new horizons in dyslipidemia management in primary … pcsk9 activity inhibits intracellular...

New Horizons in

Dyslipidemia Management

in Primary Care

Copyright © 2017 by

Sea Courses Inc.

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Optimal control of dyslipidemia in

patients with CVD

Presenter Disclosure

Presenter – Peter Lin, MD

Relationships with commercial interests:

▪ Grants/Research Support: N/A

▪ Speakers Bureau/Honoraria: AstraZeneca, BMS, Takeda, Purdue, Boehringer Ingelheim, Bayer, Lilly, Amgen, Janssen, Forest Laboratories, J&J, Merck, Novartis, Pfizer, Servier, Sanofi, Abbott, Mylan

▪ Consulting Fees: AstraZeneca, Boerhinger Ingelheim, Bayer, Lilly, Merck, Sanofi, Amgen

▪ Other: N/A

Learning Objectives

Upon completion of this activity, participants will be able to:

▪ Discuss the role of LDL-C lowering in cardiovascular risk reduction with

emphasis on the results of recently completed clinical trials

▪ Evaluate recommendations for lipid lowering agents beyond or in addition to

statin therapy for patients with atherosclerotic cardiovascular disease

▪ Explain the mechanism of action of proprotein convertase subtilisin/kexin type

9 (PCSK9) inhibitors and apply the latest clinical data to patient management

strategies

▪ Apply best guideline practice recommendations into routine clinical practice

based on specific patient characteristics

Clot

Cholesterol

Blood Pressure

History of Statin Development 70s

Dr. Akira Endo - Sankyo

• 70s drug companies focus on antibiotics

• 1971 Funghi research project started

– ML 236 B potent inhibitor of HMG Co A reductase

HeFH

Stroke

PAD

Searching for more patients to protect with Statins MI

Where did we get our LDL-C Targets?

Rx - Drug group

Pl - Placebo group

Adapted from Kastelein JJ. Atherosclerosis 1999;143(Suppl 1):S17–S21Heart Protection Study Collaborative Group. Lancet 2002;360:7–22

4S-Pl

4S-RxLipid-Pl

LIPID-Rx

CARE-Pl

CARE-Rx

25

1.3(50)

Percen

t w

ith

CH

D e

ven

t

HPS-Rx

HPS-Pl

1.8(70)

2.3(90)

2.84(110)

3.36(130)

3.87(150)

4.39(170)

4.91(190)

5.43(210)

20

15

10

5

0 End of study LDL-Cmmol/L(mg/dL)

2.5(100)

Target LDL-C 2.5 (100 mg/dL)

Rx - Drug group

Pl - Placebo group

4S-Pl

4S-RxLipid-Pl

LIPID-Rx

CARE-Pl

CARE-Rx

25

1.3(50)

HPS-Rx

HPS-Pl

1.8(70)

2.3(90)

2.84(110)

3.36(130)

3.87(150)

4.39(170)

4.91(190)

5.43(210)

20

15

10

5

0 End of study LDL-Cmmol/L(mg/dL)

A 10mg

Adapted from Kastelein JJ. Atherosclerosis 1999;143(Suppl 1):S17–S21Heart Protection Study Collaborative Group. Lancet 2002;360:7–22

Percen

t w

ith

CH

D e

ven

t

A 80mg

1.8(70)

Where did we get our LDL-C Targets?

Target LDL-C 1.8 (70 mg/dL)

Residual Risk

*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

HR = 0.78 (95% CI 0.69, 0.89)

P=0.0002

Pro

port

ion o

f patients

experiencin

g m

ajo

r CV e

vent

atorvastatin 10 mg

atorvastatin 80 mg

0.14

Time (years)

0.08

0.12

0.04

0.10

0.06

0.02

0

LaRosa JC, et al. N Engl J Med. 2005;352:1425–35

0 1 2 3 4 5 6

Residual

Risk

Residual Risk

In the Presence of PCSK9, the LDL-R Is Degraded and Does Not Cycle Back to Cell Surface

Qian YW, et al. J Lipid Res. 2007;48:1488-1498; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

Serum LDL-Cholesterol Binds to LDL-Receptors. Following Internalization, LDL is Degraded and the Receptor Recycled

LDL

LDL-R

Endocytosis

LDL-R

Recycling Endosome

LDL Degradation

LDL

LDL-R

Endocytosis

Endosome

PCSK9

PCSK9

Self-procession

Hepatocyte

Plasma

© 2013 Amgen Canada Inc. All rights reserved.

