October 30, 2007 University Hospitals Heart & Vascular Institute

Carl E. Orringer, MD, FACCHarrington Chair in

Preventive Cardiovascular MedicineUniversity Hospitals Case Medical Center

Harrington Heart and Vascular InstituteAssociate Professor of MedicineCase Western Reserve University

School of Medicine

Lipid Management in 2013Lipid Management in 2013Are You Are You

Up toUp to Date? Date?

How Increased Concentration of Apo B Containing How Increased Concentration of Apo B Containing Particles Promotes AtherosclerosisParticles Promotes Atherosclerosis

Blood

ApoB lipoproteinparticles

Modification

Macrophage

Monocytes bind toadhesion molecules

Smooth muscle

Foam cell

Inflammatory response

ApoB = apolipoprotein B.1. Tabas I et al. Circulation. 2007;116:1832–1844. 2. Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551–561.3. Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536–1540. 4. Steinberg D et al. N Engl J Med. 1989;320:915–924.

• Fibrous cap thinning

• Plaque rupture and thrombosis

• Atherothrombotic vascular disease (eg, MI and stroke)

Plaque rupture

Thinning fibrous cap

MI = myocardial infarction.1. Tabas I et al. Circulation. 2007;116:1832–1844.

Atherothrombotic Vascular Disease:Atherothrombotic Vascular Disease:Response-to-Retention ModelResponse-to-Retention Model11

Atherosclerosis ProgressionAtherosclerosis Progression1–31–3

1. Tabas I et al. Circulation. 2007;116:1832–1844. 2. Hansson GK. N Engl J Med. 2005;352:1685–1695. 3. Jawad E et al. Dis Mon. 2008;54:671–689.

Normal ArteryNormal Artery

Fatty streak involving

lipoprotein and immune cell infiltration

Fatty streak involving

lipoprotein and immune cell infiltration

Gradual outward expansion of arterial wall

Gradual outward expansion of arterial wall

Plaque rupture and thrombosis (acute

coronary event)

Plaque rupture and thrombosis (acute

coronary event)

Inward expansion causing luminal

narrowing (chronic stable angina)

Inward expansion causing luminal

narrowing (chronic stable angina)

Food isconsumed

Food is absorbedand converted totransporter particles

Muscle

Energy storage(starvation)

Disassembles transporter particlesto prevent clogged transport pathways

Assembles key bodymaintenance particles,substrates for hormone assembly

Cell membranes,Salt and H2O balanceReproductive hormonesVitamins

Particles provided thateliminate the refuse

Lipoprotein Physiology Made Simple

GI Tract

Plasma

Adipose tissue

Liver

GI Tract

Refuse eliminated from the body

Liver

Accepts refusefrom plasma

1

2

4

5

5

67

8

Transporter particles

Energy utilization

3

3

GlycerolPhytosterolsCholesterolFatty acidsBile acidsPhospholipids

Micelles

Intestinallumen

Duodenal/Jejunalenterocyte

Cholesterol

CE Apo B-48

Fatty acids

Triglycerides

Chylomicron

Lymphatics Plasma

Lipoproteinlipase

CM remnant

Freefatty acids

Muscle

AdiposeTissue

Phospholipids

CholesterolSurfaceComponents

Apo E

Liver

CM remnants

degradationVLDL

E

B-100

C2

LDLIDL

B-100

E

B-100

SRB1receptor

Macrophage

NPC1L1

ABCG5ABCG8

Acetate

Glycerol Glucose

Phospholipids

MTP

ACAT

FC

Gallbladder

Bileacids

VLDL

B-100

EC2

LDL receptor

(CM)

CM

CM

HDL

ToHDL

CMR

CMRE3

HDL

Cell membranes

Hormones

B-48

Vitamins

FCA1 A2

CETPCETP

E3

B-48

C3C3

A1 A2A4

C (trace)

E (trace)

