Thinkings on Lipids: Genetics, apoB, HDL, and PCSK9...

“Thinkings” on Lipids:

Genetics, apoB, HDL, and

PCSK9 inhibition

Daniel J Rader, MD

Chair, Department of Genetics

Perelman School of Medicine

University of Pennsylvania

Human genetics is

leading to

identification of new

pathways and to

smarter and faster

development of new

medicines

B

HDL

A-I

TG, CECE

?

LDL

TG-rich

lipoproteins

Lp(a)

Lipoproteins and CAD

ApoB-lipoproteins are biomarkers of CAD risk

LDL cholesterol

Triglycerides

Lipoprotein(a)

Clinical trait Lipoprotein classAssociation with CAD

BTG, CE

ApoB-containing lipoproteins are

causally related to coronary disease

LDL

TG-rich

lipoproteins

Lp(a)

Trait LDL TRLs Lp(a)

Epidemiology ✓ ✓ ✓Human Genetics ✓ ✓ ✓

Randomized Trials ✓ ? ?

Evidence for the causality of apoB-

lipoproteins to CAD risk

Inherited Syndromes of Extremes

of LDL-C: Story of PCSK9F

req

uen

cy (

%)

LDL-C

Gain of function

mutations in PCSK9

Loss of function

mutations in PCSK9

LDL Receptor Function and Life Cycle

8

8

For illustration purposes only

The Role of PCSK9 in the Regulation of LDL Receptor Expression

9

9

For illustration purposes only

Impact of an PCSK9 mAbon LDL Receptor Expression

10

10

For illustration purposes only

mAb

PCSK9 Inhibitors• Alirocumab and Evolocumab• SQ injection biweekly or monthly• Indications:

– Patients with heterozygous familial hypercholesterolemia on maximally tolerated statin therapy with inadequate plasma LDL levels

– Patients with a history of CHD with inadequate plasma LDL levels

• Cardiovascular outcome trials ongoing

Lipoproteins and Coronary Disease

Remaining unmet medical needs in treatment of dyslipidemia

BTG

Triglyceride-rich lipoproteins are

causally related to coronary disease

TG-rich

lipoproteins

B TG

LPL

CE

BCE

ApoC-III inhibits LPL and

TG-rich remnant uptake

apoC-III

B TG

LPL

CE

BCE

ApoC-III as a novel therapeutic target

apoC-III

Inhibitor

X

B TG

LPL

CE

BCE

Lipoprotein lipase is a nodal pathway for

new therapeutic development

apoC-III

ANGPTL4

ANGPTL3

apoA-VANGPTL8

HDL-C does not appear to be causally

associated with CAD

HDL

A-I

X

CE

CETP inhibition raises HDL-C levels…

but doesn’t reduce CV events

A-I

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

FCABCA1

ABCG1FC

SR-BI

CEB

LDLR

VLDL/LDL

CETP

TG

XCETP inhibitor

ApoA-I promotes macrophage cholesterol

efflux and reverse cholesterol transport

A-I

Liver

CECE

FCLCATFC

Bile

SR-BI

A-I

Macrophage

ABCA1

apoA-I

HDL

B

HDL

A-I

TG, CECE

?

LDL

TG-rich

lipoproteins

Lp(a)

Genetics, Lipoproteins and CAD:

Implications for new therapies