Golgi

Apparatus

Endoplasmic

Reticulum

(ER)NucleusLDL, LDL-R and

PCSK9 Degradation

Distribution of Plasma LDL Cholesterol Levels (Panel A) and Incidence of Coronary Heart Disease (Panel B) among Black Subjects, According to the Presence or Absence of a

PCSK9142X or PCSK9679X Allele

Cohen, J. et al. N Engl J Med 2006;354:1264-1272

Blocking PCSK9 Activity Inhibits Intracellular Degradation of LDL-R

Qian YW, et al. J Lipid Res. 2007;48:1488-1498; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

Monoclonal Antibody binds to PCSK9 and inhibits Binding to the LDL-Receptor

PCSK9

Self-procession

PCSK9 mAb

LDL-R

Endocytosis

Endosome

LDL

Degradation

LDL-R

Recycling

Lysosome

LDL

Hepatocyte

Plasma

© 2013 Amgen Canada Inc. All rights reserved.

Golgi

Apparatus

Endoplasmic

Reticulum

(ER)Nucleus

PCSK9 Inhibitors: Targeted Therapy

Even Maximal Statin Therapy May Not Be Sufficient

In Achieving LDL-C Target

*As per Canadian Product Monographs

1. Crestor (rosuvastatin) Product Monograph. AstraZeneca. April 21, 2015.

2. Lipitor (atorvastatin) Product Monograph. Pfizer. Feb 18, 2016.

3. Pravachol (pravastatin) Product Monograph Bristol-Myers Squibb Canada. Nov 30, 2015.

4. Mevacor (lovastatin) Product Monograph. Merck. Jul. 24, 2012.

5. Zocor (simvastatin) Product Monograph. Merck. Dec 10, 2014.

6. Lescol (fluvastatin) Product Monograph. Novartis. Aug. 26, 2016.

7. Adapted from CURVES Investigators. Am J Cardiol. 1998;81:582-587.

0% 10% 20% 30% 40% 50% 60%

Atorvastatin 10 mg 20 mg 40 mg

Simvastatin 10 mg 20 mg 40 mg

Pravastatin 10 mg 20 mg 40 mg

Lovastatin 20 mg 40 mg 80 mg

Fluvastatin 20 mg 40 mg

Rosuvastatin 10 mg 20 mg5 mg 10 mg 20 mg 40 mg

80 mg

Doubling the statin dose results in only 6% LDL-C reduction

PCSK9Expression

LDL-RExpression

Statin Influence on LDL-C Metabolism plus LDL-R and PCSK9

Acetyl-CoA + acetoacetyl-CoA

HMG-CoAreductase

Plasma

NucleusEndoplasmic

Reticulum (ER)

Hepatocyte

SREBPActivation

LDL-RPCSK9Protein

LDL Proteinat Cell Surface

LDL

PCSK9 Secretion

Hepatocyte Cholesterol

Content

HMG-CoA

Intracellular

Cholesterol

Biosynthesis

STATIN

PCSK9 and Statin Therapy

* P < 0.05 versus baseline and placebo baseline and endpoint

1. Amgen, data on file.

2. Careskey HE, Davis RA, et al. J Lipid Res. 2008;49:394–398.

This mechanism may explain the limitation in LDL lowering by statins

and why doubling the dose, only results in 6% further LDL reduction

25

50

75

Baseline Endpoint

Placebo Atorvastatin 40 mg

*

Baseline Endpoint

PC

SK

9 (

mg/m

L)

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg†p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg

–60

–50

–40

–30

–20

–10

0

Dose, mg (log scale)

10 20 40 80

X

‡

Ch

an

ge in

LD

L-C

from

b

aseli

ne (

%)

n=648

n=634*

X

X

X

X

n=473

n=485

†

LDL-C Efficacy Across the Dose RangeThe STELLAR Study

Adapted from Jones P et al. Am J Cardiol 2003; 92: 152–160

X

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg†p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg

–60

–50

–40

–30

–20

–10

0

Dose, mg (log scale)

10 20 40 80

X

‡

Ch

an

ge in

LD

L-C

from

b

aseli

ne (

%)

n=634*

n=473†

LDL-C Efficacy Across the Dose RangeThe STELLAR Study

Adapted from Jones P et al. Am J Cardiol 2003; 92: 152–160

X

8 X

PROFICIO

Program to

Reduce LDL-C and

Cardiovascular

Outcomes

Following

Inhibition of

PCSK9

In Different

Populations

(Latin): To advance ;To make progress

Evolocumab Clinical Program: PROFICIO

Reduce LDL-C

(FH, ASCVD, Intolerant)

CV EventsAtherosclerosis

PROFICIO Addresses Key Scientific Questions for Evolocumab

Question Description Study

What is the safety/efficacy of

evolocumab alone?