B-48

CM

C EA4

Remnant receptorLDL-Related protein

VLDL remnants

Dietary Priorities in DyslipidemiaDietary Priorities in Dyslipidemia

Reduced intake of saturated fat and cholesterolReduced intake of saturated fat and cholesterol Increased intake of soluble fiber and plant Increased intake of soluble fiber and plant

sterols/stanolssterols/stanols In overweight and obese patients, reduced In overweight and obese patients, reduced

caloric intake to achieve weight reductioncaloric intake to achieve weight reduction In hypertriglyceridemic patients, same as above In hypertriglyceridemic patients, same as above

plus reduced intake of simple carbohydratesplus reduced intake of simple carbohydrates Greatest impact of diet tends to be in overweight Greatest impact of diet tends to be in overweight

or obese patients with atherogenic dyslipidemiaor obese patients with atherogenic dyslipidemia

Adding Soluble Fiber to the DietAdding Soluble Fiber to the Diet

Whole grainsWhole grainsNuts and seeds Nuts and seeds FruitFruitLegumesLegumes

Adding Plant Sterols Adding Plant Sterols and Stanols to the Dietand Stanols to the Diet

Goal is 2000-2500 mg dailyGoal is 2000-2500 mg dailyDietary options containing these functional Dietary options containing these functional

foodsfoodsMargarinesMargarinesOJOJMilk and non-dairy drinks Milk and non-dairy drinks BreadsBreads

Intestinal LumenIntestinal LumenGlycerolPhytosterolsCholesterolFatty acidsPhospholipids

GlycerolPhytosterolsCholesterolFatty acidsPhospholipids

Mixed MicellesMixed MicellesNPC1L1NPC1L1

CholesterolCholesterol

Glycerol + 3 FAGlycerol + 3 FA

TriglyceridesTriglycerides

Phopsho;ipidsPhopsho;ipids

Apo B-48Apo B-48

Microsomaltriglyceridetransfer protein

Microsomaltriglyceridetransfer protein

Duodenum and Jejunal EnterocyteDuodenum and Jejunal Enterocyte

ChylomicronChylomicron

Plant sterolsand stanolsPlant sterolsand stanols

Mechanism of Action of Plant Sterols/Stanols and FiberMechanism of Action of Plant Sterols/Stanols and Fiber

SolublefiberSolublefiber

BileacidsBileacids

MicellesMicelles

LDL-C Lowering Drug TherapyLDL-C Lowering Drug Therapy

StatinsStatins Ezetimibe Ezetimibe ResinsResins High-dose niacin High-dose niacin LomitapideLomitapide MipomersinMipomersin

Microsomal triglyceride Microsomal triglyceride transport proteintransport protein

Intestinal bile acid Intestinal bile acid transportertransporter

NPC1L1NPC1L1 Adipose tissueAdipose tissue Apo BApo B HMGCoA Reductase HMGCoA Reductase

Match Drug with Site of Action

LDL-C Lowering Drugs:LDL-C Lowering Drugs:Mechanisms of ActionMechanisms of Action

Small intestine

Proximal

MicellesNPC1L1

Bile

IntestinalBile AcidTransporter

Ezetimibe

Resins

Acetyl CoA

Cholesterol

HMG CoAreductase

Statin

FFA

Tg

CE

Apo BVLDL

Liver

Adipose Tissue

FFA

Niacin

VLDL

RLP

LDLIDL

DistalDistal

Apo EApo EApo C1,2,3Apo C1,2,3

Lomitapide

Lomitapide

MipoMipo

WhatWhat’’s New in Lipids in 2013s New in Lipids in 2013

NCEP ATP 3 transitions to NCEP ATP4NCEP ATP 3 transitions to NCEP ATP4Update on dietary and drug therapy for Update on dietary and drug therapy for

lipid disorderslipid disorders Increased emphasis on the metabolic Increased emphasis on the metabolic

syndromesyndromeQuestions about role of niacin in treatment Questions about role of niacin in treatment

of atherosclerotic vascular diseaseof atherosclerotic vascular diseaseNew approaches to LDL-C lowering and New approaches to LDL-C lowering and

HDL-C raising therapyHDL-C raising therapy

NCEP ATP III Approach toNCEP ATP III Approach toPrimary Prevention of CHDPrimary Prevention of CHD

Count traditional risk factors: cigarette smoking; Count traditional risk factors: cigarette smoking; HBP or on Rx for HBP; HDL-C <40 mg/dl; family HBP or on Rx for HBP; HDL-C <40 mg/dl; family Hx premature CHD in 1Hx premature CHD in 1stst degree relatives ( degree relatives (♂<55, ♂<55, ♀<65); age (males ≥45, females ≥55)♀<65); age (males ≥45, females ≥55)

