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Dyslipidemia: Going Beyond the Current

Treatment GuidelinesNCNP Las Vegas

October 2017

J oy c e L . R os s , M S N , C R N P, C S , F N L A , F P C N AD i p l oma t e A c c re d i t a t i o n C ou n c i l F or C l i n i c a l

L i p i d ol og yP a s t P re s i d e n t P re v e n t i v e C a r d i ov a s c u l a r N u r s e s

A s s oc i a t i o nI mme d i a t e P a s t P re s i d e n t N a t i on a l L i p i d A s s oc i a t i o n

C on s u l t a t i v e E d u c a t i on S p e c i a l i s t , C a r d i ov a s c u l a r R i s k I n t e r v e n t i o n

C l i n i c a l A f f i l i a t i on : U n i v e r s i t y O f P e n n s y l v a n i a H e a l t h S y s t e m - re t i re d

P h i l a d e l p h i a , P e n n s y l v a n i aJ l r @ j oy c e r o s s n p . C o m

Disclosures

Speakers Bureau:

KOWA

AstraZeneca

Amgen

Sanofi/Regeneron

Amarin

Consultant:

Akcea Therapeutics

Kaneka America

Kastle Therapeutics

Program Objectives

After attending this presentation the participant will be able to:

1. Discuss 2016 Updated ACC Guidelines, NLA and others Recommendations for Dyslipidemia Management

2. Recall that statin therapy is the first line medication treatment for risk reduction

3. Discuss considerations for addition of “other” classes of lipid lowering medication when combination medication therapy is warranted

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Burden of Atherosclerotic Cardiovascular Disease

Annual rates in US

- Myocardial infarction – 1.1 million

- Strokes - 795,000

- CVD Mortality – 1,344,185 (every 30 seconds a death)

- Cardiac catheterization – 1.0 million

- Percutaneous revascularization – 492,000

- Surgical revascularization – 291,000

Annual cost – >$315 billion

American Heart Association. 2017 Heart and Stroke Statistical Update. At: http://www.americanheart.org. 4

AHA/ACC Focus on ASCVD Risk Reduction using

4 statin benefit groups

(those who would benefit most from treatment)

• Individuals with clinical ASCVD

Individuals with primary elevations of LDL-C >190 mg/dL

Individuals 40 to 75 years of age with DM and without ASCVD with LDL-C 70-189mg/dL

Individuals without clinical ASCVD or DM who are 40 to 75 years of age with LDL-C 70-189 mg/dL and an estimated 10 year ASCVD

risk of 7.5% or higher

Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline

ACC 2016 – Why the need for change?

Since the publication of the last guidelines the Food and Drug Administration has approved a new class of meds

proprotein convertase subtillisin/kexin 9 or most often referred to as PCSK9 Inhibitors for at high-risk patients who may

require additional therapies to bring the LDL-C to a more

acceptable threshold

The recent results of the HPS2-THRIVE and IMPROVE-IT trials have also provided new data that provided new

evidence with regard to the addition of second

non-statin agents when additional lowering is warranted

Adapted from: 1) http://www.acc.org/latest in cardiology/ten points to remember 2016. (2) Http://www.lipid.org/nla/acc16-american

college cardiology scientific sessions highlights

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2016 ACC Consensus Document onRole of Non-Statin Therapies for LDL-C Lowering

Lloyd-Jones DM, Morris PB, et al. J Am Coll Cardiol. 2016 (posted online April 1, 2016).