What is the safety/efficacy with statins?Combination

therapyLAPLACE-1/-2

Does AMG 145 work in patients with

LDLR mutations?


mutations in both LDLR alleles?

HoFH/

severe FHTESLA/ TAUSSIG

What is the safety/efficacy in statin-

intolerant patients?

What is the long-term safety/efficacy?Long-term

effectDESCARTES, OSLER-1/-2

Does LDL-C reduction via evolocumab

slow or reverse atherosclerosis?


impact CV outcomes?CV outcomes FOURIER




evolocumab alone?Monotherapy


therapy


LDLR mutations?HeFH



HoFH/

severe FH



Statin-

intolerant


effect


slow or reverse atherosclerosis?IVUS


impact CV outcomes?CV outcomes




evolocumab alone?Monotherapy MENDEL-1/-2


therapyLAPLACE-1/-2


LDLR mutations?HeFH RUTHERFORD-1/-2



HoFH/

severe FHTESLA/ TAUSSIG



Statin-

intolerantGAUSS-1/-2/-3


effectDESCARTES, OSLER-1/-2


slow or reverse atherosclerosis?IVUS GLAGOV


impact CV outcomes?CV outcomes FOURIER

Evolocumab Clinical Program: PROFICIO

Reduce LDL-C

(FH, ASCVD, Intolerant)

CV Events

Fourier TrialAtherosclerosis

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

2.37 mmol/L

FOURIER: Median LDL-C Levels Over

Time: All Patients

LDL-C was significantly reduced in the evolocumab group (median: 0.78 mmol/L) including 42% who

achieved levels ≤ 0.65 mmol/L vs < 0.1% in the placebo group

Data shown are median values with 95% confidence intervals in the two arms; ITT.

Sabatine MS, et al . NEJM. [published online ahead of print March 17, 2017]. doi: 10.1056/NEJMoa1615664

13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 79013,779Placebo13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 76813,784Evolocumab

No. at risk

40 12 24 36 48 60 72 84 96 108 120 132 144 156 168

LD

L C

ho

lest

ero

l (m

mo

l/L)

Weeks

59% mean reduction (95% CI 58-60), P < 0.001

Absolute reduction: 1.45 mmol/L (95% CI 1.43-1.47)

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

2.6

Placebo

Median 2.38 mmol/L

Evolocumab

Median 0.78 mmol/L

Screening

29

Primary Efficacy Outcome Measure:

Major Cardiovascular Events*

*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

HR = 0.78 (95% CI 0.69, 0.89)

P=0.0002

Pro

po

rtio

n o

f p

ati

en

ts e

xp

eri

en

cin

g

majo

r card

iovascu

lar

even

t

0

0.05

0.10

0.15

Atorvastatin 10 mg

Atorvastatin 80 mg

0 1 2 3 4 5 6

Time (years)

LaRosa JC, et al. N Eng J Med. 2005;352

RRR 22% ARR 2.2% NNT6 45

10.9 %

8.7 %

3.7

6.8

9.9

FOURIER:

Composite of CV Death, MI, or Stroke

HR 0.80 (95% CI 0.73 to 0.88); P < 0.001

No. at RiskPlaceboEvolocumab

Cu

mu

lati

ve In

cid

ence

(%

) Placebo + SOC

Evolocumab + SOC

Months

0

2

4

6

8

9

10

11

0 6 1812 24 3630

1

3

5

7

13,780 13,449 13,142 12,288 7,944 3,893 73113,784 13,501 13,241 12,456 8,094 3,935 724

3.1

5.5

7.9

CV = Cardiovascular; MI = Myocardial infarction; HR = Hazard ratio

Sabatine MS, et al . NEJM. [published online ahead of print March 17, 2017]. doi: 10.1056/NEJMoa1615664

Key Secondary Endpoint

RRR 20 % ARR 2.0 % NNT3 50

RRR 22% ARR 2.2% NNT6 45

TNT

FOURIER

RRR 22% ARR 2.2% NNT6 45

RRR 20% ARR 2% NNT3 50

6 YEARS

3 YEARS

Primary Endpoint — ITT

Simva — 34.7%

2742 events

EZ/Simva — 32.7%

2572 events

Cardiovascular death, MI, documented unstable angina requiring

rehospitalization, coronary revascularization (≥30 days), or stroke

7-year event rates

6.4% RRR

2% ARR

NNT7 50

Total Mortality: 4S

0.85

0.80

0.00

0.0

1.00

0.95

0.90

Pro

port

ion a

live

Years since randomisation

placebo

simvastatin

64321 5

Log rank p=0.0003

4S Group. Lancet 1994;344:1383–1389.