Use Framingham risk scoring to estimate CHD Use Framingham risk scoring to estimate CHD risk for those with 2 or more risk factorsrisk for those with 2 or more risk factors

Manage lipids based upon the principle of Manage lipids based upon the principle of matching treatment intensity to estimated risk matching treatment intensity to estimated risk

Expert Panel, ATP III. Circulation 2002;106:3143-3421

NCEP/Framingham risk scores: Estimate of 10-yr Hard CHD risk in men without CHD

Reilly MP, Rader DJ. Circulation. 2003;108:1546-51.VBWG

Point total: <0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 >1710-yr risk (%) <1 1 1 1 1 1 2 2 3 4 5 6 8 10 12 16 20 25 ?30

Age (y) 20–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79Points –9 –4 0 3 6 8 10 11 12 13

Systolic BP Points(mm Hg) Untreated Treated

<120 0 0120–129 0 1130–139 1 2140–159 1 2?160 2 3

HDL-C (mg/dL) Points

?60 –150–59 040–49 1<40 2

Age (y) 20–39 40–49 50–59 60–69 70–79

Nonsmoker 0 0 0 0 0Smoker 8 5 3 1 1

PointsTotal-C Age (y)(mg/dL) 20–39 40–49 50–59 60–69 70–79

<160 0 0 0 0 0160–199 4 3 2 1 0200–239 7 5 3 1 0240–279 9 6 4 2 1?280 11 8 5 3 1

Risk CategoryRisk Category LDL-C GoalLDL-C Goal Initiate TLCInitiate TLCConsider Consider

Drug TherapyDrug Therapy

Very High risk:Very High risk: ACS, or CHD w/ DM,multiple CRFACS, or CHD w/ DM,multiple CRF

<70 mg/dL<70 mg/dL 70 mg/dL70 mg/dL >> 70 mg/dL 70 mg/dL

High risk:High risk: CHD or CHD risk equivalents CHD or CHD risk equivalents (10-year risk >20%)(10-year risk >20%)

If LDL <100 mg/dlIf LDL <100 mg/dl

<100 mg/dL <100 mg/dL (optional goal: (optional goal:

<70 mg/dL)<70 mg/dL)

Goal <70 mg/dlGoal <70 mg/dl

100 mg/dL100 mg/dL >> 100 mg/dL 100 mg/dL (<100 mg/dL: (<100 mg/dL:

consider drug Rx)consider drug Rx)

Moderately high risk:Moderately high risk: 2+ risk factors 2+ risk factors (10-year risk 10% to 20%)(10-year risk 10% to 20%)

<100 mg/dL<100 mg/dL 130 mg/dL130 mg/dL >> 130 mg/dL 130 mg/dL (100-129 mg/dL: (100-129 mg/dL:

consider drug Rx)consider drug Rx)

Moderate risk:Moderate risk: 2+ risk factors ( risk <10%)2+ risk factors ( risk <10%)

<130 mg/dL<130 mg/dL 130 mg/dL130 mg/dL >> 160 mg/dL 160 mg/dL

Lower risk:Lower risk: 0-1 risk factor0-1 risk factor

<160 mg/dL<160 mg/dL 160 mg/dL160 mg/dL >>190 mg/dL 190 mg/dL

ATP III Update 2004:

LDL-C Goals and Cutpoints for Therapy in Different Risk Categories

Grundy S, et al. Circulation 2004;110:227

Step 1:Step 1:NHLBI Critical Review NHLBI Critical Review

of the Literatureof the Literature

1. What is the evidence that treatment to 1. What is the evidence that treatment to specific LDL-C and non-HDL-C goals reduces specific LDL-C and non-HDL-C goals reduces outcomes in atherosclerotic cardiovascular outcomes in atherosclerotic cardiovascular disease in primary and secondary prevention?disease in primary and secondary prevention?

2. What is the evidence for efficacy and safety 2. What is the evidence for efficacy and safety of statins, resins, fibrates, cholesterol of statins, resins, fibrates, cholesterol absorption inhibitors and niacin?absorption inhibitors and niacin?

