Smoking

os
Set

1. ps ww ed govicholestoraitisk-factorsfindex him.

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Health conditions,
including T2DM

and obesity

Family
pty Diet high in saturated
and trans fats
Age
Sex

‘ Not enough physical
à exercise

Ae,
E > a]

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7. Recognizing Individuals at Very High Risk’?

Very High Risk

>1 major ASCVD event

or

1 major ASCVD event
and multiple high-risk
conditions

1. Grundy SM ta. J Am Col Cardiol 2019.73:0286-0380. 2, loyé-ones DM et al J Am Col Cord 2022 A0 1966-1418. PeerView.com

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8. E : Major ASCVD Events
Very High Risk + Recent ACS

($12 months)

+ History of MI
>1 major ASCVD event . History ofischemic
stroke

+ Symptomatic PAD

or (hx of claudication with
ABI <0.85 or previous
- revascularization
1 major ASCVD event or amputation)
and multiple high-risk
conditions
1. Grundy SM otal. J Am Col Cardiol, 2019:73:0286-0350.2. LoydnJones DM etal. Am Coll Condi 202280 1966-1418. PeerView.com

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9. Recognizing Individuals at High and Very High Risk’?

Very High Risk + Recent ACS

($12 months)

+ History of MI
>1 major ASCVD event z Leu ofischemic
stroke

+ Symptomatic PAD

or (hx of claudication with
ABI <0.85 or previous
= revascularization
1 major ASCVD event or amputation)

and multiple high-risk
conditions

Consider HoFH if untreated LDL-C 2190 {GAG score 3300 may by an ASCVO rs o
rare SM ot A Cod Carol 2010986265 0980 2 Lo ocio OMA AL An GON Coa 202220 286-1818

4
3. Budoff My et a. JACC Cardiovasc Imaging, 2023;16:1181-1180

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Major ASCVD Events — High-Risk Conditions

Age 220 years with any of
the following:

LDL 2190 mg/dL.
HeFH?

History of CABG, PCI
T2DM

Hypertension

CKD (eGFR

15-59 mllmin/1.73 m?)
Current smoker

LDL 2100 mg/dL despite
max statin

History of HF
Elevated CAC score?

Age 265 years (independent
of other conditions)

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10. Risk Stratification in the US Cholesterol Guidelines
and European Dyslipidemia Guidelines

Characteristic 2018 AHA/ACC Guidelines‘? 2019 ESC/EAS Guidelines?
Risk scoring 10-y risk of CV event 10-y risk of fatal CVD
LDL-C goals
5 LDL-C <100 mg/dL and non-HDL <130 mg/dL.
Moderate zee) and 30% to 49% reduction from baseline DECO
High risk EU LOL-C <70 mg/dL and non-HDL-C <100 mg/dL | LDL-C <70 mg/dL and 250%
ig update and 250% reduction from baseline reduction from baseline
A LDL-C <55 mg/dL and non-HDL-C <85 mg/dL LDL-C <55 mg/dL and
VergnnEs and 250% reduction from baseline 250% reduction from baseline
Very high risk and second _ LDL-C <40 mg/dL
vascular event wi

may be considered

Extreme risk?

LDL-C <30 mg/dL optional

* CACS 2300, ASCVD wih 21 high-tskor very high-k our, HoFH wih or witout ASCUD, ASCVD wah recuront ACS, ASCVD wth polwaseular disease recurrent events despte LDL-C SO mg,
1 Grundy SM etal Am Cal Carol 2018.72 8285 0350. 2. Los ones DM at J Am Col Garda 2022.80 1366-1418. 3. Mach Fe al Eur Hoar 4202041 111-188

4. Puri Retab. J Gin Lol 2024:18:0351-0973. PeerView.com

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11. Key Differences Between AHA/ACC Cholesterol Guidelines
and Recommendations Endorsed by AAFP!