Screening

35

Mortality

No. of patients (%)

Atorvastatin 10 mg

(n=5006)

Atorvastatin 80 mg

(n=4995)

All-cause mortality 282 (5.6) 284 (5.7)

Cardiovascular

CHD death

Stroke death

Hemorrhagic stroke death

155 (3.1)

127 (2.5)

8 (0.2)

2 (0)

126 (2.5)

101 (2.0)

7 (0.1)

3 (0.1)

Noncardiovascular

Cancer

Trauma

Other

127 (2.5)

75 (1.5)

9 (0.2)

43 (0.9)

158 (3.2)

85 (1.7)

15 (0.3)

58 (1.2)

No single cause of death (by body system, or pathological process) and no single cancer

type drove the non-significant difference in all-cause mortality between groups

No statistically significant differences were observed between treatment groups

for any cause of deathLaRosa JC, et al. N Eng J Med. 2005;352

36

0

1

2

3

4

5

6

7

8

9

10

4S S20 4S

PL

CARE

P40

CARE

PL

LIPID

P40

LIPID

PL

HPS

S40

HPS PL TNT

A80

TNT

A10

IDEAL

A80

IDEAL

S20

Mo

rtal

ity

(%)

non-CVCV

Mortality in Statin Secondary

Prevention Trials

Against placebo Statin vs Statin

HR Simva* EZ/Simva* p-value

All-cause death 0.99 15.3 15.4 0.782

CVD 1.00 6.8 6.9 0.997

CHD 0.96 5.8 5.7 0.499

MI 0.87 14.8 13.1 0.002

Stroke 0.86 4.8 4.2 0.052

Ischemic stroke 0.79 4.1 3.4 0.008

Cor revasc ≥ 30d 0.95 23.4 21.8 0.107

UA 1.06 1.9 2.1 0.618

CVD/MI/stroke 0.90 22.2 20.4 0.003

Ezetimibe/Simva

Better

Simva

Better

Individual Cardiovascular Endpoints and CVD/MI/Stroke

0.6 1.0 1.4*7-year

event rates (%)

Fourier Trial

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School


True Atherosclerotic Disease

Are they all the sme?

PCSK9 Inhibitors

PCSK9 = Proprotein Convertase Subtilisin Kexin Type 9

▪ PCSK9 inhibitors (PCSK9i)

−Evolocumab

−Alirocumab

−Bococizumab

Terminology of Monoclonal Antibodies

1. Weiner LM. J Immunother. 2006;29:1-9; 2. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23;

3. Lonberg N. Nat Biotechnol. 2005;23:1117-1125; 4. Gerber DE. Am Fam Physician. 2008;77:311-319.

Mouse

(0% human)

Human

(100% human)

Humanized

(> 90% human)

Chimeric

(65% human)

-umab-zumab-ximab-omabGeneric suffix:

Source (% human protein)

High LowPotential for immunogenicity

PCSK9 Inhibitors

* Investigational product, not approved by Health Canada

PCSK9 = Proprotein Convertase Subtilisin Kexin Type 9

▪ PCSK9 inhibitors (PCSK9i)

−Evolocumab

−Alirocumab

−Bococizumab*

Anti-PCSK9 Antibodies

FDA Briefing Document Praluent (alirocumab) injection June 9, 2015;

FDA Briefing Document Evolocumab June 10, 2015.

Evolocumab

• Overall incidence of anti-

evolocumab binding antibodies

after at least one dose of

evolocumab was 0.3% (13 of 4915)

• Responses were of low-titer, most

were transient

• No neutralizing antibodies have

been detected

• No impact of binding antibodies on

safety, pharmacokinetics, or

pharmacodynamics

Alirocumab

• Observed in 4.8% of patients

following alirocumab treatment vs.

0.6% of patients in control group

• Most responses were of low-titer,

non-neutralizing, and/or transient

• higher incidence of local injection

site reactions (10.2% vs 5.9% if no

antibodies)

• Neutralizing antibodies were

reported in 1.2% of patients treated

with alirocumab

The detection of anti-drug binding antibody formation is highly dependent on the sensitivity and specificity

of the assay. Comparison of the incidence of antibodies to evolocumab with incidence of antibodies to

other products may be misleading.

FAQ

PCSK9 Inhibitor Ongoing OUTCOME Studies

ACS: acute coronary syndrome; CHD: coronary heart disease; CV: cardiovascular; LLT: lipid lowering therapy; MI: myocardial infarction

clinicaltrials.gov accessed August 31, 2015; Swartz GG, et al. Am Heart J. 2014;168(5):682-9.

