pcsk9-inhibitor treatment for hypercholesterolemia

PCSK9-Inhibitor Treatment for Hypercholesterolemia:

Primary Care Update

Eliot A. Brinton, MD, FAHA, FNLAImmediate Past-President, American Board of Clinical Lipidology

Director, Atherometabolic ResearchUtah Foundation for Biomedical Research

President, Utah Lipid CenterSalt Lake City

[email protected]

25th Annual Southwestern Conference on MedicineTucson Osteopathic Medical Foundation

Tucson, AZ; April 28, 2016

Duality of InterestDr. Brinton has received:• Research funding: Amarin, Aurora Foundation,

NIH• Honoraria as consultant/advisor: Aegerion,

Amarin, Amgen, Aralez, Kowa, Merck, PTS Diagnostics, Regeneron, Sanofi-Aventis

• Honoraria as speaker: Alexion, Amarin, Amgen, AstraZeneca, Genzyme, Janssen, Kowa, Merck, Regeneron, Sanofi-Aventis, Takeda

Why Not Just Use a High-Intensity Statin?


Isn’t that what the 2013 ACC/AHA Guidelines Say?



Let’s look at the evidence

Lower On-Treatment LDL-C IS Better!

*Adjusted for age, gender, baseline LDL-C, diabetes mellitus, and prior MI.

Lower/better Higher/worse0 1 2

> 80-100> 60-80> 40-60≤ 40

Referent0.80 (0.59, 1.07)0.67 (0.50, 0.92)0.61 (0.40, 0.91)

Hazard Ratio

Ach

ieve

d LD

L-C

(m

g/dL

) n = 256

n = 631

n = 576

n = 193

PROVE-IT/TIMI 22 Substudy. Wiviott SD et al. JACC. 2005;46:1411-1416.Similar result reported in 8-study meta-analysis: Boekholdt SM, et al. JACC 2014;64;485–94.

Atorvastatin 80 mg vs pravastatin 40 mg, N=2099 ACS pts, 24 mos, f/u.Endpoint: CHD death, nonfatal MI, CVA, recurrent ischemia, revascularization

Wiviott, SD, et al for the PROVE-IT TIMI-22 Investigators. Am J Cardiol. 2005;46(8):1411-16.Similar result reported in 8-study meta-analysis: Boekholdt SM, et al. JACC 2014;64;485–94.

0

5

10

15

20

25

Achieved LDL-C (mg/dL)

But LDL-C Can Still be Elevated on a High-Intensity Statin!

LDL-C levels at 4 months on Atorvastatin 80 mg

% o

f Sub

ject

s

37.1% of patients ≥70 mg/dL (1.81 mmol/L)

0.1

15.2

19.2

8.2

1.70.5

18

13.3

8.3

5.6

3.22.1

1.4

3.2



Lower is betterGoals help us direct treatment with statins and statin-adjuncts

to get lower LDL-C



The 2013 Guidelines: 1.Are NOT the “official” US guidelines2.Saw no evidence for LDL-C goals

because they had excluded it3.Are being updated to add back

LDL thresholds and goals

ACC Statement on Lipid Rx Thresholds for Non-statins

Stable ASCVD

Comor-bidities1

Base LDL-C

2First look for LDL-C↓< 50%

2May consider if LDL-C

2May consider if non-HDL-C

+ + NA + >70 >100+ - NA + >100 NA+ - >190 + >70 NA- - >190 + >100 NA- -3 70-189 + >100 >130- -4 70-189 + >100 >130

1. Comorbidities = DM1, DM2, acute ASCVD < 3mos ago, ASCVD event while on statin, baseline LDL-C > 190, poorly controlled major ASCVD RF, ↑Lp(a), CKD.

2. 1st round: address statin non-adherence, intensify lifestyle, consider phytosterols, ↑to high-intensity statin, consider Lipidologist referral if statin intolerant or HoFH, control other RFs. 2nd round: consider non-statin (ezet, BAS, PCSK9-I)

3. DM1 or DM2 present: 1st & 2nd rounds as #2 above except no PCSK9-I4. 10-y ASCVD Risk >7.5% and age 40-75; iterative adjustments, see #3.

Lloyd-Jones DL. JACC 2016, eub Apr 1; doi; 10.1016-j.jacc 2016 03.519

How do mAb PCSK9-Inhibitors

Work?