Statin Benefit Groups

Adults ≥21 yrs of age

with clinical ASCVD

on statin for 2°

prevention

Adults ≥21 yrs of age

with LDL-C ≥190 mg/dL

on stain for 1°

prevention

40-75 yrs w/o ASCVD

but with DM & LDL-C 70-

189 mg/dL on statin for

1o prevention

40-75 yrs w/o ASCVD or

DM, LDL-C 70-189 mg/dL

& 10-yr ASCVD risk

≥7.5%, on statin for 1°

prevention

Factors to consider

• Adherence and lifestyle

• Statin intolerance

• Control of other risk factors

• Clinician-patient discussion of the benefits, risks, and patient preferences regarding addition

of non-statin meds

• Percentage LDL-C reduction

• Monitoring of response to therapy, adherence, and lifestyle

Optional interventions to consider

• Referral to lipid specialist and registered dietitian

• Ezetimibe, bile acid sequestrants, or PCSK9 inhibitors

• Mipomersen, lomitapide, LDL apheresis may be considered by a lipid specialist for

patients with familial hypercholesterolemia

2016 ACC Consensus Document onRole of Non-Statin Therapies for LDL-C Lowering

First- and second-line non-statin medications to consider for

additional LDL-C lowering in the 4 statin benefit groups:

*Alternative to percentage LDL-C reduction as a marker for adequate response to therapy.PCSK9 = proprotein convertase subtilisin/kexin type 9 inhibitor; BAS = bile acid sequestrant; TG = triglyceride1. Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488. 2. Jellinger PS, et al. Endocr Pract. 2012 Mar-Apr;18(suppl 1):1-78. 3. European Association for Cardiovascular Prevention & Rehabilitation, et al. Eur Heart J. 2011;32(14):1769-1818. 4. Anderson TJ, et al. Can J Cardiol. 2013;29(2):151-167. Lloyd-Jones DM, Morris PB, et al. J Am Coll Cardiol. 2016 (posted online April 1, 2016).

Risk Category Treat-to-target

goal*

First-line non-statin

agent

Second-line non-statin

agent

Clinical atherosclerotic

CVD

LDL-C <100

mg/dL

First-line: ezetimibe Second-line: PCSK9

inhibitor

LDL-C ≥190 mg/dL LDL-C <70 mg/dL First-line: ezetimibe or

PCSK9 inhibitor

Second-line: BAS

(alternative to ezetimibe

if TG <300 mg/dL)

DM and aged 40-75

years and LDL-C 70-189

mg/dL

LDL-C <100

mg/dL

First-line: ezetimibe Second-line: BAS

No DM and aged 40-75

years and LDL-C 70-189

mg/dL + 10-year ASCVD

risk ≥7.5%

LDL-C <100

mg/dL

First-line: ezetimibe Second-line: BAS

2017 AACE Guidelines for Management of Dyslipidemia and Prevention of CVD

Jellinger PS, et al. Endocr Pract. Apr 2017;23(Suppl 2):1-87.

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2016 ESC/EAS Guidelines for the Management of Dyslidemias

Riskcategory

Definition LDL-C Goal

Very high • Documented CVD• DM with target organ damage

or a major risk factor• 10-year risk ≥10% for fatal CVD

<70 mg/dL

Or ≥50% reduction

if LDL-C 70-135

mg/dL

High • Cholesterol >310 mg/dL or BP ≥180/110 mmHg

• Most people with DM

• Moderate CKD

• 10-year risk ≥5% for fatal CVD

<100 mg/dL

Or ≥50% reduction

if LDL-C 100-200

mg/dL

Moderate 10-year risk 1% - <5% for fatal

CVD

<115 mg/dL

Low 10-year risk <1%for fatal CVD <115 mg/dL

10

Catapano AL, et al. Eur Heart J. Oct 14 2016;37(39):2999-3058.

2014 IAS Global Recommendations for the Management of Dyslipidemia

Category Total long-term

risk*

Therapy LDL-C Non-HDL-C

Established ASCVD

NA Lipid-lowering therapy

<70 mg/dL <100 mg/dL

High risk ≥45% Lipid-lowering therapy

<100 mg/dL

<130 mg/dL

Moderatelyhigh risk

30-44% Consider lipid-loweringtherapy

<100 mg/dL

<130 mg/dL

Moderate risk 15-29% Lipid-lowering therapy optional

Low risk <15%

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*Total long-term (lifetime) risk includes multiple risk factors (eg, LDL-C, smoking, hypertension, diabetes, low

HDL-C, family history of ASCVD); Calculated with Framingham or QRISK calculators

Expert Dyslipidemia Panel of the IAS. J Clin Lipidol. Jan-Feb 2014;8(1):29-60.