AHA/ACC AAI
Screening for dyslipidemia in children, * Reo 8 pro ns ana
adolescents, and adults before age 40 en and 17-21 years; after age 21 every Current evidence is insufficient to assess the
Note: the AAP, NHLBI, and NLA advocate . Reasonable to perform selective screening balance of benefits and harms of screening
universal screening of children?» ae
Risk enhancing factors Favor initiation of intensification of stalin therapy Current evidence is insufficient to assess the

balance of benefits and harms of adding ABI,
x a Tn king SCRP, or CAC score to traditional CVD risk
feasonable secondary shared decision-making assessment in asymptomatic adults to
ezo tool for considering statin therapy ee
+ Moderate intensity statin in Ihe intermediate
risk group; high intensity in the high-risk group

Lipid lowering medications for primary should be recommended Low to moderate intensity statin when
prevention in adults age <75 + Ezetimibe or bile acid sequestrants may ASCVD risk >10%

be reasonable as add-ons to a statin in

higher-risk patients

Lipid lowering medications in adults age Insufficient evidence to assess the balance
>75 for primary prevention Reasonable to initiate moderate-intensity statin of benefits and harms initiating statin use

1. Wojek C, Shapito MO. Creulaton. 2018:140709711. 2. Expert Panel on Integrated Guidelines tor Cardiovascular Heath and Risk Reducton in Chien and ñ
‘Adolescents; NHLBI, Pediatrics. 2011:120(5uppl 5/5213-5256. 3. Goldberg AC at al. Cin Lipid. 2011:5:133-140. PeerView.com

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12. It’s Not Just the Target, It’s the Time: Lessons Learned From
the CARDIA Prospective Observational Study!

rase Event, %

P<.0001 by log-rank test

3

Event Rate at Age 55 Years

Upper quartile

LDL-C Eventrate
mg/dL at Age 55, %
>1307 1,238 86

Third quartile 112.7-130.7 1,237 55

Second quartile 96.1-1126 1,239 44

Lower quartile <96.1 1,238 26

Group LDL-C at Age 40

All (N = 4,958) 110.7 +325

Women (n = 2,740) 106.9 + 30.6

Men (n = 2,218) 115.3 + 32.0

Competency in medical knowledge: The risk of CVD depends on both the cumulative exposure to LDL-C, measured as the area under
the LDL-C versus age curve, and on the time course of area accumulation. These data and Mendelian randomization studies suggest that
early optimization of LDL-C level may be more beneficial than later intervention. Late LDL-C intervention does not overcome risk

accumulated during early LDL-C exposure.

Translational outlook: Future trials of maintaining very low LDL-C at a young age may support this strategy to reduce the prevalence of

coronary heart disease.

1. Domanski MY et al Am Ga Cardiol 2020;76:1507-1516,

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13. Do We Really Need to Pursue Such Aggressive Targets?
The goal of therapy is to stop the progressive accumulation of
atherosclerotic plaque which leads to MACE y

An LDL-C level of ~77 mg/dL will stop plaque
progression in ~50% of the population!

Y Span eta cove can Anna 20073 0744
LB ME ea Engl led 2017.76 171:1722 4 Gupta RP otal JANA Cool 2017210851981. 6. ones JE tal J Oi Mod. 2023427482 PeerView.com

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14. Why Would Anyone Set an LDL-C Goal <30 mg/dL?
Post-Hoc Analysis From FOURIER"?

ted patients with stal

LDL-C Levels Over Time

Median 21mgjdL, IQR 11.5-37 mg/dL.
Median 0.5 mmol/L, IQR 0.3+1.0 mmol.

100
u 9
2 Median 66 mg/dL, IQR 56-78 mg/dL. a
Median 1.7 mmol/l, IQR 1.4-2.0 mmol Placebo ge a a)
2 27
a0 36
Em 66% mean reduction (95% Cl, 62-69) 3 Placebo
4 P<.00001 ag?
5, 34
2 Evolocumab HE Evolocumab
2 32

CVD with baseline LDL-C <70 mg/dL (N

CV Death, MI, or Stroke

0 12 24 36 48 60 72 84 96 108 120 132 144

Time, wk

o y 2 18 24 30

Time From Randomization, mo

1. Giugtano RP et a. JAMA Coit 2017:2:1385-1381. 2. Giuglano RP et al. Lancet. 2017:380:1962-1971 PeerView.com

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15. The Importance of Early Screening, Prompt Detection,
and Accurate Diagnosis of Hyperlipidemia, continued

Do the Statins are Nonadherence Selecting
basics first often not to lipid- additional
=> enough = lowering = lipid-
therapy lowering
is high therapies

Many patients
on statins are
Screen, not at goal

treat, and
follow up Goals have

changed; new
evidence shows
lower goals

are better

Copyright © 2000

16. Gaps in LDL-C Goal Achievement in Community Practice?»

90

80 753

70.4
70

60 m Not on statin

‘= Lower intensity treatment
17 than recommended

Treated appropriately

40
60 293

211
20

Patients With LDL-C 2100 mg, %

10

Overall Primary Prevention Secondary
Prevention

5905 stage paets tom 138 PALM Registry practices, 2015.° P < 001 ñ
1.Navar AM etal Am Heat J. 2017:193:24-92 PeerView.com