Monocl. Ab

mAb

Evolution of mAb Therapies

After Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1):18–28

Imm

unog

enic

ity

Fully Mouse1st generation

Chimeric2nd generation

Humanized3rd generation

“Fully” Human4th generation

Highly Immunogenic

Still immunogenic

Less immunogenic

Least immunogenic

~30% mouse

5%–10% mouse

100% human

100% mouse Mouse variableMouse constantHuman variableHuman constant

AlirocumabEvolocumab

Bococuzumab

Dynamic Relationship Between mAb Levels, Free PCSK9, and LDL-C

Stein et al. N Engl J Med. 2012;366:1108-18.

0 1000 20000

20

Free

/ To

tal P

CSK

9 C

onc.

(ng/

mL)

Tota

l REG

N72

7 (n

g/m

L) x

0.0

1

200

40

120

160

80

500 2500 30001500-70

-60

LDL-C

Mean C

hange (%)

0

-50

-30

-20

-40

Free PCSK9, Total REGN727 / SAR236553 Concentration,and LDL-c Mean % Change vs Time

60

140

180

100

-10

Total REGN727 / SAR236553

Free PCSK9

LDL-C

3 6 9 12 15Weeks

Phase 3 Data from Alirocumab and

Evolocumab

AMG 145 Antibody to PCSK9 Clinical TrialsLAPLACE- TIMI 57

PCSK9-I mAb LDL-C Dose-Response

Drug Dosage % LDL-C Lowering

Alirocumab 75 mg every 2 wks. 40-45%

150 mg every 2 wks. 50-60%

Evolocumab 140 mg every 2 wks. 50-65%

420 mg every 4 wks 50-60%

After Eckel, R. unpublished

Robinson, JG. NEJM epub 3/15/15 Suppl.

LDL-C Decrease By Subgroup

Possible sub-additivity of statins and CAI?

Similar LDL-C Decrease FH vs non-FH

Robinson, JG. NEJM epub 3/15/15 Suppl.

Little or No LDL-C Lowering Efficacy with More Severe HoFH (TESLA)

LDL Receptor Mutations

Number of Subjects

Change in LDL-C*

Defective/Defective 8 -32% (-19 to -45%)Defective/Negative 6 -21% (-11 to -31%)Negative/Negative 1 +10%ARH** 1 +4%

Raal, FJ; Lancet 2015; 385: 341–50

*Rx was evolocumab 420 mg sc q 4 weeks x 12 weeks.Trial was placebo-controlled but due to low and variable N of placebo control patients in each of these rarer categories, placebo effects are not given and placebo subtraction not done.**ARH = autosomal recessive hypercholesterolemia which is due to a defect in internalization of the LDL/LDL-receptor complex.

Alirocumaba Alirocumaba

PCSK9 Inhibitors:Lipid Efficacy Beyond LDL-C

ParameterRange of Mean Changes with

PCSK9 InhibitorsApo B -32 to -53%Non-HDL-C -37 to -52%Lipoprotein(a) -17 to -30%Triglycerides -6 to -26% HDL-C +3 to +9%Apo A-1 +2 to +7%

After Eckel, R. unpublished

Long-Term PCSK9-I Effects

• Lipid Efficacy• Safety and Tolerability • CVD Efficacy (preliminary)

PCSK9-I Maintain Consistent LDL-C Reductions over 1 yr +

39

53

67

81

95

109

123

137

151

1

1.5

2

2.5

3

3.5

4

0 4 8 12 16 20 24 28 32 36 40 44 48 52Week

3.1 mmol/L118.9 mg/dL




mg/

dL

PlaceboAlirocumab

LDL-

C, L

S m

ean

(SE)

, mm

ol/L

Alirocumab achieved LDL-C Over Time on 150 mg q 2 wksAll patients on background of maximally-tolerated statin ±other lipid-lowering therapy

Intent-to-treat (ITT) analysisRobinson, JG. NEJM

2015 epub Mar 15.

Treatment-Emergent Adverse EventsAt least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit

% (n) of patientsAll on max-tolerated statin ±other lipid-lowering therapy

Alirocumab(n=1550)

Placebo(n=788)

TEAEs 78.6% (1218) 80.6% (635)

Treatment-emergent SAEs 16.5% (255) 17.6% (139)

TEAE leading to death 0.5% (7) 1.0% (8)

TEAEs leading to treatment discontinuation 6.2% (96) 5.5% (43)

Mean treatment duration: 65 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) completed 78

weeks

Robinson, JG. NEJM 2015 epub Mar 15.