Who may need additional therapies beyond statins to control LDL-C?

• Any patient with hypercholesterolemia not achieving

LDL-C goal1,2

• Patients who are intolerant or have a inadequate

response to statin therapy3,4

• Difficult to treat patients5,6

– Familial hypercholesterolemia

– Diabetes

1. Ballantyne CM, et al. Am Heart J. 2005;149:464-73. 2. Karalis DG, et al. Cholesterol. 2012;2012:861924. 3. Sullivan D, et al.

JAMA. 2012;308(23):2497-2506. 4. Kataoka Y, et al. Arterioscler Thromb Vasc Biol. 2015;35(4):990-5. 5. Stein EA, et al. Am J

Cardiol. 2003;92(11):1287-93. 6. Stark Casgrande S, et al. Diabetes Care. 2013;36(8):2271-9.

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Integrating Emerging Clinical Data Into Clinical Practice: An Evolving Treatment Algorithm

Post-ACS/CAD patient with

hypercholesterolemia

ACC/AHA Guidelines:

Optimize statin therapy

LDL<70 LDL≥70

Add

ezetimibe

LDL<70 LDL ≥ 70

Add PCSK9 inhibitors

or other LLT

Statin

therapy

Step 1:

Statin

Statin +

Ezetimibe

Step 2:

Check LDL

Step 3:

Add Rx as needed*

Slide courtesy of Christopher Cannon, MD.

*This pathway is consistent with the Non-statin

Therapies Document for individuals with ASCVD with

comorbidity.

Applying the Guideline

SA is a 60 y.o patient with a long history of DM, which is well

controlled at this time and HTN

she has a strong family history of premature heart disease

and is worried about her risk given her DM, poor exercise

history, dietary status and family history

Meds currently include: Metformin ER 2,000 mg daily

Sitagliptin (januvia) 10 mg daily

Hyzaar (ARB) Hctz 50-12 mg/daily

Weight: 154 pounds, height 5’4”, BP 132/88, waist 30”

Last lipid panel > 1 year ago.

How do the guidelines apply?

Individuals 40 to 75 years of age with DM and without ASCVD with LDL-C 70-189mg/dL

The appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit

A high level of evidence supports the use of moderate-intensity statin therapy in persons with diabetes 40 to 75 years of age.

In those of the same age group with diabetes high-intensity statin therapy preferentially for individuals with diabetes and a ≥7.5%

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Risk Assessment

for this patient to estimated 10-year ASCVD risk

Problem: consideration for those with diabetes 40 to 75

years of age recognizes that these individuals are at

substantially increased lifetime risk for ASCVD events and

death

individuals with DM experience greater morbidity and worse survival follow the onset of ASCVD

In persons with diabetes <40 or >75 years of age, statin therapy

should be individualized based on considerations of ASCVD risk

reduction benefits, the potential for adverse effects and drug-

drug interactions, and patient preferences

Goal: establish the level of treatment with statin

therapy

Risk Factor Acceptable range of values

Patient Value

Sex M OR F F

Age 20 – 79 60

Total Cholesterol 130 320 mg/dL 290 md/dL

HDL Cholesterol 20 – 100 mg/dL 35 mg/dL

Systolic BP 90 – 200 mm Hg 132 mm Hg

Tx. For BP Y or N Y

Diabetes Y or N Y

Smoker Y or N N

Race AA or WH WH

10 year ASCVD Risk % 15.7 %

* The calculator only provides lifetime risk estimates for individuals 20 – 59 years of age

Risk Calculator which may be found online or can be

downloaded to smart phone etc.

Intensity of Statin Therapy

*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response.