Step 2:Step 2:Collaboration of Experts to Translate Collaboration of Experts to Translate

Literature Review into GuidelinesLiterature Review into Guidelines

American College of Cardiology American College of Cardiology FoundationFoundation

American Heart AssociationAmerican Heart AssociationNational Lipid AssociationNational Lipid Association

Evidence-Based ReviewsEvidence-Based Reviews

Statin therapy reduces relative risk of CHD Statin therapy reduces relative risk of CHD events in all groups, regardless of events in all groups, regardless of Framingham Risk scoreFramingham Risk score

High-dose statin is more beneficial than High-dose statin is more beneficial than low or moderate dose statin therapylow or moderate dose statin therapy

Statin therapy is unassociated with Statin therapy is unassociated with increased risk of cancerincreased risk of cancer

Statin therapy is the most effective means Statin therapy is the most effective means of risk reduction in diabetic patientsof risk reduction in diabetic patients

Restrictions on Simvastatin 80 mgRestrictions on Simvastatin 80 mg

Use 80 mg daily dose only in those who Use 80 mg daily dose only in those who have been on that dose for have been on that dose for ≥ 12 months ≥ 12 months and have not experienced toxicityand have not experienced toxicity

Do not start new patients on 80 mg dailyDo not start new patients on 80 mg dailyTreat patients who require >40 mg with an Treat patients who require >40 mg with an

alternate lipid-altering therapyalternate lipid-altering therapySwitch patients who need to be started on Switch patients who need to be started on

a drug interacting with simvastatin to an a drug interacting with simvastatin to an alternate statinalternate statin

www.fda.org 6/8/11

Simvastatin Dosing RegulationsSimvastatin Dosing Regulations

Contraindicated: itraconazole, ketoconazole, Contraindicated: itraconazole, ketoconazole, posconazole, erythromycin, telithromycin, HIV posconazole, erythromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, protease inhibitors, nefazodone, gemfibrozil, cyclosporine and danazolcyclosporine and danazol

Do not exceed 10 mg daily: diltiazem, verapamilDo not exceed 10 mg daily: diltiazem, verapamil Do not exceed 20 mg daily: amlodipine, Do not exceed 20 mg daily: amlodipine,

ranolazine, amiodarone ranolazine, amiodarone

www.fda.gov 6/8/11, 12/15/11

Hepatic Function Testing in Hepatic Function Testing in Patients Receiving StatinsPatients Receiving Statins

Traditionally ALT and AST have been routinely Traditionally ALT and AST have been routinely measured during statin maintenance therapymeasured during statin maintenance therapy

Irreversible hepatic damage due to statins is Irreversible hepatic damage due to statins is extremely rare and likely idiosyncratic (less than extremely rare and likely idiosyncratic (less than 2 per one million patient-years)2 per one million patient-years)

There are no data to support routine LFT There are no data to support routine LFT monitoring to identify such patientsmonitoring to identify such patients

FDA therefore recommends only baseline FDA therefore recommends only baseline hepatic function studies and follow-up testing as hepatic function studies and follow-up testing as clinically warranted; routine LFT monitoring is no clinically warranted; routine LFT monitoring is no longer recommended. longer recommended.

www.fda.gov 2/28/12

Cognitive Adverse Effects of StatinsCognitive Adverse Effects of Statins

Occasional patients over age 50 experience notable, but Occasional patients over age 50 experience notable, but ill-defined memory impairment that resolves upon ill-defined memory impairment that resolves upon discontinuation of statin therapydiscontinuation of statin therapy

Such memory impairment may occur at any time during Such memory impairment may occur at any time during statin therapystatin therapy

There is no association between statin therapy and There is no association between statin therapy and AlzheimerAlzheimer’’s dementias dementia

There is no association between memory loss and There is no association between memory loss and specific statin, dose, patientspecific statin, dose, patient’’s age or any specific drug-s age or any specific drug-drug interactiondrug interaction

Consider withdrawing the drug and using alternate Consider withdrawing the drug and using alternate therapies when new memory loss is clinically evident therapies when new memory loss is clinically evident

www.fda.gov 2/28/12

Changes in Blood Glucose in Changes in Blood Glucose in Patients Receiving StatinsPatients Receiving Statins