ODYSSEY LONG TERM Study: TEAEs ≥5%Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients

who completed W78 visit)

% (n) of patients Alirocumab(n=1550)

Placebo(n=788)

Infections and infestations 45.5% (705) 46.1% (363)Musculoskeletal and connective tissue disorders 27.2% (422) 28.6% (225)Gastrointestinal disorders 18.6% (288) 18.8% (148)Nervous system disorders 17.0% (264) 17.8% (140)General disorders and administration site conditions 15.4% (238) 17.0% (134)Injury, poisoning, and procedural complications 13.4% (207) 14.2% (112)Respiratory, thoracic, and mediastinal disorders 11.0% (171) 10.9% (86)Cardiac disorders 9.1% (141) 11.8% (93)Skin and subcutaneous tissue disorders 9.1% (141) 8.5% (67)Metabolism and nutrition disorders 9.1% (141) 8.4% (66)Vascular disorders 7.9% (122) 8.9% (70)Eye disorders 6.5% (100) 6.1% (48)Investigations (lab parameters) 6.1% (95) 5.2% (41)Psychiatric disorders 5.9% (91) 8.0% (63)

Robinson. Presented at ESC; Barcelona, August 31, 2014.

PCSK9-I mAbs have NO apparent immunomodulatory effects!

. .

Alirocumab

Adverse Reactions with Alirocumab

Alirocumaba

Evolocumab Safety Profile, 52 week Controlled Trial*

*Evolocumab 420 mg q month. Injection site reactions include erythema, pain bruising.Evolocumab prescribing information, Amgen, Inc.

evolocumabevolocumabevolocumab

Neurocognitive Adverse EventsAt least 52 weeks for all patients continuing treatment, including 607 patients completing W78 visit

% (n) of patientsAll patients on background of max tolerated statin ± other lipid-lowering therapy

Alirocumab(n=1550)

Placebo(n=788)

Any neurocognitive disorder† 1.2% (18) 0.5% (4)Amnesia 0.3% (5) 0% (0)Memory impairment 0.3% (5) 0.1% (1)Confusional state 0.3% (4) 0.1% (1)Confusion postoperative <0.1% (1) 0% (0)Dementia <0.1% (1) 0.1% (1)Disorientation <0.1% (1) 0% (0)Disturbance in attention <0.1% (1) 0.1% (1)Frontotemporal dementia <0.1% (1) 0% (0)Transient global amnesia <0.1% (1) 0% (0)

†Company MedDRA Queries (CMQ).Statistical analyses have not been performed. Robinson, JG. NEJM 2015 epub Mar 15.

Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin or Ezetimibe

0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00Cum

ulat

ive

prob

abili

ty o

f eve

nt

Week

Atorvastatin

Alirocumab

0 4 8 12 16 20 24 28 32 36

Kaplan-Meier estimates for time to first skeletal muscle event

Cox model analysis:HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042

Ezetimibe

HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096

Moriarty PM JCL (2015) 9, 758–769

Can LDL-C be Too Low?• Abetalipoproteinemia & homozygous

hypobetalipoproteinemia (LDL-C 0-25 mg/dL)– Autosomal recessive LoF MTP or apo B gene mutations– V. Low-absent apo B-cont. lipos (chylos, VLDL, LDL)– Neurological/ophthalm sequelae prevented by fat-

soluble vitamins– Malabsorption Sx reduced by low fat diet + MCT oil +

essential fatty acids– Hepatic steatosis and AST/ALT elevations (no fibrosis)– No ASCVD

• Heterozygous and Homozygous PCSK9 LoF (LDL-C 10-130 mg/dL)– Low to absent PCSK9– Decreased ASCVD– Normal neurological and reproductive function

Lee J & Hegele RA, J Inherit Metab Dis 37:333, 2014Cohen, JC. NEJM 2006;354:1264-72.