†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

High- Moderate- and Low-Intensity of Statin Therapy Expert Panel)*

High-Intensity Statin Therapy

Moderate-Intensity Statin Therapy

Low-Intensity Statin Therapy

Daily dose lowers LDL-C on average, by approximately ≥50%

Daily dose lowers LDL-C on average, by approximately 30% to <50%

Daily dose lowers LDL-C on average, by <30%

Atorvastatin (40†)-80 mgRosuvasatin 20 (40) mg

Atorvastatin 10 (20) mgRosuvastatin (5) 10 mgSimvastatin 20-40 mg‡Pravstatin 40 (80) mgLovastatin 40 mgFluvastatin XL 80 mgFluvastatin 40 mg bidPitavastatin 2-4 mg

Simvastatin 10 mgPravastatin 10-20 mgLovastatin 20 mgFluvastatin 20-40 mgPitavastatin 1 mg

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Initiating statin therapy in individuals with clinical

ASCVD

Not currently on statin therapy Initial evaluation prior to statin

initiation

Fasting lipid panel

ALT

CPK

Consider evaluation for other secondary causes or conditions that may

influence statin safety

Aged <75 y without contraindications, conditions or drug-drug

interactions

influencing statin safety, or a history of statin intolerance

• - Initiate high-intensity statin therapy

• - Counsel on healthy lifestyle habits

Progression of Atherogenic Cholesterol-Lowering Drug

Therapy20

Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline

Lifestyle as the Foundation for ASCVD Risk Reduction

Efforts

Newest ACC/AHA guidelines adds increased emphasis on

lifestyle management for treatment

It must be emphasized that lifestyle modification (i.e., adhering

to a heart healthy diet, regular exercise habits, avoidance of

tobacco products, and maintenance of a healthy weight)

remains a critical component of health promotion and ASCVD

risk reduction

both prior to and in concert with the use

of cholesterol- lowering drug therapies. Healthy

diet or lifestyle modifications were recommended as

background therapy for the RCTs of cholesterol-lowering drug

therapy.

Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline

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HMG CoA Reductase Inhibitors (Statins)

Competitive Inhibition

Cholesterol production

Expression of LDL

receptors

LDL, VLDL, and

IDL particles

LDL-C Lowering

Acetyl CoA

HMG-CoA

Mevalonate

Cholesterol production

Statins - HMG CoA-Reductase Inhibitors22

VLDL=Very Low Density

Lipoprotein

IDL

HMG-CoA reductase inhibitors

Wwwlipid.org wwwlipid.org NLA

NEWSFLASH !!!!!

All Statins Are Not Created Equal

• How are they different ?

• strength at starting dose

• way the body metabolizes it

• hydro/lipophilic

Taking a walk on the Cytochrome

P450 Pathway

Ross J 2004

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Role of CYP450 3A4 in Drug Metabolism

• Responsible for converting lipophilic

substrates to water-soluble products to

facilitate urinary excretion

• High potential for drug-drug interactions, as

approximately 50% of drugs are metabolized

by this enzyme

• Hydrophilic agents do not require clinically

significant metabolism through this pathway

Wilson. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. Hardman et al, eds. In: Goodman and Gilman’s The Pharmacological

Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2003:3-30.

Dose Efficacy of Statin-Based Therapies for LDL-C Reduction (%)

Dose Efficacy in STELLAR1*

Drug 10 mg 20 mg 40 mg 80 mg

CRESTOR® (rosuvastatin calcium) 46 52 55

Lipitor® (atorvastatin calcium) 37 43 48 51

Pravachol®

(pravastatin sodium)

20 24 30 *

Zocor® (simvastatin) 28 35 39 46

•VytorinTM (ezetimibe 10 mg/simvastatin)* reduces LDL-C by 46% to 59%2*

•Data derived from the prescribing information for Vytorin •Peter H. Jones, MD, Michael H. Davidson, MDComparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses

(STELLAR* Trial) The American Journal of Cardiology Vol. 93 July 15, 2003

ACC/AHA/NHLBI Clinical Advisory Risk Factors for Statin-Myopathy

Advanced age (especially >80 yr; women > men)

Severe chronic kidney disease

Impaired liver function

Perioperative periods

Alcohol abuse

Large quantities of grapefruit juice (certain statins)

Interacting medications

Hypothyroidism

27

Pasternak RC et al. J Am Col Cardiol. 2002;40:567-572.

