FATS OF LIFE The Clash Of Guidelines

While our arteries are getting cl gged

Ahdy Wadie Helmy, MD, FACP Associate Professor of Medicine

IU School of Medicine- VA Medical Center

lineees

Lipoprotein Particles

NON-POLAR LIPID CORE

Cholesterol Ester

Triglyceride

POLAR SURFACE COAT

Phospholipid Free cholesterol

Apolipoprotein Apolipoprotein

Apolipoprotein

Atheroma

Liver Intestine

The Liver Secretes Apo B-100 Lipoproteins (VLDL) Into the Circulation

VLDL

Cholesterol Pool

Goldstein JL, Brown MS. Science. 2001;292:1310.

Peripheral Tissues

Hepatic Apo B-100

Blood

Liver Intestine

Apo B-100 Lipoproteins Carry Triglycerides, Cholesterol, and Cholesterol Esters into the Circulation

TG Lipoprotein

Lipase

LDL

lDL

TG VLDL

Atheroma

Peripheral Tissues

1. Goldstein JL, Brown MS. Science. 2001;292:1310.; 2. Shepherd J. Eur Heart J Suppl. 2001;3:E2.

Cholesterol Pool

D

Hepatic Apo B-100

Blood

12 mg//kg/d

VLVVVVVV4 hours

llllllIDL 1-2 hours

Liver Intestine Peripheral Tissues

The Liver Clears Apo B-100 Lipoproteins Via The LDL Receptor

LDL lDL

Hepatic Apo B-100

VLDL

LDLR

Atheroma 1. Kesanami YA et al. J Clin Invest. 1983;71:950.; 2. Goldstein JL, Brown MS. J Biol Chem. 1974;249(16):5153.; 3. Brown

MS, Goldstein JL. Proc Natl Acad Sci. 1974;71:788.; 4. Goldstein JL, Brown MS. Science. 2001;292:1310.; 5. Rudling MJ et al. Proc Natl Acad Sci. 1990;87:3469.

Cholesterol Pool

Blood

3.5 days

F a t D i g e s t i o n

I I

I I I I

I

I I I I I I

Fatty Acids + Lysophospholipid

Phospholipids

I I I

Triglycerides

Fatty Acids + Monoglycerides

I I

I I I I I

I I I TDietary

Cholesterol

Biliary Lipid Secretion

Sinusoidal Membrane

Blood Hepatocyte

Canalicular Membrane

Bile Salt

ABCG5/G8 Cholesterol

ABCB4 Phospholipid

ABCB11

Bile Lymph

Enterocyte

Intestinal Lumen

Cholesterol Absorption

Cholesteryl Ester

ACAT

Cholesterol ster

NPC1L1

ABCG5/G8

rolro

NN

oooloool

NPCNPCCCC1L1C1L1X

Intestinal Lumen

Enterocyte (Jejunum)

Lymph

Absorbed Cholesterol and Triglycerides are Packaged into Chylomicrons and Secreted into the Lymph

NPC1L1

Cholesterol Cholesterol Ester ACAT

2 Fatty Acid

Monoglyceride + DGAT

Triglyceride

Chylomicron

Apo B-48

ACAT: Acyl Co-A:Cholesterol AcylTransferase; DGAT: DiacylGlycerol AcylTransferase; MPT: Microsomal Triglyceride Transfer Protein

MTTP

ABCG5/8

1. Cohen DE, Armstrong EJ. In: Principles of Pharmacology 2nd ed. Golan et al eds. Philadelphia: Lippincott, Williams and Wilkins; 2007.; 2. Wang. Ann Rev Physiol.2007;69:221.; 3. Berge, et al. 2000. Science 290:1771.; 4. Lee, et al. 2001. Nat. Genet. 27:79.; 5. Yu et al. J Clin Invest 2002; 110:671.