TEAEs of Interest in Patients with 2 Consecutive LDL-C < 25mg/dL

Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit)

% of Patients (All on maximally tolerated statin ±other lipid-lowering therapy)

Alirocumab Total

(N=1550)

Alirocumab with 2 consecutive

LDL-C <25mg/dL(N=575)

Placebo(N=788)

Summary of AE – no. of patients (%)Any adverse event 1255 (81.0) 435 (75.7) 650 (82.5)Serious adverse event 290 (18.7) 98 (17.0) 154 (19.5)Adverse event leading to death 8 (0.5) 4 (0.7) 10 (1.3)Adverse event leading to study drug discontinuation 111 (7.2) 26 (4.5) 46 (5.8)

Adapted from Robinson JG et al. N Engl J Med. 2015;372(16):1489-99

TEAEs w/ Very Low LDL-C (2 consecutive < 25 mg/dL)% (n) of patients All maximal statin therapy ± other LLT

Alirocumab(n=1550)

Alirocumab* with 2 consec. LDL-C <25 mg/dL (n=562)

Placebo(n=788)

Infections + infestations 48.3% (748) 42.3% (243) 48.6% (383)Musculoskeletal + connective tiss. disord. 30.1% (467) 26.1% (150) 30.7% (242)Gastrointestinal disorders 20.5% (318) 16.7% (96) 20.6% (162)Nervous system disorders 18.6% (289) 12.9% (74) 19.7% (155)General disorders + injection site rxn 16.1% (250) 11.3% (65) 17.8% (140)Injury, poisoning, + proced. complics. 15.5% (241) 13.2% (76) 15.7% (124)Respiratory, thoracic, + mediast. disord. 11.7% (182) 8.9% (51) 12.6% (99)Cardiac disorders 11.0% (171) 10.6% (61) 12.9% (102)Skin + subcutaneous tissue disorders 10.1% (156) 8.3% (48) 9.4% (74)Metabolism + nutrition disorders 10.2% (158) 9.6% (55) 9.3% (73)Vascular disorders 8.6% (133) 5.4% (31) 10.0% (79)Eye disorders 7.0% (108) 7.0% (40) 6.2% (49)Laboratory investigations 6.4% (99) 4.3% (25) 5.5% (43)Psychiatric disorders 6.5% (101) 5.2% (30) 8.5% (67)Renal + urinary disorders 5.5% (85) 4.7% (27) 6.6% (52)Neoplasms, benign, malign. (+cysts/polyps) 3.0% (47) 3.8% (22) 4.3% (34)Reproductive system + breast disorders 3.2% (50) 2.8% (16) 3.4% (27)Blood + lymphatic system disorders 3.0% (46) 2.4% (14) 3.7% (29)Ear + labyrinth disorders 2.4% (37) 1.7% (10) 3.9% (31)

After J. Robinson et al NEJM 372:1489, 2015, Appendix

PCSK9 Safety w/ LDL-C <25 mg/dL

(N=575 of 1550)

• No increase in:– Total mortality– Cancer– Myopathy– Cognitive symptoms– Metabolic/reproductive disorders– Skin disorders

Most AEs↓(!) →↑compliance/healthy-user? Robinson, JG. NEJM 2015 epub March 15.

Can LDL-C be Too Low?• Abetalipoproteinemia & homozygous

hypobetalipoproteinemia (LDL-C 0-25 mg/dL)– Autosomal recessive LoF MTP or apo B gene mutations– V. Low-absent apo B-cont. lipos (chylos, VLDL, LDL)– Neurological/ophthalm sequelae prevented by fat-

soluble vitamins– Malabsorption Sx reduced by low fat diet + MCT oil +

essential fatty acids– Hepatic steatosis and AST/ALT elevations (no fibrosis)– No ASCVD

• Heterozygous and Homozygous PCSK9 LoF (LDL-C 10-130 mg/dL)– Low to absent PCSK9– Decreased ASCVD– Normal neurological and reproductive function

Lee J & Hegele RA, J Inherit Metab Dis 37:333, 2014Cohen, JC. NEJM 2006;354:1264-72.

Probably not!

And remember: Lower On-Treatment LDL-C IS Better for ↓CVD!

*Adjusted for age, gender, baseline LDL-C, diabetes mellitus, and prior MI.

Lower/better Higher/worse0 1 2

> 80-100> 60-80> 40-60≤ 40

Referent0.80 (0.59, 1.07)0.67 (0.50, 0.92)0.61 (0.40, 0.91)

Hazard Ratio

Ach

ieve

d LD

L-C

(m

g/dL

) n = 256

n = 631

n = 576

n = 193

PROVE-IT/TIMI 22 Substudy. Wiviott SD et al. JACC. 2005;46:1411-1416.Similar result reported in 8-study meta-analysis: Boekholdt SM, et al. JACC 2014;64;485–94.