JUPITER reported an increased incidence of JUPITER reported an increased incidence of investigator reported diabetes in the rosuvastatin investigator reported diabetes in the rosuvastatin treated patientstreated patients

A meta analysis of 13 statin trials reported a 9% A meta analysis of 13 statin trials reported a 9% increased risk of incident diabetesincreased risk of incident diabetes

Statin labels have now been revised to reflect Statin labels have now been revised to reflect that statin therapy may be associated with a rise that statin therapy may be associated with a rise in HgbA1C and fasting plasma glucosein HgbA1C and fasting plasma glucose

Consensus is that benefits of statin therapy in Consensus is that benefits of statin therapy in appropirate patients far outweighs DM riskappropirate patients far outweighs DM risk

www.fda.gov 2/28/12

The Metabolic Syndrome andThe Metabolic Syndrome andNon-HDL CholesterolNon-HDL Cholesterol

The Metabolic SyndromeThe Metabolic Syndrome

Requires 3 or moreRequires 3 or moreWaist circumference Waist circumference >35>35””♀ or 40♀ or 40””♂♂Fasting glucose 100-125 mg/dlFasting glucose 100-125 mg/dlBP ≥130/85 or on anti-HBP medsBP ≥130/85 or on anti-HBP medsHDL-C < 50 mg/dl♀ or <40 mg/dl ♂HDL-C < 50 mg/dl♀ or <40 mg/dl ♂Triglycerides ≥ 150 mg/dlTriglycerides ≥ 150 mg/dl

Increased risk for type 2 DM and CHDIncreased risk for type 2 DM and CHDLDL-C is not a good CHD risk predictor in LDL-C is not a good CHD risk predictor in

these patientsthese patients

The Metabolic SyndromeThe Metabolic SyndromeA Growing Cardiometabolic A Growing Cardiometabolic

Phenotype in the U.S.Phenotype in the U.S.

1994 – 20021994 – 2002 2003 – 20102003 – 2010 ∆ ∆ (%)(%)

MetSMetS 23.7%23.7% 34.0%34.0% +10.3+10.3

High TGHigh TG 27.0%27.0% 33.0%33.0% +6.0+6.0

High TG and low HDL-CHigh TG and low HDL-C 2.1%2.1% 4.8%4.8% +2.7+2.7

Type II diabetes mellitusType II diabetes mellitus 7.9%7.9% 10.7%10.7% +2.8+2.8

Impaired fasting glucoseImpaired fasting glucose 6.1%6.1% 25.9%25.9% +19.8+19.8

ObesityObesity 19.8%19.8% 33.7%33.7% +13.9+13.9

Ramjee V, et al. J Am Coll Cardiol. 2011;58:457-463.

5 10 20 40 60 80 1000

Diameter (nm)

1.20

1.10

1.06

1.02

1.006

0.95

Den

sity

(g/

ml)

HDL2

HDL3

ChylomicronRemnants

Chylo-microns

VLDL

IDL

LDL

Lp(a)

The Heterogeneity of Lipoprotein Particles

Non-HDL Partic

les (1 apo B m

olecule/particle)

Non-HDL-C= cholesterolconcentration in all apo B-containing particles

Non-HDL-C = Total cholesterol – [HDL-C]; or Non-HDL-C = Total cholesterol – [HDL-C]; or [LDL-C] + [VLDL-C][LDL-C] + [VLDL-C]

Goal for non-HDL-C is <30 mg/dl above LDL-C Goal for non-HDL-C is <30 mg/dl above LDL-C goal because desirable Tg is <150 mg/dlgoal because desirable Tg is <150 mg/dl

When non-HDL-C is >30 mg/dl above LDL-C When non-HDL-C is >30 mg/dl above LDL-C goal, more intensive lipid therapy is warrantedgoal, more intensive lipid therapy is warranted

Total Cholesterol

HDLCholesterol

LDLCholesterol

VLDLCholesterol

Usually Anti-atherogenic

+ +

Pro-atherogenic

Non-HDL-CholesterolAddress only when Tg = 200-499 mg/dl

Tg/5

UnderstandingNon-HDL Cholesterol

+IDL-C+RLP-C+Lp(a)-C

Appears on all UH lipid profileswhen triglycerides are 200-499

Treatment of the Treatment of the Metabolic SyndromeMetabolic Syndrome

Treatment of choice is diet and cardiovascular Treatment of choice is diet and cardiovascular exercise to achieve IBWexercise to achieve IBW