Free Cholesterol

Triglyceride glyceri

Lipase

Atheroma

Liver

Most Absorbed Cholesterol is Delivered to the Liver via Intestinally Derived (Chylomicron Remnants)

Cholesterol Pool (Micelles)

NPC1L1

Intestinal Apo B-48

Cholesterol Pool

Free Chol

75% Biliary chol

25% Dietary chol

Intestine

Lipoprotein Lipase

TG

TG

Bile Acids

1. Rohlman et al. J Clin Invest. 1998;101:689.; 2. Yu, Cooper. Front Biosci. 2001;6:332.; 3. Shepherd Eur Heart J. 2001;E2.

CMR

Chylomicron 1 hour

Peripheral Tissues

Blood

Atheroma

Liver Intestine

Cholesterol Pool

LDL-C Accounts for About 2/3 of the Cholesterol in Circulating Lipoproteins and Can Penetrate the Arterial Subendothelium

Bile Acids Cholesterol Pool (Micelles)

25% Dietary chol

NPC1L1

Hepatic Apo B-100

Intestinal Apo B-48

Free Chol

1. Goldstein, Brown. Science. 2001;292:1310.; 2.Quintao et al. J Lipid Res. 1971;12:233.

75% Biliary chol

CMR

CM

VLDL

lDL

LDL

00

Peripheral Tissues

Blood

Development of an Atheroma

ß-VLDL=beta very low-density lipoprotein; Lp(a)=lipoprotein (a); VCAM-1=vascular cell adhesion molecule-1; ICAM-1=intercellular adhesion molecule-1; MCP-1=monocyte chemoattractant protein-1; CCR-2=specific receptor present on the surface of monocytes; oxLDL=oxidized low density lipoprotein; MMP=matrix metalloproteinases; GM-CSF=granulocyte macrophage-colony stimulating factor; SR-A=macrophage scavenger receptor class A. Adapted with permission from Fan J et al. J Atheroscler Thromb. 2003;10:63–71.

Monocyte

Induction of adhesion molecules and chemotaxis

Adhesion VCAM-1 ICAM-1 P-selectin E-selectin

Migration MCP-1 CCR-2 oxLDL

oxidation

Cytokines MMPs Endothelin-1

Endothelial cells

Intim

a Lu

men

Induction of adhesionmolecules and chemotaxis

ICICICIC MMMMMMMMMMMMMMAMAMAMAMCACACACA 111111PPPPPP-- eelle tictecses nnnelectieelleectiectecsesess nnnEEEE- electielectisesess nn

MCMCMCPPPPPPPPP---------111111CCRRRRRCCRRRRR--222222oxLLDDLL

oxox

CytokinesMMPsEndothelin 1

EndoEndoEndothelthelthelialialialcells

Intim

aLLL

CD36 SR-A

Differentiation (GM-CSF)

Macrophage Foam cell

T lymphocyte

CD40 IFN-gamma

molemolemoleculeculecules ans ans and chd chd chemotemotemotaxisaxisaxisxxxidationxxxidation

EndoEndoEndothelthelthelininin-111

CD36SR-A

Differentiation(GM-CSF)

MacrophageFoam cell

T lymphoc

CD40IFN-ga

LDL-C, β-VLDL, Lp(a)

Treatment of Hyperlipidemia

High LDL-C

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice: Statin Mechanism: Promote LDL Clearance

Statins: Mechanism of Action

LDL receptor–mediated hepatic uptake of LDL and VLDL remnants

Serum VLDL Rs Serum VLDDL RsL RRL RLSerum LDL-C

Cholesterol synthesis

LDL receptor (B–E receptor) synthesis

Intracellular Cholesterol

Apo B

Apo E

Apo B

Systemic Circulation Hepatocyte Reduce hepatic cholesterol synthesis, lowering intracellular

cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic

circulation.

LDL

Serum IDL

syntssyyntynt

LL((( rrr

p

Aprrrrrrrrrrrrr))))))))))))))))r)rr)r)))))))ApAp

Ap

A

AAAAAAAAAAVLDLR

VLDL

Extending and confirming benefit of LDL-C lowering beyond current guidelines

LaRosa JC et al. N Engl J Med. 2005;352.

