Lipoprotein Management:the role of genes and drugs

W. Virgil Brown, MD

Emory University

CAD

Stroke

Mortality from ASCVD In USA(2000 through 2011)

AHA Heart Disease and Stroke Statistics – 2015 (Circulation 01-27-15)

National Center for Health Statistics

CV Death

CAD

Stroke

33%

42%

38%

Mortality from ASCVD In USA(2000 through 2011)

AHA Heart Disease and Stroke Statistics – 2015 (Circulation 01-27-15)

National Center for Health Statistics

CV Death

New HoFH Treatment Target: Apolipoprotein B-100 Synthesis

4

4

Cholesterol

Apo B Triglyceride

VLDL

VLDLIDL

LDL1LDL2 LDL3

Lp(a)

Apo(a)

4

Lipoprotein Transport from LiverVLDL to LDL

Remnants of VLDL due to LPL action

Spectrum of LDL-C Levels in the USA

300-400 400---------------------------1000+0-100 100-200 200-300

mg/dL

HoFH patientsRange of treated LDL-C levels

typically reported in the literature1

Desirable

Overlap zone

LDL-C target treatment goals<100 mg/dL (<2.6 mmol/L) for patients at high risk of CVD

<70 mg/dL (<1.8 mmol/L) for patients at very high risk of CVD

HeterozygousFamilial Hyper-

Cholesterolemia

Prevalence in USA: 1,500,000 1,000

Treatable

Genetic Diagnosis of Severe FHSecond Genes involved in individual cases.

Genes involved Prevalence

• LDL receptor common (>70%)

• Apolipoprotein B uncommon (<5%)

• PCSK-9* rare (<1%)

• LDLRAP-1** very rare

* proprotein convertase subtilisin/kexin 9

**low density lipoprotein receptor adaptor protein 1

Liver cell

Circulation

LDL particles

Apo B

Main ligand, binding LDL

particle to receptor

LDL receptor

LDLRAP1 (ARH defect)

Mediates LDL-R internalization via clathrin-coated pitsLDL-R returns to plasma membrane

Plasma Clearance of LDL by Liver

Binds to LDL transports to coated pit.

Synthesis driven by reduced cell cholesterol

Liver cell

Circulation

LDL particles

Apo B

Main ligand, binding LDL

particle to receptor

LDL receptor

LDLRAP1 (ARH defect)

Mediates LDL-R internalization via clathrin-coated pitsLDL-R returns to plasma membranePCSK9

Promotes LDL receptor

degradation

Plasma Clearance of LDL by Liver

Binds to LDL transports to coated pit.

Major Gene Defects in LDL Metabolism

• Very high LDL-C (i.e. >400 mg/dL) is usually associated with more than one genetic abnormality. The same defect on both alleles is Homozygous Hypercholesterolemia.

• One defective LDL receptor gene is present in approximately 95% of patients.

• The second dysfunctional gene may not be in the LDL receptor sequence but in the Apo-B, PCSK-9 sequence or in an undefined sequence in approximately 20% of patients.

Physical Signs of Severe FH

From:

Familial Hypercholesterolemia: A model of care for Australia

Proteins and Genes of Importance

LDL-receptor: Pulls LDL into the liver - degrades it .

HMG-CoA red: Regulates cholesterol synthesis

in liver and other cells.

NPC1 L1: Cholesterol transporter from

intestinal lumen into cells.

PCSK9: Down regulates LDL-receptors.

Apo B: Essential for VLDL production.

Apo CIII: Controls lipase action that removes triglyceride from VLDL.

HoFH Treatment with Statin Adjuncts

Newer therapies

Goldberg AC et al. J Clin Lipidol. 2011;5(3 Suppl):S1-8.Hopkins PN, Toth PP, Ballantyne CM, Rader DJ; National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S9-17. Robinson JG, Goldberg AC. J Clin Lipidol. 2011;5(3 Suppl):S18-S29.