Evolocumab

FOURIEROutcome Study (5 yrs), N=27 500

• Inclusion criteria: High-risk 2º

prevention population with

LDL-C ≥ 1.8 mmol/L or non-HDL ≥ 2.6

mmol/L

• Evolocumab 140mg Q2W or 420mg

QM + optimal LLT

• 1º endpoint: Time to CV death, MI,

hospitalization for unstable angina,

stroke, or coronary revascularization

Alirocumab

ODYSSEY OutcomesOutcome Study (64 months), N=18 000

• Inclusion criteria: Hospitalized for

ACS within past 1-12 months

• LDL≥ 1.8mmol/L

• Alirocumab 75mg Q2W, up-titrate to

150mg Q2W as needed

• 1º endpoint: Time to CHD death, any

non-fatal MI, fatal and non-fatal

ischemic stroke, unstable angina

requiring hospitalization

Distribution of Plasma LDL Cholesterol Levels (Panel A) and Incidence of Coronary Heart Disease (Panel B) among Black Subjects, According to the Presence or Absence of a

PCSK9142X or PCSK9679X Allele

Cohen, J. et al. N Engl J Med 2006;354:1264-1272

Meta-analyses suggest earlier, prolonged exposure to lower LDL-C is associated with greater reduction in the risk of CHD

CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol

Ference BA, et al. J Am Coll Cardiol. 2012;60:2631-9.

Lower LDL-C

1.0 mmol/L

(38.7 mg/dl)

0.5 mmol/L

(19.3 mg/dl)

0.25 mmol/L

(9.7 mg/dl)

0.125 mmol/L

(4.8 mg/dl)

Sample

Size (N)

Genetic Studies

Statin Trials

Genetic Studies

Statin Trials

Genetic Studies

Statin Trials

Genetic Studies

Statin Trials

312,321

169,138

312,321

169,138

312,321

169,138

312,321

169,138

Meta-Analysis

0.46 (0.41-0.51)

0.76 (0.74-0.78)

0.67 (0.64-0.72)

0.87 (0.86-0.88)

0.82 (0.80-0.85)

0.93 (0.93-0.94)

0.91 (0.89-0.92)

0.96 (0.96-0.97)

8.4x10-19

8.4x10-19

8.4x10-19

8.4x10-19

OR (95% CI) p (difference)

0.40 0.50 0.60 0.70 0.80 0.90 1.0

3.1

1.2

53% RRR1.2% ARRNNT1 83

PCSK9 Inhibitors and Their Current Indications

ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low density lipoprotein cholesterol;

PCSK9, proprotein convertase subtilisin kexin type 9.

1. Praluent Canadian Product Monograph, April 11, 2016; 2. IRepatha Canadian Product Monograph, June 29 2016;

▪ Alirocumab1

o Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with

• HeFH

• Clinical ASCVD

▪ Evolocumab2

o Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with

• HeFH

• Clinical ASCVD

o Adjunct to diet and other LDL-C lowering therapies in persons ≥12 years with HoFH who require additional LDL-C lowering

PCSK9 Inhibitors and Their Indications

ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low density lipoprotein cholesterol;

PCSK9, proprotein convertase subtilisin kexin type 9.

1. Praluent Canadian Product Monograph, April 11, 2016; 2. IRepatha Canadian Product Monograph, June 29 2016;

▪ Alirocumab1

– Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with

• HeFH

• Clinical ASCVD

▪ Evolocumab2

– Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with

• HeFH

• Clinical ASCVD

– Adjunct to diet and other LDL-C lowering therapies in persons ≥12 years with HoFH who require additional LDL-C lowering

Recommendations for PCSK9i in

FH and ASCVD

• We suggest the use of PCSK9 inhibitors (evolocumab, alirocumab) to lower LDL-C for

patients with heterozygous familial hypercholesterolemia whose LDL-C remains

above target despite maximally tolerated statin therapy (Conditional recommendation, moderate quality

evidence)

• We suggest that PCSK9 inhibitors be considered to lower LDL-C for patients with

atherosclerotic cardiovascular disease in those not at LDL-C goal despite maximally

tolerated statin +/- ezetimibe therapy (Conditional recommendation, moderate quality evidence)

• We suggest that evolocumab be added to background therapy in patients with

homozygous familial hypercholesterolemia and continued if LDL-C lowering is

documented (Conditional recommendation, moderate quality evidence)

Anderson et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of

Cardiovascular Disease in the Adult Canadian Journal of Cardiology 2016;32:1263-1282

Maximize Statin First

Then

PCSK9

Inhibitors

new horizons in dyslipidemia management in primary … pcsk9 activity inhibits intracellular...

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