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Managing Statin-Associated Myalgia

Well Accepted:

Rule out secondary causes

Switch to a different statin

Alternate day dosing of higher potency statins

Use lowest statin dose that is tolerated; adding a second agent if needed

Debatable:

Red yeast rice (Monascus purpureus) 2400 mg/day

Vitamin D supplementation

Coenzyme Q10 (CoQ10) supplementation

Ahmed W, et al. Translational Research 2009;153:11–16.

Reindl EK, et al, Ann Pharmacother 2010;44:1459–1470.

Halbert SC, et al. Am J Cardiol 2010;105:198 –204) Marcoff L, Thompson PD. J Am Coll Cardiol. 2007;49:2231–2237.

Meanwhile back to our patient

High risk patient R/T DM, HTN, Dyslipidemia

Full lipid panel needed: TG 203, TC 290, HDL 40, LDL 169, Glucose 118, HbA1c 6.5, TSH, ALT/AST, Renal function all WNL

Lipid Dx: Familial Combined Hyperlipidemia

LDL Threshold: < 100/70 ?

Treatment Plan

Lifestyle Management

Exercise and Diet

Medications

Rosuvastatin 20 mg

Low dose ASA

No change with DM meds

No change with ARB/HCTZ for

BP control and renal protection

Labs and RTC X 6 WKS

1st FOLLOW UP APPT.

Returns in 6 weeks with some change in lifestyle management

Tolerating changes in the medication regimen without untoward side effects

Labs: TG: 150, TC: 170, HDL: 38, Non-HDL: 132 , LDL 102, other studies WML

Weight: 151, BP 116/78

Treatment Plan:

Congratulate on changes, continue with same

LDL at 102 ? Enough?

Could increase statin to 40 mg for 6% further reduction or consider a cholesterol absorption inhibitor for a 20% further reduction

No change with other medications

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Cholesterol Absorption Inhibitor

Ezetimibe

Mechanism of Action

Inhibits cholesterol absorption in the intestine thereby increasing hepatic LDL receptors

Dose and Route of Administration

10 mg orally once daily

Lipoprotein Effects

Decreases LDL 15-20 %

Decreases TGs 10 %

Increases HDL 1-2 %

Contraindications

None

IMPROVE-IT: Conclusions

• First trial demonstrating incremental clinical benefit

when adding a non-statin agent (ezetimibe) to statin

therapy:

– Non-statin lowering LDL-C with ezetimibe reduces

cardiovascular events

– Even lower is even better (achieved mean LDL-C 54 vs.

70 mg/dL at 1 year)

– Confirms ezetimibe safety profile

• Reaffirms the LDL hypothesis, which suggests that

reducing LDL-C prevents cardiovascular events

Primary end point (cardiovascular death, MI, unstable angina, coronary revascularization, or stroke).

Cannon CP, et al. N Engl J Med. 2015;372(25):2387-97.

Case Study # 2

- 50 y.o. male with + family history of premature

ASCVD (Father fatal MI age 52)

- Presents for evaluation and recommendations for

cardiovascular risk

- PMH: Known HTN X 5yrs, Rx: HCTZ 25 mg

- Denies history of CAD, DM, or Thyroid disease

- Denies chest pain, SOB, or calf pain when walking

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Lifestyle evaluation:

- no regular exercise program

- high stress job as manager in an investment firm

- Diet: often “eats on the run”

- Smoking 24 year history approximately 1pk/day

- ETOH: generally has 2-3 drinks per day after long hours at work (feels it helps him to unwind)

- Social history: married with 3 children

Laboratory Studies &

Physical Exam

• Lipids:• TG 584• TC 302• HDL 29• LDL 204 (d)• Non-HDL: 273

• Glucose 118• BUN/Creatinine: WNLs, GFR: <

60• ALT/AST: WNLs

Physical Exam: unremarkable except

- Extremities: normal pulses throughout, mild bilateral achilles tendon xanthomas > L side

BP: 146/84HR: 92BMI: 28Waist: 38.5”

The elbow and feet of the patient showing xanthomas at 10 years of age

(a,b). Complete regression of xanthomas shown at the age of 23 (c,d).