12

Bile Acid Sequestrants

Lomitapide* Niacin

Mipomersen* Ezetimibe

Statin therapy, maximum dose

if tolerated

LDL apheresis

Statins Introduced1987

1. Lovastatin2. Pravastatin3. Simvastatin4. Fluvastatin5. Rosuvastatin6. Atorvastatin7. Pitavastatin

Primary prevention trials

Secondary prevention trials

50 70 110 130 150 170 19090 210

Pat

ien

ts w

ith

CH

D e

ven

t (%

)

LDL-cholesterol

CARE-Rx

4S-Rx

LIPID-PL

4S-PL

CARE-PL

LIPID-Rx

AFCAPS-Rx

WOSCOPS-Rx

WOSCOPS-PL

AFCAPS-PL

25

20

15

10

5

0

ASCOT-PL

ASCOT-Rx

HPS-Rx

HPS-PL

HPS

LRC-PLLRC-Rx

POSCH-PL

POSCH-Rx

Non-statin trialsStatin trials

(mg/dL)

1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)

TNT-80A

TNT-10A

Effect of Lowering LDL-C on CHD Events (1998)

Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q. O’Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142-2146.

The TARGET Lipoproteins (Importance of Monitoring)

1. Elevated cholesterolLDL-C, LDL-p, apoB

2. Elevated VLDL triglycerides non-HDL-C, apoB

How do we reduce TG?Is beneficial?

Is it safe?

New HoFH Treatment Target: Apolipoprotein B-100 Synthesis

1717

Cholesterol

Apo B Triglyceride

VLDL

VLDLIDL

LDL1LDL2 LDL3

Lp(a)

Apo(a)

17

Remnants of LPL

Mipomersen [an injectable ASO] Targets ApoB mRNACholesterol

Apo B Triglyceride

VLDL

VLDLIDL

LDL1LDL2 LDL3

Lp(a)

Apo(a)

Mipomersen

ASO - antisense oligonucleotide

Decreased number of VLDL Particles

ASO binds and induces mRNA degradation

LDL-C Lowering with Mipomersen in HoFH

-24.70%

-3.30%

Percent Change of LDL-C (mg/dL) from Baseline

26 weeks of therapy (200mg/wk)

PlaceboMipomersen

Raal FJ et al. Lancet. 2010;375(9719):998-1006.19

HIGHLY VARIABLE

Mipomersen

Mechanism of Action:•Blocks ApoB synthesis

(via mRNA degradation)

• Reduces productionand secretion of VLDL

• Side effects include:injection-site reactions,

• Flu-like symptoms•myalgias and malaise

• Fatty liver ALT and AST elevations

Hussain M. J Lipid Res. 2003;44:22-32.

Microsomal Triglyceride Transfer Protein (MTP)

21

LYMPH

Lomitapide, Inhibiting MTP

Hussain M. J Lipid Res. 2003;44:22-32.

22

Lomitapide: Trial Results

-38%

-44%

-50%

Week 78

Week 56

Week 26

Percent Change of LDL-C from Baseline26, 56, and 78 weeks of therapy

Lomitapide

Raal FJ et al. Lancet. 2010;375(9719):998-1006.

Lomitapide

Mechanism :•Inhibits MTP•Reduces production and

secretion of chylomicronsand VLDL

Side effects include:nausea, diarrhea,abdominal pain, fatty liver and ALT and AST elevation.

LDL Apheresis: Adsorption of Apo-B–Containing Lipoproteins

25

Lp(a)a

• Severe hypercholesterolemia requires aggressive treatment

• Statin therapy is always 1st line for LDL-C lowering

• Traditional statin adjuncts:– Bile acid sequestrants– Ezetimibe– Niacin

• LDL Apheresis

-- Physical removal of plasma apoB lipoproteins –

• Two new medication classes (approved for HoFH only):– Microsomal triglyceride transfer protein (MTP) inhibitor—lomitapide– Apolipoprotein B (ApoB) ASO (antisense mRNA)—mipomersen

Exetimibe: Enhancing LDL receptor number by reducing

cholesterol absorption – inhibiting NPC1L1

Huff, MW ATVB 2006;26:2433-2438

Cannon CP, etal. N Engl J Med 2015; 372:2387-2397

Exetimibe: Enhancing LDL receptor number by reducing

cholesterol absorption – inhibiting NPC1L1

Huff, MW ATVB 2006;26:2433-2438

Cannon CP, etal. N Engl J Med 2015; 372:2387-2397

Humanized monoclonal antibodies specific for human PCSK9.

Adapted from Poirier S, Mayer G. Drug Des Devel Ther. 2013;7:1135-1148.