Atorvastatin 80 mg vs pravastatin 40 mg, N=2099 ACS pts, 24 mos, f/u.Endpoint: CHD death, nonfatal MI, CVA, recurrent ischemia, revascularization

†Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy

Kaplan-Meier Time to First Adjudicated Major CV Event/TEAEsSafety Analysis (> 52 wks for all patients continuing Rx, incl. 607 at W78 visit)

No. at RiskPlaceboAlirocumab

Weeks

Mean treatment duration: 65 weeks

Placebo + max-tolerated statin ± other LLT

Cum

ulat

ive

prob

abili

ty o

f eve

nt Alirocumab + max-tolerated statin ± other LLT

Cox model analysis:HR=0.46 (95% CI: 0.26 to 0.82)Nominal p-value = <0.01

847260483624120

0.06

0.05

0.04

0.02

0.01

0.00

0.03

7881550

7761534

7311446

7031393

6821352

6671335

321642

127252

Alirocumab Post-hoc CVD Events†

Robinson et al . Presented at ESC hotline session; Barcelona, Aug 31, 2014Robinson, JG. New Eng J Med 2015 epublished March 15

*Cumulative Incidence of Cardiovascular Events: CV death, MI, USA req hospit, correvasc, stroke TIA, CHF hospitalization.Inset shows expanded y axis. P value by log-rank test.Sabatine MS et al. N Engl J Med. Published March 15, 2015. doi: 10.1056/NEJMoa1500858.

No. at RiskStandard ther. 1489 1486 1481 1473 1467 1463 1458 1454 1447 1438 1428 1361 407Evolocumab 2976 2970 2962 2949 2938 2930 2920 2910 2901 2885 2871 2778 843

Days Since Randomization

100

90

80

70

60

50

40

30

20

10

0

Cum

ulat

ive

Inci

denc

e* (%

)

0 30 60 90 120 150 180 210 240 270 300 330 365

0 30 60 90 120 150 180 210 240 270 300 330 365Days Since Randomization

Standard therapy

Evolocumab

Hazard ratio, 0.47(0.28-0.78)P = .003

3

2

1

0

CVD Event Reduction with Evolocumab (Phase II/III Open-label OSLER-1 & -2)

2.18%(31 of 1489)

0.95%(29 of 2976)

Pooled PCSK9 Safety & Efficacy(Alirocumab, Bococizumab & Evolocumab; N=10,159)

Event Odds Ratio (95% CI)Total Mortality 0.45 (0.23-0.86)CVD Mortality 0.50 (0.23-1.10)MI 0.49 (0.26-0.93)Unstable Angina 0.61 (0.06-6.14)CK 0.72 (0.54-0.96)SAE 1.01 (0.87-1.18)

Navarese, EP. Ann Intern Med 2015 epub. 28 April. doi:10.7326/M14-295.

Evolocumab(AMG 145)

Alirocumab(SAR236553 /REGN727)

Bococizumab (RN 316)

Sponsor Amgen Sanofi / Regeneron Pfizer

Trial FOURIER ODYSSEY Outcomes SPIRE I SPIRE II

Sample size 22,500 18,000 12,000 6,300

Patients MI, stroke or PAD 4-52 wks post-ACS High risk of CV event

Statin Atorva ≥20 mg or equiv Evid-based med Rx Lipid-lowering Rx

LDL-C mg/dL(mmol/L) ≥70 (≥1.8) ≥70 (≥1.8) 70-99 (1.8-2.6) ≥100 (≥2.6)

PCSK9i Dosing 140 mg Q2W or Q4W 75-150 mg Q2W Q2W

Endpoints 1°: CV death, MI, stroke, revasc or hosp for UA,

Key 2°: CV death, MI, or stroke

CHD death, MI, ischemic stroke, or hosp for UA

CV death, MI, stroke, or urgent revasc

Completion 12/2017 (vs 2H16?) 1/2018 (vs interim 2H16) 8/2017

PCSK9 Inhibitor OngoingCVD Outcomes Trials

www.clinicaltrials.gov

Beyond PCSK9-Inhibitors

• LDL apheresis• Lomitapide• Mipomersen• Liver transplant

NB: all these require referral to Lipidologist

Summary and Conclusion

PCSK9-I mAb: RCT Summary• Very rapid translation:

– Clinical discovery → basic science definition– Basic science → clinical development – Clinical development → regulatory approval

• Very impressive lipid efficacy (>statins)• Revolutionary re:

– LDL-C lowering—proven (40-65%)– Lp(a) lowering—proven (15-30%)– CVD reduction—suggestive preliminary data (~50%),

likely proven soon• Impressive safety/tolerability (site rxn, “flu-like”

nasal congestion, allergic rxn)• Unlikely to replace statins, but • Likely to be “gold-standard” (after ezetimibe) as

– Statin adjuncts for FH & severe CVD– Statin alternatives for statin intolerance

Alirocumab vs EvolocumabAlirocumab• IgG1 (most Rx mAbs,

more complement activation, more placental transfer)

• Half-dose available• Less Efficacy? (likely not)• More robust phase-III• More solid early CVD data

– More events– All Rx double-blind

Evolocumab• IgG2• HoFH efficacy (only one

tested)• More q 4 wk data• Less anti-drug

antibodies? (likely not)• Larger ongoing CVOT

Similarities >> any differences:• Appear equally efficacious re: ↓LDL-C, apo B, Lp(a)• Appear equally safe/well tolerated

Alirocumab vs Evolocumab vs BococizumabAlirocumab• IgG1 (most Rx mAbs,

more complement activation, more placental transfer)

• Half-dose available• Less Efficacy? (likely not)• More robust phase-III• More solid early CVD data

– More events– All Rx double-blind

Evolocumab• IgG2• HoFH efficacy (only one

tested)• More q 4 wk data• Less anti-drug

antibodies? (likely not)• Larger ongoing CVOT

Similarities >> any differences:• Appear equally efficacious re: ↓LDL-C, apo B, Lp(a)• Appear equally safe/well toleratedBococizumab• Potential disadvantage: humanized vs human • Otherwise v. similar to alirocumab & evolocumab

Advent of PCSK9-I Requires Return to On-Rx LDL-C

(albeit Thresholds > Goals)• Main question: WHO “requires more

LDL-C lowering”*• NLA PCSK9-I Rx thresholds = goal +

30; so 2o prev. >100, HR 1o prev. >130• ACC statement reinstates thresholds• PCSK9-I class allows us to overshoot

LDL-C goals in most cases– How low is too low? (likely no such thing)– Should we back-titrate statins? (likely not)

*After Shrank WH JAMA 2015 epub Aug 10. See also PCSK9-I prescribing info.

Using FDA-Approved PCSK9 Inhibitors in Clinical Practice: Conclusions

• ↓ LDL-C by 45-60% (so ok up to 2-3 x goal)– Always use after max statins (+ ezet, BAS? NA?)

• Appear safe & well tolerated, even if LDL-C <25• Likely →↓CVD by 20-50% (by base LDL-C)• Indicated when need extra ↓LDL-C:

– Clinical ASCVD (+high risk?) LDL-C>threshold• High baseline LDL-C, • Poor response to statin and/or • Relative or absolute intolerance to statin (or ezetimibe)

– FH (how to define?) LDL-C>threshold• Genetic testing?• Formal scoring • Baseline LDL-C >190 mg/dL

LDL Rx in PCSK9-I Era• Establish LDL-C goal, then:• Use statins to max as needed/tolerated• Establish LDL-C non-statin threshold, then:• Add ezetimibe (chol. absorp. inhib.—CAI)• Consider referral to Lipidologist for:

– PCSK9-I for 40-65% further ↓ LDL-C– BAS for 10-18% further ↓LDL-C– Niacin for 10-18% further ↓LDL-C– Other: LDL apheresis, lomitapide, mipomersen

for 25-70% further ↓LDL-C

Referral to a LipidologistWhen?*• To consider LDL Rx beyond statin & CAI (BAS,

NA, PCSK9-I, LDL apheresis, lomitapide, mipomersen) – Severe hypercholesterolemia: LDL-C >100-200

depending on age, ASCVD risk, and Rx response– ASCVD bad/progressive (adv. testing & Rx)– Statin intolerant/phobic

To Whom?• ABCL certified physician—see lipidboard.org• Other lipid experts—NLA members (lipid.org),

FH foundation, etc.• Become a lipidologist—as noted above*Also consider Lipidology referral for: • Severe HTG (> ~700, or 200-500 if risk/history ASCVD)• High Lp(a)

pcsk9-inhibitor treatment for hypercholesterolemia

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