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17. Primary Prevention Treatment Gaps’

Nearly 75% of individuals with elevated 10-year risk
of ASCVD are not using statin therapy

ace nd Emi sosa
AA M nie) CURE + In the National Health Examination
= rs 9.99 65% 6 Surveys representing 39.4 million US
091-103) EN adults, Black and Hispanic participants
x cis osa Er had significant lower stain use than
$°) er mean An White participants
3
082050 casero Having health insurance or a routine
9] omescı BZ location for health care were

087.090)
FA

significantly associated with increased
stain use across race and ethnicity
groups

Racial and ethnic disparities in the use
of statins are associated with poor
access to care among Black and
Hispanic individuals

Prevalence of Stati
8

S075 751020 220
10-y Predicted ASCVD Risk Category, %

1. Jacobs JA et ol. JAMA Cardiology: 2023:8:443-452. PeerView.com

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18. Gaps In Dyslipidemia Care!”

+ Statins are not effective in achieving lipid goals
in everyone

+ In addition, intolerance and poor adherence
necessitates the use of alternative treatments

therapy are not appropriately identified and

— Patients who may benefit from PCSK9-targeting
© consequently undermanaged

— Although PCSK9-targeting therapies are
available, they are underutilized

— The route of administration may not align with
patient preference

1. Alyoa RK ot al Heart 2018:105:975.981. 2 Marop ot al. Cardovase Ther 20228129513. 3. Warden BA et a Trends Cordovase Mod. 202030: 179.185,
À: MeO et a CO 2021 88.381.387. 5. Amok SV ot al JARA. 2021.10.020693.6. Loa S o ah Org Target Insights 2021.18 13.20. 7. Amos SV ut a m
Circulation, 2019;140:618-620, PeerView.com

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19. Applying the Latest Evidence

The Role of PCSK9-Targeted Therapies in Addressing
Unmet Treatment Needs

Do the
basics first

Screen,
treat, and
follow up

Statins are
often not
enough

Many patients
on statins are
not at goal

Goals have
changed; new
evidence shows
lower goals

are better

Nonadherence Selecting
to lipid-

lowering

therapy lowering
is high therapies

>50% of high-risk
patients are not
using a statin
Patients are not
taught why
they're taking
lipid-lowering
medications

Copyright © 2

24, PeerView

20. Prescriber and Patient Factors Contributing to Poor
Adherence to Lipid-Lowering Therapies

Prescriber Factors Patient Factors

Difficulty risk-stratifying patients! Medications are not taken as prescribed®

Uncertainty about benefit in certain Skepticism about goals or the need
patient groups! for treatment!

Discrepancies among guidelines! Concern about treatment safety!

Clinical inertia*5 Underestimating personal risk of recurrent

CV events?

Diffused responsibility for prescribing
and monitoring response to therapy’

Unaware of their cholesterol levels or goals®

Limited time to discuss! Unaware of why cholesterol medications

were prescribed®

Lack of formal training on cholesterol
disorders among pediatric cardiologists*

1. Butala $ et al. CJC Open. 2020:2:530-538.2. Connon CP et al. Am Hoar J. 2020219:70:77., Gupta K et a. Prog Cardiovasc Die. 2022:75:78-82. PeerView:
4 Hokanson JS ot al Pediatr 2023253-14-17. 5. Underberg Jet al Postgrad Mad, 2022.134:752-762. 6, Anold SV et al J Am Hear Assoc. 2027; 10002089, eerView.com

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21. Management of Statin-Associated
Muscle Symptoms: NLA Perspective’
SAMS are infrequent

10% experience symptoms
1% to 2% have symptoms causally related to statins

ESO AAA

Same statin at a Switch to a Add a nonstatin Use nonstatins
lower dose different statin toa statin without a statin

+ Alirocumab
+ Bempedoic acid

+ Bile acid sequestrants
+ Evolocumab

+ Ezetimibe

+ Indlisiran.

