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 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
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
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