0

30

5

10

15

20

25

Statin

Placebo

HPS CARE E

LIPID

HPS

CARE

LIPID

4S

4S

LDL cholesterol (mg/dL)

00 210 190 170

llllll150

ttt130

hh llll110

LLDLDDDLDLDLDL90 70

TNT (80 mg atorvastatin)

HPPSSHPPSSTNT (10 mg atorvastatin)

55111Event (%)

beyond current guidelinesesThe Statin Decade: For LDL: “Is Lower

Better??”

(%%%))(%%%))

55

But, how low should we go?

HPHHHHHHPSS

TNTTTT

wwwww w ooooooo?o?o?

Changes to NCEP /ATP III LDL-C Goals

Risk Category Publication LDL-C Goal Highest-risk patient •Known CVD •Diabetes plus ≥ 1 additional major CVD risk factora

ATP III <100 mg/dl (2.5 mmol/L)

Modification Optional goal of <70 mg/dl (1.8 mmol/L)

Moderately High-risk patients •No diabetes or known CVD but ≥ 2 major CVD risk factorsa

•Diabetes but no other major CVD risk factorsa

ATP III <130 mg/dl (3.4 mmol/L)

Modification Optional goal of <100 mg/dl (2.5 mmol/L)

for 10%–20% risk group

Adapted from Grundy SM et al Circulation 2004;110:227–239; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486–2497.

But Patients on statins will have heart attacks too !!

4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.

6 Downs JR, et al. JAMA. 1998;279:1615-1622.

14S Group. Lancet. 1994;344:1383-1389. 2LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

3Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

0

10

20

30

40

N 4444 4159 20 536 6595 6605 9014

Secondary High Risk Primary

1

2

3

1

2

3

Patie

nts

Expe

rienc

ing

M

ajor

CH

D E

vent

s, %

4S1 LIPID2 CARE3 HPS4 WOSCOPS5

660005660005

AFCAPS/ TexCAPS6

Placebo aceboebboStatin

19.4

12.3 10.2 8.7

5.5 6.8

28.0

12111115.9

1111113.2

8888811.8

57.9

10.9

CHD events occur in patients treated with statins

19

HDL LDL IDL VLDL Chylomicron

Remnant

BAD GOOD

Non–HDL-C = Total cholesterol − HDL-C

11119919999

Executive Summary of the Third Report of NCEP ATP III. JAMA. 2001;285:2486–2497. Blaha MJ, et al. J Clin Lipidol. 2008;2:267–273. Ballantyne CM, Clinical Lipidology: A companion of Braunwald’s Heart Disease. Philadelphia, PA: Saunder Elsevier; 2009

Cholesterol/ Proteins/ Phospholipids

Ch l tCh l l/l/Triglyceride

BABABABABAAAAAADDDDDDDDDDDDDDDBAD GOOGOOGOOGOOGOOOOOOODDDDDDDDDDDDDDDGOOD All Apo B-Containing Lipoproteins

Non–HDL-C

Apo A-I &

Apo A-II

Apo B Apo B Apo B Apo B

Non–HDL-C is a Measure of All Atherogenic Particles

RemnanRemnanRemnannnnntntnt

20

How To Calculate Non–HDL-C

Total Cholesterol HDL-C CCCCCCC

IDL-C CCCCCCCCCCCCCCCCCCCVLDL-C

IDIDDIDIDIIIIIILDL-C

+

“Good”

“Bad” – HDL-C

Non–HDL-C

Rx of Mixed Hyperlipidemia

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

High LDL-C and TGs

Therapeutic Lifestyle Change

Drug Therapy

Achieve the LDL-C goal, then

1 1STEP

Achieve the non-HDL-C goal AA2 2STEP

,g ,,,Beyond LDL as a Target

Then the lipid community took a Nap for 12 years

Nov 2013, ACC/AHA put out

New Lipid Guidelines

N

NNHLBI ACC/AHA

First new guidelines since ATP III guideline update in 2004 Statements or changes presented in these guidelines

No longer have therapeutic targets New risk calculator Use medications proven to reduce risk, i.e statins

Avoid medications or supplements that may lower the cholesterol number, but have no data to decrease CV risk

Not a comprehensive approach to lipid management

• Consume good fats

MUFA up to 20%, PUFA up to 10%

Saturated FA 5-6%

• Avoid

– Trans fatty acids*

• Add

– Dietary fiber ( 20-30 grams/d ).