S. Lind et al., J Int Med 2004; 256: 406-12

Eruptive Xanthomas

Before and After Treatment

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Courtesy of Anne Goldberg, MD

Tendon Xanthomas & Arcus Cornea

Focus on ASCVD Risk Reduction

Individuals with LDL–C ≥190 mg/dL or triglycerides ≥500 mg/dL should be evaluated for secondary causes of hyperlipidemia

Adults ≥21 years of age with primary LDL–C ≥190 mg/dL should be treated with statin therapy (10-year ASCVD risk estimation is not required)

Use high-intensity statin therapy unless

contraindicated

Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline

Applying Guideline

Patient has a combined lipid problem but current

LDL-C suggests potential FH with superimposed

elevated TGs and Non-HDL-C

Would not need to use Global Risk Assessment

since 10-year and lifetime risk are very high with FH

Would treat with high intensity statin therapy along

with lifestyle management

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Dx. & Treatment Plan

Problem List:

Dyslipidemia &

Smoking (low HDL)

Overweight

High Stress

High ETOH intake (high TG)

Elevated glucose

Elevated BP

Lifestyle Management Smoke Cessation Meet with dietician Decrease ETOH Exercise for risk management and

decrease stress – stress test first?

Medications ASA 81 mg

rosuvastatin 40 mg ? Why

Add ace inhibitor, continue with HCTZ

RTC: 6 weeks with labs including HbA1c & TSH. CMP and lipids with Lp(a)

1st Follow Up Appt.

Stress test WNL

Coronary Arterial Calcium Score: 216 = 90% for age

Returns with changes in diet as recommended by dietician, walking 1 X week, wt. down 3 pounds

No changes with ETOH

Changed office hours to be home for dinner with family

Taking all medications without difficulty

BP with combination therapy – 130/82

Labs on return:

Glucose 129, HbA1c 7.2

TSH: normal range

ALT/AST: WNL

Renal: WNL

Lipids:

TG 316

TC 180

HDL 31

Non HDL 149

LDL 96

Lp(a) 107 mg/dL

Treatment Plan

Continue with lifestyle changes – congratulate for all efforts made BUT:

Decrease ETOH

Stop smoking

Increase exercise

Decrease Kcal to 1,800 daily for ongoing wt. loss

Medications:

Change with current medications

Need to add further LLM & possibly some changes for elevated glucose

Would you:

Change statin to simvastatin?

Add ezetimibe 10 mg?

Add PCSK9 Inhibitor?

Add glucophage 500 mg BID?

Add sulfonylurea?

Add omega 3 fatty acid?

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We should consider use of PCSK9-Inhibitors in

patients with:

known CAD or those identified and those who have very

high risk

whose LDL-C cannot be lowered to an acceptable range (goal , generally < 70 mg/dL)

who are on maximally tolerated statin therapy

Use of PCSK9 Inhibitors

*Alternative to percentage LDL-C reduction as a marker for adequate response to therapy.

PCSK9 = proprotein convertase subtilisin/kexin type 9 inhibitor; BAS = bile acid sequestrant; TG = triglyceride

Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488. 2. Jellinger PS, et al. Endocr Pract. 2012 Mar-Apr;18(suppl 1):1-78. 3. European Association for

Lloyd-Jones DM, Morris PB, et al. J Am Coll Cardiol. 2016 (posted online April 1, 2016).

PCSK9 Inhibitors

PCSK9 Inhibitors: Obtaining Approval

Low rates of approval for PCSK9 inhibitors FH and LDL-C >190 mg/dL despite LLT

63.3% of PCSK9 prescriptions rejected

9% of ezetimibe prescriptions rejected

Clinical ASCVD and LDL-C >100 mg/dL despite LLT

57.5% of PCSK9 prescriptions rejected

8.2% of ezetimibe prescriptions rejected

Gaining approval requires use of strong definitions:

Heterozygous or homozygous FH

Clinical ASCVD

Maximally tolerated statin dose

45

Knowles JW, et al. Circulation. May 30 2017;135(22):2204-2206.