+ Intermittent dosing,
xk

+ Washout period prior
to strenuous physical
exercise

+ Rosuvastatin
+ Fluvastalin-XL

+ Pravastatin

+ Pitavastatin

+ Avoid simvastatin

1. Warden BA et al. J Ci Lipid. 2028:17:19-98 PeerView.com

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22. Considering Race and Ethnicity
When Treating Patients With ASCVD Risk!

Important Racial and Ethnic Considerations for the Treatment of ASCVD Risk

Race/Ethnicity Asian Black
Intensity of .

statin therapy * Japanese patients may be sensitive to statin dosing + No sensitivity to statin dosage is seen,

and response to . Consider using low- or medium-intensity pravastatin as compared with non-Hispanic White individuals
LDL-C lowering

+ Higher rosuvastatin plasma levels are seen in Japanese,

Chinese, Malay, and Asian Indians as compared with + Baseline serum CK values are higher
White patients in Black patients than in White patients

Safety + FDA recommends a lower starting dose (eg, 5 mg of + 95th percentile race/ethnicity-specific and sex-
rosuvastatin in Asian patients versus 10 mg in White specific serum CK normal levels are available for
patients) assessing changes in serum CK

+ Caution is urged as dose is uptitrated

+ Using a lower statin intensity in Japanese patients may give results similar lo those seen with higher intensities in
non-Japanese patients

Comments + Clinicians should take Asian race into account when prescribing dose of rosuvastatin (see package insert)
+ In adults of East Asian descent, other statins should be used preferentially over simvastatin
+ Hispanic individuals are managed the same as non-Hispanic White individuals

1. Grundy SM et al. J Am Col Caria. 201973:0285:0350 PeerView.com

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23. Barriers and Facilitators of Adherence
to Lipid-Lowering Therapies’

+ Educational tools to inform patients + Educational initiatives targeted
on risks and benefits of LLT at patients and HCPS
M Pationt-related
Healthcare system-related
El Therapy-related

+ Educational ntiatives targeting + Shared decision-making and decision tools

non-specialist physicians + Educational digital tools
—_ + ——
Ñ BARRIERS:
TOUT
‘ADHERENCE
— — —
+ Routine LDL-C monitoring + Heath economic analyses to assess.
+ Standardized LDL-C thresholds, ea cost-effectiveness
= + Ciinica guideine recommendation
on treatment cost
+ Advocacy by professional societies
Potetarmacy
+ Pharmacy-based programs + Pharmacy-based programs (reminders; mail order pharmacy,
(medication synchronization) medication synchronization)
+ Altemaivotherapies with loss frequent administration
1. Desai NR etal. in Carlo. 2023:46:13-21 PeerView.com

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24. Applying the Latest Evidence

The Role of PCSK9-Targeted Therapies in Addressing
Unmet Treatment Needs, continued

Do the
basics first

Screen,
treat, and
follow up

=>

Statins are

often not
enough =>

Many patients
on statins are
not at goal

Goals have
changed; new
evidence shows
lower goals

are better

Nonadherence
to lipid-
lowering
therapy

is high

>50% of high-risk
patients are not
using a statin
Patients are not
taught why
they’re taking
lipid-lowering
medications

additional
lipid-
lowering
therapies

We have
great tools
that let us
get excellent
results

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Statins Are Still the Foundation of LLT

Effective in Primary Effective in Secondary Rapid Time to Benefit
Prevention of MACE'# Prevention of MACE? and Well Tolerated4c

28% reduction in MI
20% reduction in stroke

d with lower mortality

These are only short-term reductions in ASCVD events during clinical trials
Treatment for 10-50 years will provide even greater benefit; possibly 75% to 80% after 52 years®

+ Psico comparison fom 120.456 paricipants in 62 ae flowed for an average of 9 yeas >25% random sample of 2015 AARP MadicaroSupplemertpartispants

insuod by UntodHeatnare, n= 49,530 men, = 44.710 woman *P<.05 betwnan groups Eh studs ncucing 65,383 aus winout CVD, age 50.78 yars at aselno

1.Col Tel. BMJ. 2021:874:n1537. 2, Musch Set al. Popul ee Manog. 2018.2 74-82. 3. Yourman LG eta. JAMA Inte Med, 2021:181:179-185 oe

4. Warden BA et al. J Ci Lipid. 2028:17:19-98. 5 Ference BA eta. Eur Heart J 2017.38:2459-2472. PeerView.com

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26. Relative Efficacy of Nonstatin Therapies When Added to
Maximally Tolerated Statins‘?