– Plant sterol/stanol ester margarines

2013 ACC/AHA/NHLBI Guideline on Lifestyle for CVD Prevention

Eat a dietary pattern that is rich in fruit, vegetables, whole grains, fish, low-fat dairy, lean poultry, nuts, legumes, and nontropical vegetable oils consistent with a Mediterranean or DASH-type diet.

Engage in aerobic physical activity of

moderate to vigorous intensity lasting 40 minutes per session three to four times per

week.

But Guess What!!

In The Action for Health in Diabetes ( Look AHEAD ) study with life style aggressive intervention, 8% wt loss year one, & 3.6%

By year 4. After many years of F/U, the study was halted Because there was no benefit in reducing cardiovascular Events

Absence of Evidence is not an evidence of absence ,

Just a thought!!

�ased on e�tensive revie� of t�e evidence, t�e e�pert panel identified � groups t�at �ould benefit from statin t�erapy�

Four Ma�or Statin �enefit �roups

1) �ndividuals �it� clinical ASC�D

2) �ndividuals �it� �D� �1�0

3) �ndividuals �it� DM, �0-�5 yo �it� �D� �0- 1�� � �it�out clinical ASC�D �) �ndividuals �it�out clinical ASC�D or DM �it� �D� �0- 1�� and estimated 10-year ASC�D ris� ��.5%

Percentage C�ange in �D�-C� Pair�ise Comparisons

0 -10 -20 -30 -40 -50 -60

10 mg *

-5 -15 -25 -35 -45 -55

20 mg **

40 mg †

10 mg

20 mg

80 mg

10 mg

20 mg

40 mg

80 mg

10 mg

20 mg

40 mg

RosuvastatinAtorvastatin AtorvastatinAtorvastatiinnnininnnSimvastatin Pravastatin

40 mg

*P<.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg. **P<.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg. †P<.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg. Adapted from Jones et al. Am J Cardiol 2003;92:152–160.

22200 303300 4440051155 252255 353355 4-22200 -33300 -44400- 51155 -252255 -353355 -44 55454455 -5--454455

The STELLAR Trial

STELLAR = Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin.

�ig� �ntensity (Lowers LDL-C by > 50%)

Moderate-�ntensity (Lowers LDL-C by 30-50%)

�o�-�ntensity (Lowers LDL-C by < 30%)

Atorvastatin 40-80 mg Rosuvastatin 20-40 mg

Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin 40 mg BID Pitavastatin 2-4 mg

T�ree Statin intensity

levels

Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg

�is� calculator

Image from ASCVD �isk Calculator App.

-Patient’s 10 year risk -10 year risk of someone

the same age with optimi�ed risk factors

-Patient’s lifetime risk of

ASCVD -Lifetime risk of someone with optimi�ed risk factor

�es �es

No

No

No

No

�es

�es

�es Calculate 10-yr ASC�D ris� using

Pooled Co�ort ��uations

Adults � 21 years of age and candidate for statin

Clinical ASC�D�

�D�-C � 1�0 mg/d��

Diabetes�

�0-�5yrs � �.5% 10-yr ASC�D ris��

�ig�-intensity statin (Moderate-intensity if � �5 yo or not candidate for �ig�-intensity

statin)

�ig� intensity statin (Moderate-intensity if not

candidate for �ig�-intensity)

Moderate-intensity statin (�ig�-intensity if 10-yr

ASC�D ris� � �.5%)

Moderate-to-�ig� intensity statin

ASC�D prevention benefit less clear, but may be considered

Calculate 10-yr ASCVD risk using

Pooled Cohort E�uations

�egardless of t�e pretreatment basal �D�-C

��at �as c�anged from ATP ��� guidelines�

• initiate either moderate-intensity or �ig�-intensity statin therapy for patients who fall into the four categories.