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Barrier Studies and Recommendations

National Lipid Association – A recent study conducted by the National Lipid Association found that 70% of respondents wait more than 30 days from the time of writing the PCSK9i prescription to fulfillment of the first prescription for their patients with FH. Approximately 50% of respondents spend more than 1 hour per week on each patient’s prior authorization.

Carl E. Orringer, MD, Terry A. Jacobson, MD, Joseph J. Saseen, PharmD, Alan S. Brown, MD, Antonio M. Gotto, MD, Joyce L. Ross MSN, CRNP, James A. Underberg, MD. National Lipid Association Updated Recommendations on the Use of PCSK9. Available online at NLA website

Baum SJ, Toth PP, Underberg JA, Jellinger P, Ross J. & Wilemon, Clin Cardiol. 2017 Mar 22. PCSK9 inhibitor access barriers-issues and recommendations: Improving the access process for patients, clinicians and payers.

Proprotein Convertase Subtilisin/KexinType 9 (PCSK9)

• PCSK9: plays an important role in regulating the

expression of the LDL-receptor (LDL-R)

– Secreted primarily by hepatocytes into circulation and

binds to LDL-R on the surface liver cells

– The PCSK9/LDL-R/LDL-C complex is internalized into

hepatocytes and undergoes lysosomal degradation

Abifadel M, et al. Curr Atheroscler Rep. 2014;16(9):439.

PCSK9 Inhibitors: Mechanism of Action

PCSK9 self-processing,

secretion, and export

PCSK9

PCSK9

LDL

Particle

LDL-R

Endocytosis of

LDL-R/PCSK9

complex

Plasma

LDL, LDL-R,

and PCSK9

degradationLysosome

Endosome

LDL-R = LDL receptors

Adapted by Lilian McVey from

Shimada YJ, Cannon CP.

Eur Heart J. 2015;36(36):2415-2424.

Used with permission.

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Currently Available PCSK9 Inhibitors

Alirocumab Evolocumab

FDA Approval July 2015 August 2015

Indication

Adjunct to diet and maximum-

tolerated statin for adults with HeFH

or clinical ASCVD who require

additional lowering of LDL-C

Adjunct to diet and maximum-

tolerated statin for adults with

HeFH or clinical ASCVD who

require additional lowering of

LDL-C, HoFH patients on other LLT

Dosing 75-150 mg SC Q2W140 mg SC Q2W or 420 mg SC

monthly

How Supplied

Single-dose pre-filled autoinjector

pens and pre-filled glass syringes that

deliver 75 mg/mL or 150 mg/mL

Single-use pre-filled syringe or

autoinjector pens that deliver 1 mL

of 140 mg/mL

MonitoringCheck LDL-C levels 4 to 8 weeks

after initiating or after titrating therapy

Check LDL-C levels 4 to 8 weeks

after initiating therapy

HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; SC =

subcutaneous.

www.fda.gov. Praluent [package insert]. Bridgewater, NJ: sanofi-aventis; 2015. Repatha [package insert]. Thousand Oaks,

CA: Amgen; 2015.

Available PCSK9 Inhibitors

Alirocumab

Fully human IgG1 mAB

Indicated for:

HeFH

Clinical ASCVD

Dose:

75-150 mg SQ q 2 weeks

LDL reduction:

50% to 60%

Evolocumab

Fully human IgG2 mAB

Indicated for: HeFH

Clinical ASCVD

HoFH

Dose: 140 mg SQ q 2 weeks or

420 mg SQ (3 injections) q month

LDL reduction: 50% to 60%

HeFH = heterozygous familial hypercholesterolemia, HoFH = homozygous familial hypercholesterolemia.