Oral Medications Injection Medications

Bempedoic acid Ezetimibe Inclisiran Alirocumab Evolocumab

o
A -17
-30 -25
40 CVOT Status
-50

Benefit proven
8 cvor ongoing

04 46 8 4 4

+ Mean dteence from basen eave op Fs
‘on PP ae LA Haan Assoc 2022 (e025. 2 Mplnkatals gov2howlecordNCTOOTOS2N. PeerView.com

LDL-C Reduction at 24 Weeks," %

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27. Better Together: Combination Therapy Is Essential for Many
Patients to Meet LDL-C Goals!

250
+ Don't give up if 1, 2, or 3 LLTs
LDL-C Interventic ane
200 200 > niece don't get the patient
to goal!
-50% statin + Keep adding agents with
2 150 complementary actions until
z goals are met
5 — Note: doubling statin doses only
reduces LDL-C by -6%?
am joe -22% ezetimibe — ie
3 78» Ss + In this example, 4 LLTs were
OAS ale bampedoicuc needed to reach the goal
$0 om PesKe-targeti"g Refer to a lipid specialist
312» if needed
0
1.Brands J, Ray KK. Am Col Cordial 2021.78:1831-1843. 2. Kadson BW tal. Eur Prov Candil 2016:23744-747, PeerView.com

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28. Mechanisms of Action of Approved Lipid-Lowering Agents‘?

1. Tominson B et al. Endoerinl Metab, 2021:36:279-205.2. Ray KK et al. Circulation. 2018:138:1304-1316.

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\
QUE

PCSKO ga
C receptor Sequesters circulating
Va
Tl / RS mRNA
Reduced ie
cholesterol

absorption

Bile acid
juestrants

Asialoglycoprotein

upregulated O inducing
xf receptor

Hepatocyte silencing complex

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29. PCSK9-Targeting mAbs: Detailed Mechanism of Action!

oie parce D) Ss

Lysosome

Hepatocyte

1. Roth EM, Davidson MH. Rev Cardovase Mod. 2018:19(cupol1):531:S48. PeerView.com

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30. PCSK9-Targeting Therapy
Reduced LDL-C by >50% in CVOTs

ODYSSEY OUTCOMES'#

Alirocumab

Placebo

a Alirocumab

Mean LDL-C, mg/dL.
&

Mean LDL-C, mg/dL.

FOURIER?
Evolocumab

100

Placebo

Evolocumab

85883388

20
10

mean LDL-C reduction vs
acebo

0 4 8 12 16 20 24 28 32 36 40 44 48

Time Since Randomization, mo

"Sol Ines, intent-to-treat analysis: dashed Ines, on-reatment analysis.

4, Schwartz GG et aM Engl) Med. 2018:379:2007-2107. 2. Sabatino MS otal N Engl J Mod. 2017:376:1713-1722,

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ot
04 12 24 36 48 60 72 84 96 108 120 132 144 156 188
Time, wk

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31. Large Proportions of Patients Using PCSK9i mAbs
Discontinue Therapy During First Year of Use!

Medications Used Before PCSKGQi Initiation Time to PCSKQi Discontinuation

Wi Statin only IM Ezetimibe only Stat andlor 100 y
ezctimibe combination

Log-rank test
P=.168

628
104

‘Commercial (51.2%)

8883838

Patients Without Discontinuation, %
8

o

|
SMons * 12Months * 18Months * 26 Months EELERTEITTTTE
rans Deine

+ N= 13,151 PCSKSi initiators (6,771 evolocumab; 6,380 alirocumab) + 57% of PCSKSi prescribers
+ 47% had ASCVD-related diagnosis or procedure were cardiologists

1. Hines DM et al. Vase Hoa Risk Manag. 2018;14:409-418, PeerView.com

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32. Lower Treatment Burden May Facilitate
Patient Adherence to Lipid-Lowering Therapy’

High-potency statins PCSK9 mAbs PCSK9 siRNA

99990 y
300004 2 injections
39000

99000

a

365 pills 26 injections

Annual Medication Burden
to Achieve Approximately
50% LDL-C Lowering

Adherence

1.Brandis J, Ray KK. Giculoin.2020.141:873:6. PeerView.com

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33. How Does PCSK9 siRNA Differ From PCSK9 mAbs?1?2

In the presence of PCSK9,
the LDL receptor is destroyed,

thereby causing less LDL to
be cleared from plasma

The receptor, LDL,
and PCSK9 are all

1.Katzmann JL et al. Front Physiol 2020:11:596819. 2. Mach Fetal. Eur Heart J 2020.41:111-188. PeerView.com