• �at�er t�an �D�–C or non-�D�– C targets, ne� guideline uses t�e intensity of statin t�erapy as t�e goal of treatment.

• Unlike ATP III , Do not titrate to a specific �D� c�olesterol target

• Measure lipids during follow-ups to assess ad�erence to treatment, not to ac�ieve a specific �D� target

�es

No �es No

No �es

Assess ad�erence �it� fasting lipid panel

Statin �ntolerance�

�einforce medication ad�erence Manage �ntolerance

�einforce �mproved Ad�erence �ncrease intensity �� consider

addition of non-statin t�erapy

�einforce continued ad�erence

Follo�-up in 3-12 mont�s

��pected �esponse�

��pected �esponse�

T�ere are no longer treatment targets for �D� or non-�D�.

•T�is is a �uge c�ange for patients and providers. •�o longer treat to target

•Doesn’t fit in well with “know your numbers.” •Goal is no longer “lower is better.”

��at if you don’t fall into one of the 4

categories ��ere statins are indicated� • There are no recommendations for treatment in selected individuals

who are not in the 4 statin benefit treatment groups

• In these individuals whose 10 year risk is less that 7.5%, or when

the decision is unclear, other factors may be considered, like ;

• Family �istory of premature CAD • �D� � 160 mg/dl • �ncreased C�P greater t�an 2.0 • Coronary calcium greater t�an 300 Agaston units • A�� � 0.�

�o recommendations for • Starting or discontinuing statins in the following:

– NYHA class 2-4 – Or those on dialysis – HIV patients – Solid organ transplant patients – Insufficient data from RCT available ?

• Treatment of hypertriglyceremia • Use of non-HDL in decision making • Whether on-treatment markers such as Apo B, Lp(a), or LDL

particles are useful to guide treament

Problems � T�e Calculator may not al�ays ma�e sense

• One of the leading cardiologists cites examples ( from TIMI cardiology Group )

• 60 year old African-American with no ris� factors, TChol 150, SBP

125 on no meds, nondiabetic, nonsmoker has 10 year risk of �.5%.

• 44 year old nonsmoking, nondiabetic white man with strong family �istory of M�, total cholesterol of 250 mg/dl, �D� 1�2, �D� 2�, SBP 120 on no meds has a 10 year risk of 5%.

yy

•�ot �it�out controversy, as t�is calculator

�as never before been publis�ed or validated

Pooled Co�ort Calculator�

Calibration in Primary Prevention Co�orts

Lancet, Nov 1� 2013

AACE says “that the new cardiovascular disease calculator

that was published along with the guidelines is already outdated. �It is based upon outmoded data,

does not model the totality of the US population, has not been validated,

and therefore has only limited applicability. There is also a considerable Number of high risk patients with

multiple risk factors or established CVD who do not attain ade�uate �eductions in LDL-c and other lipid abnormalities without

further therapies in addition to statins”.

Dr. �ruce �ancin �rote in Cardiology �e�s Digital �et�or� (12/12/13)

• T�e controversial ������������������������������������������������of statins in patients > 75 yrs, citing a lack of persuasive evidence because such patients were often excluded from participation in the major statin trials, sounds like being unjust twice to a whole age segment !

�n Addition t�e guidelines called t�e contribution to ris� for ASC�D of t�e follo�ing as uncertain �

• Apolipoprotein � ( despite actual documentation of the presence

of both apo B 48 & apoB 100 in plaques )

• C�ronic �idney disease

�� an A�A position statement Circulation. 2003� 10�� 215�-216�

• T�ere is a �ig� prevalence of C�D in sub�ects �it� C�D. T�e presence of C�D, ��et�er it is manifested by proteinuria

(albuminuria) or reduced �F�, appears to be an independent ris� factor for C�D outcomes, particularly in

�ig�er-ris� populations. T�ese findings are consistent �it� t�e ��F tas� force recommendation t�at patients �it� C�D

s�ould be considered in t�e �ig�est-ris� group for C�D events.

T�en �ust last mont� ( Sept 201� ), ����� �uidelines

came out T�e Panel

• Considered Evidence from �CTs. As well as evidence from �pidemiological, Metabolic � �enetics studies.