Gain-of-Function and Loss-of-Function PCSK9 Mutations: Mean LDL-C Levels

Gain-of-function mutations Loss-of-function mutations

• Caucasian woman, aged 32 years, with no measureable PCSK9 levels and an LDL-C of 14 mg/dL1

• African woman, aged 21 years, with no measureable PCSK9 levels and an LDL-C of 15 mg/dL2

• Caucasian male, aged 49 years, with no detectable PCSK9 levels and an LDL-C of 16 mg/dL3

• All three patients were otherwise healthy.1–3

1. Zhao Z et al. Am J Hum Genet. 2006;79(3):514-523. 2. Hooper AJ et al. Atherosclerosis.2007;193:445-448. 3. Cariou B et al. Arterioscler Thromb Vasc Biol. 2009;29:2191-2197.

Double Loss-of-Function PCSK9 Mutations: Case Reports (2009)

Glagov Trial:Change in LDL-Cholesterol During Treatment

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

0 8 16 24 32 40 48 56 64 72 80 88

LD

L-C

Ch

an

ge

fro

m B

ase

line

(m

g/d

L)

Study Week

Mean LDL-C 93.0 mg/dL

Mean LDL-C 36.6 mg/dL

Change from baseline 3.9%

Change from baseline -59.8%29 mg/dL

90 mg/dL

N = 423 on max tolerated statin

N = 423 on max tolerated Statin + evolocumab

140 mg Sub Q @ 2wk or420 mg sub Q @ 4wk intervals.

Nissen et al. AHA abst Sessions 2016Nichols SJ ..Nissen JAMA 2016 Nov 15.

Evolocumab vs placeboMean On-Treatment LDL-C vs. Change in PAV

IVUS baseline with repeat at 18 months

Change P

erc

ent A

thero

ma V

olu

me (

%)

On-Treatment LDL-C (mg/dL)

846 patients completed study

Duration of follow-up: 76 weeksMean patient age: 60 yearsPercentage female: 28%Percentage with diabetes: 21%

Nissen et al. AHA abst Sessions 2016

Nichols SJ ..Nissen JAMA 2016 Nov 15.

Fourier: MI, Stroke and CV Death

20 %

Proteins and Genes of Importance

LDL-receptor: Pulls LDL into the liver - degrades it .

HMG-CoA red: Regulates cholesterol synthesis

in liver and other cells.

NPC1 L1: Cholesterol transporter from

intestinal lumen into cells.

PCSK9: Down regulates LDL-receptors.

Apo B: Essential for VLDL production.

Apo CIII: Controls lipase action that removes triglyceride from VLDL.

VLDL Remnant

HTGL

LDL

Apo-CIII

Lipoprotein Lipase and Hepatic Triglyceride Lipase work in sequence to produce LDL particles from VLDL

Prolonged residence in the circulation

GWAS Studies of ApoCIIINHLBI Working Group Sequencing Project

NEJM 2014; 371:22 – 31)

1. Screened 110,970 individuals for apoCIII gene variants associated with low TG

2. Prevalence of at least one of these mutations was 1/150 participants.

3. Mean TG concentrations reduced by 39% and apoCIII concentration by 46% .

4. CAD disease prevalence was 40% lower in 498 carriers of any of these

mutations than the risk among 110,472 noncarriers .

5. Confirmed by Copenhagen Heart Study with very similar reduction in TG

concentrations and prevalence of vascular disease.

ASO treatment of Hypertriglyceridemia.1. Placebo versus weekly doses of Volasenorsen2. Triglycerides at baseline: 200 - 1400 mg/dL.3. Fifty seven patients randomized to : placebo, 100, 200, 300 mg/wk. Gaudet et.al. N Engl J Med 2015; 373:438-47.

Change in Triglycerides

Change in HDL-C

Gaudet et.al. N Engl J Med 2015; 373:438-47 (July 2015)

General Messages from Current Data

1. Drugs are needed to further reduce LDL and VLDL.

2. Reducing LDL is proven safe at levels below 50 mg/dL.

3. Pancreatitis in FCS can be prevented by enhancing clearance of chylomicrons with diabetes control, diet and current medications.

4. HDL cholesterol elevation is a marker of risk but not a target of any known therapy.

Thank you for your attention.

QUESTIONS?