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34. How Does PCSK9 siRNA Differ From PCSK9 mAbs?1?2

PCSK9 mAbs sequester PCSK9

Inclisiran prevents production
of PCSK9

Both prevent PCSK9 degradation
of the LDL receptor

1.Katzmann Jt al Front Physi 2020:11:595819.2. Mach F et al Eur Hood J. 2020:41:111-188. PeerView.com

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35. Long-Term PCSKO9 Inhibition With Inclisiran: ORION-812

1
E ASCVD Risk

x 0 ASCVD (n=2,205) Equivalent (n = 526)

z “10

fe :

Ë =

Se 4

à go

E so e

zo 8.

we: E

3 + a

4 E

100 a 424
Visit day BLDGO 0270 D450 B30 0810 0990 01,080 EOS Su (45 to -39.9)
aa ai
Year First Year * Second Year * Third Year 3 ese ws
Patent BL D9O D270 D450. D630 B10 0990 01,080 EOS Peine) o
CEA 3.274 3224 3012 2887 2661 2550 2431 2377 2731 um DIE Cry pren
Included patients om ORION 9-10, 41 PeeiVienicom

{Wight RS et al Cordovase Res. 2024 May 16 [Epub ahead of rn,

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36. Inclisiran Has a Favorable Long-Term Safety Profile:
ORION-812

MACE-Related Safety Events

02 : 453 (138)

+ Censored Diabetes metitus inadequate control 229 (7.0)
5; Km 2070)
2 En Diabetes meltus 206 (63)
3 Artrakgia 205 (6.3)
3 un 158 (88)
Et Osteoarthritis 149 (4.6)
2 Inclisiran Back pain 431 (4.0)
2 11084)
E 110/94)

100 (8.1)
Inclisiran

o 1 2 3 4 5

y of TEAE at Injection Sito nm)
Mid 167 (5.

Moderate 26 (0.8)

Severe, o

+ Boselno valve of LDL-C was taken rom the base of ho parent is. To distinguish rom vit in ORION 8, the sulla was cod to ist intro parent (feeder)
tins ORIONO,ÓRIOACIO. and ONION 11, The dashed no Gentes o ran fom e paren tial to ORION-B. TEAÉS errang m 23% ol pal en
1. Wight RS eta. Carchovasc Ros. 2024 May 16 [Epub ahead of prit} PeerView.com

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37. FDA-Approved PCSK39 Inhibitors
Comparison by Class'4

Mechanism of action Inhibits PCSK9 production Inhibits PCSK9 binding LDL-R
Location of action Intracellular Extracellular

LDL-C reduction ~50% 50% to 60%

Lp(a) reduction 17% to 25% —25% to 30%
Delivery method (person, site) Healthcare provider, clinic Patient, home
Administration Subcutaneous injection Subcutaneous injection
Administration frequency Days 1 and 90, every 6 months Every 2 wk to 4 wk
Most common adverse event ISR (2.6% to 17%) ISR (2.1% to 3.8%)
MACE reduction TBD Yes

Mortality reduction TBD Yes

Anproved inetons dus, mme

3. Praluen (atrocumet) Prescröng natn, np wa sccossóaa Ka govorgsatia.Socsadel2024 1255940350 pl hass
4. Ropatna (evolocumab) Presebing information, tps accosscaa a govideugsatida_doesabel2022!126572s0331 pa PeerView.com

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38. Safety Data For Evolocumab, Alirocumab, and Inclisiran

Evolocumab' Alirocumab?
A f patie of pati
+ Primary hyperlipidemia: + Primary hyperlipidemia: + Injection site
nasopharyngitis, URTI, injection site reaction, arthralgia,
influenza, back pain, reactions, influenza bronchitis
and injection site 4 7
reactions + Established CVD:
myalgia

+ Established CVD:
diabetes mellitus,
nasopharyngitis, URTI

1 Repata(evlocumsd) Presebing nlomason,htps un acorendate fa. gousrgsatsa_socslabev2022/1255225033 pal
2 Prataont alrocamab) Prog infomation: Papa immo accossdata fda gong, Bocetabel2024 125650803090 pl. ñ
3.Leavo (ncistan)Prescbing Information. tps ww accesscata da govierugsaiéa. docslabel2024/214012501 paf PeerView.com

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39. Emerging PCSKQis for LDL Reduction!”