• The Panel acknowledges that while �CTs represent the strongest evidence, it �as limitations, is often incomplete, or is of uncertain relevance to patients with characteristics that may differ from those who were recruited in the RCTs.

�uiding principles/Conclusions • An elevated level of Cholesterol carried by circulating Apo B-

containing lipoproteins ( �on-�D�-c � �D�-c, termed atherogenic cholesterol ( AC ) ) is a root cause of most ASCVD events.

• Reducing elevated levels of AC will lower ASCVD risk in proportion & extent that the AC is reduced. ntensity of reduction should be tailored to patients A� for ASCVD.

• �on-�D�-c is listed first because the panel consensus was that it is a better 1ry target than LDL-c.

• For those whom lipid-lowering drug therapy is indicated, statins are t�e 1ry modality for reducing ASC�D ris�.

�uiding principles/Conclusions • Apo � is considered an optional, 2ry target for therapy.

Apolipoprotein B is; Apo �

Strongly associated with ASCVD event risk; -More predictive of ASCVD than LDL-c, but not consistently superior to non-HDL-c -A potential contributor to lipoprotein-related residual risk, as it may remain elevated in some patients who have attained their non-HDL-c &/or LDL-c goals; & may be accurately assessed in the non-fasting state.

• Optional Apo B goals for 1ry & 2ry/very high risk prevention are

<90 & <80 mg/dl, respectively.

• ��ile only �bservational studies strongly suggest that lifestyle habits have an important impact on AC levels, as well as related disturbances ( i.e . Obesity, HTN, & IR ).

• ����������������������������������������������������������������������an important element of risk-reduction W or W/O drug therapy.

y.

DHHDLLLLL-----cccccccccccc

Similarly • While the strategy of treating patients to a specific level of LDL-c or

non-HDL-c has not been tested in any of the large trials assessing ASCVD morbidity or mortality.

• Still, results from RCTs that have employed various methods for

lowering AC, have indicated that lower on –treatment levels have been consistently associated with lower AR for an ASCVD event, & align with observational studies that suggest a log-linear relationship between levels of AC & absolute ASCVD event risk.

• T�us, �������������������������������������treatment goals are

useful to ensure t�at t�e aggressiveness of t�erapy to lo�er AC is matc�ed to absolute ris� for an event, and to facilitate effective communication bet�een patients � clinicians while maximizing long-term adherence to treatment plan.

Calculate 10-yr ASCVD risk using Pooled Cohort E�uations

Using Framingham, Framingham longterm, or

�yenolds �isk score

ADA and ACC �� Consensus Statement on �ipoprotein Management

Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822

Highest-risk patients

including those with 1) known CVD or 2) Diabetes plus one

or more CVD risk factors

High-risk patients including those with 1) no diabetes or known clinical CVD but 2 or more additional major CVD risk factors or 2) Diabetes but no other CVD risk factors

LDL-C (mg/dL)

Non-HDL-C (mg/dL)

ApoB (mg/dL)

< 70 < 100 < 80

< 100 < 130 < 90

Highesstt isk pati nti ts TREATMENT GOALSLS

Targets of Therapy- Triglycerides

• Elevated TG level is not a target of therapy per se, except when very high ( severe; = or> 500 mg/dl )

• When TGs are between 200-499 mg/dl, the

targets of therapy are non-HDL-c & LDL-c.

• When the triglycerides concentration is very high

(> 500 mg/dl, and especially > 1000 mg/dl ), reducing it’s concentration to < 500 mg/dl becomes the 1ry goal of therapy.

Targets of Therapy- HDL-c

• While the level of HDL-c is an important rsik indicator, used in risk factor counting & quantitative risk assessment. Low HDL-c is also a component of the Metabolic syndrome.

• HDL-C is not recommended as a target of therapy per se,

but the level is often raised as a consequence of efforts to reduce the atherogenic dyslipidemia through life style and drug interventions.