Medical therapy is used when diet and exercise Medical therapy is used when diet and exercise does not achieve goalsdoes not achieve goals

Goals of lipid therapy depend upon serum Goals of lipid therapy depend upon serum triglycerides:triglycerides: Tg <200: Achieve LDL-C goalTg <200: Achieve LDL-C goal Tg 200-499: Achieve LDL-C goal, then non-HDL-C Tg 200-499: Achieve LDL-C goal, then non-HDL-C

goalgoal Tg Tg ≥500: Lower Tg to <500; then achieve LDL-C goal ≥500: Lower Tg to <500; then achieve LDL-C goal

and then non-HDL-C goal and then non-HDL-C goal

Niacin Therapy: Does it Help?Niacin Therapy: Does it Help?

Lipid Effects of NiacinLipid Effects of Niacin

Raises HDL-CRaises HDL-CLowers triglyceridesLowers triglycerides In high doses lowers LDL-CIn high doses lowers LDL-CLowers Lp(a)Lowers Lp(a)

Earlier Studies on NiacinEarlier Studies on Niacin

Reduced risk of non-fatal MI in post MI Reduced risk of non-fatal MI in post MI men in pre-statin eramen in pre-statin era

Reduced angiographic CAD progression in Reduced angiographic CAD progression in combination with statin therapycombination with statin therapy

Reduced CIMT when used in combination Reduced CIMT when used in combination with a statinwith a statin

AIM-HIGH: Niacin Plus Statin AIM-HIGH: Niacin Plus Statin to Prevent Vascular Eventsto Prevent Vascular Events

3414 subjects, age 3414 subjects, age ≥ 45 yrs≥ 45 yrs with established ASCVD with established ASCVD (documented CHD, cerebrovascular or carotid disease or (documented CHD, cerebrovascular or carotid disease or symptomatic PAD)symptomatic PAD)

Documented atherogenic dyslipidemia (LDL-C Documented atherogenic dyslipidemia (LDL-C ≤ 160 mg/dl; ≤ 160 mg/dl; HDL-C ≤ 40 mg/dl in men or ≤ 50 mg/dl in women; and HDL-C ≤ 40 mg/dl in men or ≤ 50 mg/dl in women; and triglycerides ≥ 150 mg/dl or ≤ 400 mg/dl)triglycerides ≥ 150 mg/dl or ≤ 400 mg/dl)

All patients received simvastatin to achieve LDL-C 40-80 All patients received simvastatin to achieve LDL-C 40-80 mg/dl and if necessary, ezetimibe 10 mg dailymg/dl and if necessary, ezetimibe 10 mg daily

Subjects randomized to receive Niacin E-R 2000 mg daily, Subjects randomized to receive Niacin E-R 2000 mg daily, or if not tolerated,1500 mg daily; or placeboor if not tolerated,1500 mg daily; or placebo

Primary outcome: Composite endpoint of CHD death, non-Primary outcome: Composite endpoint of CHD death, non-fatal MI; ischemic stroke; hosp. for NSTE ACS; or symptom-fatal MI; ischemic stroke; hosp. for NSTE ACS; or symptom-driven coronary or cerebrovascular revascularizationdriven coronary or cerebrovascular revascularization

Study enrollment began September 2005 Study enrollment began September 2005

AIM-HIGH: AIM-HIGH: Study Prematurely Terminated Study Prematurely Terminated

5/26/11: US FDA reports early termination of trial 5/26/11: US FDA reports early termination of trial due to lack of benefit of niacin vs. placebo when due to lack of benefit of niacin vs. placebo when added to that achieved with simvastatin or added to that achieved with simvastatin or simvastatin plus ezetimibesimvastatin plus ezetimibe