Age Class Phase LDL Route and Dosing
MK-0616 Macrocyclic peptide 2 60.9% Oral tablet, once daily
VERVE-101 CRISP-Cas 9 1b2 60% IV infusion, once in a lifetime
LIBOO3 Adnectine 3 250% SC injection, once monthly
ATO4A Epitope vaccine 1 13% SC injection, once yearly

Envoiment pause as of Apr 2024 1 nvogate laboratory abrormaltes.
{Agno Fo a Y Cin Mod. 2024.13:1251. 2 Mia new gonengrews.comopicelgodome-otingbitrsweet-symphonyvores-pause-on vo 101-narous in. ñ
delenr-sratogr. 3. ps cialis govstudy/NCTO4797247. PeerView.com

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40. Practical Application of PCSK9-Targeting Therapies
How To Optimize Hyperlipidemia Outcomes

in a Family Practice Setting

Do the Statins are Nonadherence Selecting
basics first often not to lipid- idditional
enough lowering lipid-
therapy lowering
is high therapies

>50% of high-risk
Many patients on patients are not using We have great
Screen, treat, Statins are not at goal eun tools that let us
and follow up expanda Gi get excellent
new evidence shows results
lower goals are better

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41. Simple Clinical Guide to Treatment Intensification

Add nonstatin
therapies

Optimize treatment
with statin + ezetimibe
first

+ Inexpensive « Bempedoic acid
+ Safe + PCSK9-targeting
+ Proven efficacy for therapies

LDL-C lowering + Refer to lipid
and ASCVD specialist if goals
prevention cannot be reached

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42. Who Is Most Likely to Benefit
From PCSK9-Targeting Therapy ?'2

High-risk
patients

with ASCVD Patients who are Bel DL win Patients with

wu ay nee statin-intolerant eantelneleiteng HeFH or HoFH
lipid to statins
management

goals

1. Grundy SM etal. J Am Col Cano 2018.73:0285.0350, 2. LoyóxJones DM et a. J Am Col Gait 2022.80-1366:1418. PeerView.com

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43. Patient Case 1: Chandani, a Woman Aged 41 Years
of European and South Asian Descent

Chandani

BMI: 27 kg/m?

TIA (3 years ago) and hypertension
BP: 122/77 mmHg; LDL-C: 200 mg/dL.
FH? Family history? Genetic markers?

Current daily medications: ezetimibe 10 mg,
icosapent ethyl 4 g, losartan/HCTZ
100 mg/25 mg, and aspirin 81 mg

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Patient Notes

New patient

Statin-intolerant with aching pain and
fatigue on rosuvastatin 40 mg in the past
Medical records show previous physician
considered ordering a gene panel for FH

What is her risk level?

What is her LDL-C goal?

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44. Patient Case 1: Chandani, a Woman Aged 41 Years
of European and South Asian Descent

Chandani
High
BMI: 27 kg/m? E
TIA (3 years ago) and hypertension Risk
BP: 122/77 mmHg; LDL-C: 200 mg/dL
FH? Family history? Genetic markers? Chandani’s risk features
Current daily medications: ezetimibe 10 mg, + LDL-C 200 mg/dL on ezetimibe

icosapent ethyl 4 g, losartan/HCTZ
100 mg/25 mg, and aspirin 81 mg

+ Treated HTN

+ TIA

« Overweight

+ South Asian ancestry

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45. Patient Case 1: Chandani, a Woman Aged 41 Years
of European and South Asian Descent

Chandani

BMI: 27 kg/m?

TIA (3 years ago) and hypertension

BP: 122/77 mmHg; LDL-C: 200 mg/dL.
Continue ezetimibe and add low-dose

rosuvastatin (5 mg) or atorvastatin Recommendations

(10 mg) + AHA/ACC goals: LDL-C <70 mg/dL
Add a PCSK9-targeting therapy if (250% reduction from baseline)
insufficient response or intolerant of + Discuss dosing frequencies, LDL-C
low-dose statin reduction data, and AEs to
Consider referral for genetic testing individualize care

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46. Patient Case 2: Walter, a White Man Aged 74 Years

Walter

T2DM (10 years), neuropathy, MI, PCI with stent placed | Visit Notes
3 years ago, HF (NYHA class Ill), CKD G3A2 (eGFR:
40 mL/min), hypertension

Presents for his routine quarterly
follow-up visit

AIC: 7.1% Mentions that he doesn’t need any
BP: 118/71 mmHg; LDL-C: 150 mg/dL medication refills, he still has plenty

K+: 4.2 mEq/L. left over since his last visit

Current medications: atorvastatin 80 mg, ezetimibe
10 mg, metoprolol/HCTZ 100 mg/50 mg,
sacubitril/valsartan 97 mg/103 mg, finerenone 10 mg, OS
metformin ER 1,500 mg, empagliflozin 25 mg, What is his risk level?

clopidogrel 300 mg, aspirin 81 mg, furosemide 40 mg What is his LDL-C goal?