Mature HDL

LCAT

FC

A-I

A-I

CE HL, EL

Macrophage

Mature HDL-C SR-BI

FC

Nascent HDL-C

HDL Empties—Direct Pathway

Bile

SR-BI Liver FC

CE LCAT

FC

A-I

A-I

CE HL, EL

Macrophage

Mature HDL-C SR-BI

FC

Nascent HDL-C

�EWL� �ppro�ed Lipid Lowering

Therapies � LLT �

�pp�pp�pp�ppowowowowes eseses

Life goes on� and progress Continues

Intest�na� Lu�en

Enteroc�te ��e�unu��

L�� ph

��sor�ed Cholesterol and Triglycerides are Pac�aged into Chylomicrons and �ecreted into the Lymph

NPC1L1

Cholesterol Cholesterol Ester ACAT

2 Fatty Acid

Monoglyceride � D�AT

Triglyceride

Ch��o��cron

Apo B-��

�C��� ���l C�-��C��le��er�l ���l�r����er��e� ����� �i���l�l��er�l ���l�r����er��e� ���� �i�r�����l �ri�l��eri�e �r����er �r��ei�

MTTP

ABCG5/8

y y ; y y y ; g y1. Cohen DE, Armstrong EJ. In: Principles of Pharmacology 2nd ed. Golan et al eds. Philadelphia: Lippincott,

Williams and Wilkins; 2007.; 2. Wang. Ann Rev Physiol.2007;69:221.; 3. Berge, et al. 2000. Science 290:1771.; 4. Lee, et al. 2001. Nat. Genet. 27:79.; 5. Yu et al. J Clin Invest 2002; 110:671.

Free Cholesterol

Triglyceride iglyceri

Lipase

• MTTP inhibitors ( disrupting Chylomicrons & VLDL assembly Lomitapide just being approved as PO capsules under

juxtapid (REMS )

Lomitapide

The idea developed from the rare disorder ARD Abetalipoproteinemia ( LDL usually around 10-20s ), given PO, with a average reduction in LDL of about

50 %, we start low as low as 5 mg, and uptitrate gradually given it’s intestinal effect, as tolerated to 60 mg..

There was about 8 % increase in liver fat over the initial 6 months, stabilized over the next 18 months..

Atheroma

Liver Intestine

The Liver Secretes Apo B-100 Lipoproteins (VLDL) Into the Circulation

VLDL

Cholesterol Pool

Goldstein JL, Brown MS. Science. 2001;292:1310.

Peripheral Tissues

Hepatic Apo B-100

Blood

Liver Intestine

Apo B-100 Lipoproteins Carry Triglycerides, Cholesterol, and Cholesterol Esters into the Circulation

TG Lipoprotein

Lipase

LDL

lDL

TG VLDL

Atheroma

Peripheral Tissues

1. Goldstein JL, Brown MS. Science. 2001;292:1310.; 2. Shepherd J. Eur Heart J Suppl. 2001;3:E2.

Cholesterol Pool

Hepatic Apo B-100

Blood

Atheroma

Antisense oligonucleotides (ASO ) reducing Apo B synthesis ( mipomersen, Kynamro ) REMS

VLDL

Cholesterol Pool

Goldstein JL, Brown MS. Science. 2001;292:1310.

Hepatic Apo B-100

Blood

X

Mipomersen

The idea developed from the

Hypo-betalipoproteinemia ( LDL usually around 30s ), The drug increases the RNA degradation from transcripts of the

ApoB gene, thereby reducing the ApoB production.. It is given as a SQ Injection 200 mg /week.. We’ve seen about 25 % reduction in LDL, with

4 yrs worth of data in the HeFH Main A/E flu like c/os within 24 hrs post injection in some,

Injection site reactions in some, and increased hepatic fat that Stabilizes after a period of time.

PCSK� Mutations Increase Degradation o� LDL Receptors, Limiting Binding and Endocytosis�

ApoB A

P�S�� P

LDL particle

LDL receptor

LDL receptors degraded at a faster rate by increased P�S�� activity

Normal FH� P�S��� Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

PCSK9 monoclonal abs

save LDL Rs

Support your heart, it keeps pumping.

Thank YOU from the bottom of mine.

Questions?