Alirocumab [injection] Prescribing Information, 2015; Evolocumab Prescribing Information, 2015; Dadu RT, Ballantyne CM. Nat Rev Cardiol. 2014;11(10):563-575; Gumbiner B, et al. Circulation. 2012;126:a13322; www.clinicaltrials.gov; www.pharmacist.com/express-scripts-cover-both-new-cholesterol-drugs.

OSLER Program: LDL-C

0

140

40

100

80

120

20

Med

ian

LD

L-C

(m

g/d

L)

Baseline

N=4465

60

4 weeks

N=1258

12 weeks

N=4259

24 weeks

N=4204

36 weeks

N=1243

48 weeks

N=3727

61% Reduction (95% CI, 0.59-0.63), P<0.0001

Absolute Reduction: 73 mg/dL (95% CI, 71-76)

Standard of Care Alone

Evolocumab + Standard of Care

OSLER = Open-Label Study of Long-Term Evaluation Against LDL-CSabatine MS, et al. N Engl J Med. 2015;372:1500-1509.

OSLER-1 and OSLER-2 are open-label extension studies of phase 2 and 3

evolocumab trials, respectively

(Parent Study)

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18

Adverse Events

Alirocumab Placebo

Nasopharyngitis

11% 11%

Influenza 6% 5%

UTI 5% 5%

Injection site reaction

7% 5%

LFT >3x ULN 1.7% 1.4%

Myalgias 4% 3%

Drug discontinuatio

n0.4% 0.2%

Neurocognitive

0.8% 0.7%

Antidrug antibodies

(ADAs)5% 0.6%

Neutralizing antibody (Nab)

1.2% (of which, in 0.3% led to

decreased efficacy)0

Alirocumab [injection] Prescribing Information, 2015.

Evolocumab – Adverse Events

Evolocumab Placebo

Nasopharyngitis 11% 10%

Influenza 8% 6%

UTI 5% 4%

Injection site reaction 6% 5%

Myalgias 4% 3%

Drug discontinuation 2% 1%

Neurocognitive ≤0.2% ≤0.2%

Antidrug antibodies (ADAs) 0.1% 0

Neutralizing antibody (Nab) 0 0

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125522s000lbl.pdf.

FOURIER Trial - Evolocumab

Sabatine MS et al. Am H J 2016; 173: 94-101

54

Primary end point was the composite of cardiovascular death, myocardial infarction,stroke, hospitalization for unstable angina, or coronary revascularization.

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Fourier Trial lipid results

Sabatine MS et al. Am H J 2016; 173: 94-101

55

Fourier Trial: Primary Outcome

Sabatine, M.S. et al. NEJM March 17, 2017DOI: 10.1056/NEJMoa1615664NEJM 2017

15% RRR

56

Fourier Trial: MI/Stroke/CV Death

20% RRR

Sabatine, M.S. et al. NEJM March 17, 2017DOI: 10.1056/NEJMoa1615664NEJM 2017

57

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20

2nd Follow Up Appt

Returns looking and feeling well with no changes to healthcare status since last visit

Continues to slowly implement lifestyle recommendations

No difficulty with toleration of current medications

Considering a change in employment

Wt. reduced 4 pounds

No changes with smoking

Now only 2 drinks/day

Walking now 2-3Xs week with family

B/P 128/70

Labs: glucose 89, - HbA1c 7

TG 175, TC 125, HDL 37, Non-HDL 88, LDL 53

Immediate Questions

Is his LDL too low?

Should you stop or decrease statin?

What needs to be done with his still abnormal TG and Non-HDL?

Nothing his LDL is GREAT

Just continue lifestyle management

Continue lifestyle management and add omega 3 fatty acids?

Treating Other Factors

Smoking – offer aides to assist with stopping

Metabolic Syndrome: Elevated TGs, low HDL, Blood Pressure, waist circumference

1. congratulate on all his accomplishments

2. decrease ETOH

3. weight loss

4. exercise

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21

Thank you for your

kind attention

We will now open the

floor to questions &

discussion