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47. Patient Case 2: Walter, a White Man Aged 74 Years

Walter Very

T2DM (10 years), neuropathy, MI, PCI with stent placed H Ig h

3 years ago, HF (NYHA class III), CKD G3A2 (eGFR: .

40 mL/min), hypertension Risk

AIC: 7.1%

BP: 118/71 mmHg; LDL-C: 150 mg/dL Walter’s goals

K+: 4.2 mEq/L + AHA/ACC goals

Current medications: atorvastatin 80 mg, ezetimibe

10 mg, metoprolol/HCTZ 100 mg/50 mg, — LDL-C <55 mg/dL
sacubitril/valsartan 97 mg/103 mg, finerenone 10 mg, — Non-HDL-C <70 mg/dL

metformin ER 1,500 mg, empagliflozin 25 mg, i <80-
clopidogrel 300 mg, aspirin 81 mg, furosemide 40 mg CRÉES EEE)

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48. Patient Case 2: Walter, a White Man Aged 74 Years

Walter

T2DM (10 years), neuropathy, MI, PCI with stent placed
3 years ago, HF (NYHA class III), CKD G3A2 (eGFR:
40 mL/min), hypertension

AIC: 7.1%

BP: 118/71 mmHg; LDL-C: 150 mg/dL. Recommendations

K+: 4.2 mEq/L + AHA/ACC goals: LDL-C
Discontinue atorvastatin 80 mg and add <55 mg/dL and non-HDL-C
rosuvastatin 40 mg <70 mg/dL ideally

Add inclisiran 284 mg Greater adherence to his lipid-
Refer to pharmacist for education lowering therapies may further
reduce his LDL-C level

At his next visit, his LDL-C is 60 mg/dL

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49. 2018 AHA/ACC Cholesterol Guidelines:
Shared Decision-Making Checklist for Initiating Therapy!

1. Grundy SM ot al. J Am Col Carla.
2019; 73:0285-0360,

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Y ASCVD risk assessment
V Lifestyle modifications

y” Potential net clinical benefit
of pharmacotherapy

Y” Cost considerations

Y” Shared decision-making

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50. Interdisciplinary Approach May Improve Adherence’

+ Ateam approach to dyslipidemia may offer
many benefits

= =) + Who's on the team? Cardiologists, endocrinologists,
nurses, pharmacists, dietitians, and educators?
+ Multidisciplinary teamwork may improve
— Diagnosis
— Individualizing treatment plans according to CV

risk profile, comorbidities, patient preferences,
o and goals

— Adherence to lifestyle modifications
and pharmacotherapy

1. Pappan N etal. ln: StaPoads tomos). Treasure Island (FL): StatPearis Publishing; 2024, hips we ncb.im ni gowbooksNBKEGO891/ PeerView.com

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51. Medication Access Starts With
Appropriate Patient Selection

Tips for insurance approval of bempedoic acid and PCSK9-targeting agents

Indication earn } Statin intolerant

Background
therapy

+ Max statin (can be zero)
+ Current and prior LLT

+ Indication + Document the details in

Why this + Degree of LDL-C your clinic note
medication? | reduction + Explain to the insurance
+ Adverse event profile — plan why the drug

needs to be approved
Don't be
afraid to
appeal

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52. Key Takeaways

Hyperlipidemia is common, underdiagnosed, and undertreated

LDL-C goals have become more stringent as we learn more about the risks of hypercholesterolemia

PCSKGis are the most effective second-line lipid-lowering treatments, but adherence to mAbs has
been challenging

Patients at high and very high risk are the “low-hanging fruit” for intensified lipid control

Combination lipid therapies are typically required to achieve the LDL-C goals in patients
at high and very high risk

Use of statins and nonstatin therapies (ezetimibe, bempedoic acid, PCSKQis) needs to increase

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