Small, unexplained increase in ischemic strokes in Small, unexplained increase in ischemic strokes in niacin arm vs. placebo (28 strokes [1.6%] versus 12 niacin arm vs. placebo (28 strokes [1.6%] versus 12 strokes [0.7%] in niacin versus placebo arms. strokes [0.7%] in niacin versus placebo arms. Role that niacin played in these strokes is uncertain as 9 Role that niacin played in these strokes is uncertain as 9

of the strokes in the niacin group occurred in subjects of the strokes in the niacin group occurred in subjects who d/cwho d/c’’d niacin 2 months to 4 years before their strokesd niacin 2 months to 4 years before their strokes

HPS-2 THRIVEHPS-2 THRIVE

25,673 pts in UK, China and Scandinavia 25,673 pts in UK, China and Scandinavia with established atherosclerotic vascular with established atherosclerotic vascular diseasedisease

All received simvastatin All received simvastatin ± ezetimibe to ± ezetimibe to lower TC to ≤ 135 mg/dl.lower TC to ≤ 135 mg/dl.

Patients randomized to receive niacin 2g Patients randomized to receive niacin 2g daily + laropiprant 40 mg daily and daily + laropiprant 40 mg daily and followed for major vascular events for followed for major vascular events for medain follow-up of 4 yearsmedain follow-up of 4 years

HPS-2 THRIVE ResultsHPS-2 THRIVE Results

No benefit on MVE of adding Niacin-No benefit on MVE of adding Niacin-laropiprant to aggressive LDL lowering laropiprant to aggressive LDL lowering regimenregimen

Increased incidence of serious adverse Increased incidence of serious adverse events (myopathy) in Chinese patientsevents (myopathy) in Chinese patients

European Heart Journal doi:10.1093/eurheartj/eht055

Newer Drugs for LDL-C Lowering Newer Drugs for LDL-C Lowering and HDL-C Raising and HDL-C Raising

CETP inhibitorsCETP inhibitorsPCSK9 inhibitorsPCSK9 inhibitors

Small Intestine

Liver

Macrophage

ABC A1transporter

ABC G1transporter

Apo A1

FCPre-β HDL

Phospholipids (PL)

TGCE

HDL-2

Lecithin cholesterylAcyltransferase(LCAT)

PL

Apolipoproteins

FC

TGCE CE

TG

CETP

LDL -R

SR-B1

CE

CE

VLDL, LDL

Apo B

FC

Bile

Basic HDL Metabolism

TGCE

Fecalelimination

HDL-3

LCAT

CETG

VLDL, Remnant particles

PL

Small Intestine

Liver

Macrophage

ABC A1transporter

ABC G1transporter

Apo A1

FCPre-β HDL

Phospholipids

CETG

HDL-2

Lecithin cholesterylacyltransferase

PL

Apolipoproteins

Lipoproteinlipase

FC

CETG CE

TG

CETP

LDL -R

SR-B1

CE

CE

VLDL, LDL

Apo B

FC

Bile

Effect of CETP Inhibition

CETG

Fecalelimination

HDL-3

LCATLPL

↑HDL-C↓LDL-C

CETP inhibitorsCETP inhibitors

TorcetrapibTorcetrapib Improved lipids, increased mortalityImproved lipids, increased mortality

DalcetrapibDalcetrapibNo reduction in events post MINo reduction in events post MI

AnacetrapibAnacetrapibEvacetrapibEvacetrapib

Sterol Regulatory Element Binding Protein

LDL-R

PCSK9

Cholesterol

Lysosomaldegradation

LDL particles -

+

+

Apo B

Mutations Causing Familial Hypercholesterolemia

1. Abnormal # or function of LDL-R2. Defective apo B3. PCSK9 overexpression4. Abnormality of LDL adaptor protein (ARH)5. Chol 7 alpha OH ase ↓

Cholesterol 7 alphahydroxylase

Statin

12

3

4

5

Hepatocyte

Bile

PCSK9 InhibitorsPCSK9 Inhibitors

Subcutaneously administredSubcutaneously administredDosing is every 2 or every 4 weeksDosing is every 2 or every 4 weeksReduces LDL-C by about 60-70%Reduces LDL-C by about 60-70%Has been shown to lower LDL-C in statin Has been shown to lower LDL-C in statin

intolerant patients, patients with FHintolerant patients, patients with FHOngoing trials assesing safety and efficacy Ongoing trials assesing safety and efficacy

in reducing CHD eventsin reducing CHD events