Lipids made simple
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Transcript of Lipids made simple
LIPIDS in primary care
• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion
Lipoprotein metabolism
The Lipids and Lipoproteins1. Ester. Cholesterol
(EC)2. Triglycerides (TG)
What are the important
components (two) of
lipids in the plasma ?
What are the other two
components in lipids in
their outer layer ?
1. Free Cholesterol (FC)2. Phospholipids (PL)
What are Apoproteins ? Why are they needed
in the lipid molecules ?
1. The outer protein coat is made of Apoproteins
2. To make lipids soluble and thus help transport
ECTG
Apoprotein boat
1.Make the lipids soluble and transportable
2.Structural Integrity of the lipoprotein
3.Act as ligands for cell receptors4.Activate enzymes such as LPL, LCAT
as cofactors
Cholesterol biosynthesis
CORECHOLESTEROL
ESTERS
TRIGLYCERIDES
MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOL
INTEGRAL APOPROTEINS
PERIPHERAL APOPROTEINS
Structure of lipoprotein
The Lipoprotein Particles
Lipemic Turbid Serum
The Atherogenic Particles
Apolipoprotein B
Non-HDL-CMeasurements
TG-rich lipoproteins
VLDL VLDLR IDL LDL SLDL
The smaller the particleThe greater is the danger
Lp(a)Chylo M
Duodenum
Fat
CCK
Bile salts
Micelles
Enterocytes
ACAT
Lacteal Thoracic duct Systemic circulation
apo B-48
apo-Capo-E
Chylomicron
Liver
Chylomicron
apo-B-48
apo-E
apo-C
Adipocyte
Chylomicron remnant
When TGs < 20% remaining, they loose apoC
apoE
VLDL
LDL-R Chylomicron remnant receptor
Liver
apo-B-100
TGs <50%
TGs <30%
VLDL Remnant
IDL
TGs < 10%Loses apoE & apoC
LDL
LDL-R
apo-B-100
Cell wall Aldosterone
CortisolSex
hormones
apoB-100
VLDL
VLDL
LPL
Adipocyte &Myocyte
Remains attached to LPL
Chylomicrons and VLDL
• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion
LDL
LDLEndothelium
Vessel LumenMonocyte
Macrophage
AdhesionMolecules
Havoc by LDL at Endothelium
Foam Cell
Intima
Modified LDLCytokines
Cell ProliferationMatrix Degradation
Growth FactorsMetalloproteinases
Ross R. N Engl J Med 1999;340:115-126.
MCP-1
21
Statin Evolution
1991 1993 1994 1995 1997 1999 2001 20032004
Pravastatin ApprovedSimvastatin Approved
NCEP(ATP II)
Atorvastatin Approved
Cervastatin Approved
NCEP(ATP III)
Cervastatin Withdrawn
Ezetimibe Approved
Rosuvastatin Approved
MARS4S
WOSCOPS
CAREPost CABG
LIPID –AFCAPS/TexCAPSMIRACL
FLORIDAHPS
PROSPER
ALLHAT
ASCOT
REVERSAL
CARDS
PROVE IT - TIME22AZZ
TNTIDEA
L
SEARCH
PI=placebo; Rx=treatment
Shepherd J et al. N Engl J Med. 1995;333:1301-1307.4S Study Group. Lancet. 1995;345:1274-1275.Sacks FM et al. N Engl J Med. 1996;335:1001-1009.Downs JR et al. JAMA. 1998;279:1615-1622.Tonkin A. Presented at AHA Scientific Sessions, 1997.
Mean LDL-C level at follow-up (mg/dL)
Relation Between CHD Events and LDL-C in Recent Statin Trials
0
5
10
15
20
25
30
90 110 130 150 170 190 210
% withCHD event CARE-Rx
LIPID-Rx
4S-Rx
CARE-PILIPID-PI
4S-PI
2° Prevention
1° Prevention
WOSCOPS-PI
WOSCOPS-RxAFCAPS/TexCAPS-Rx
AFCAPS/TexCAPS-PI
-20
-26
5
-31-33
-22-25
-35
8
-34
-42
-30
-20
-28
5
-24
-20
-9
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159)
N=number enrolled.
TC LDL-C
HDL-C
1o prevention
2o prevention
2o prevention
Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Recent Statin
TrialsNonfatal MI/CHD death
CHD death
All-cause mortality
%+
Lipid Profile Report
PP Fasting
26
Lipid profile report
• TC 200 mg/dl • HDL 40 mg/dl• TGL 150 mg/dl
• VLDL = 30 (TGL/5)• LDL =130 (TC-HDL-
VLDL)
• TC 200 mg/dl • HDL 40 mg/dl• TGL 450 mg/dl
• VLDL = 90 (TGL/5)• LDL =70(TC-HDL-
VLDL)
Non HDL
NON HDL C=Total Cholesterol– HDL cholesterol
VLDL
IDL
LDL
VLDL
IDL
LDL
NONHDL
SMALL DENSE APO B
NON HDL GOAL: 30mg above LDL goal
ATP III
• Obtain a fasting lipid profile • CHD risk factor • Major risk factors (ABC HF)• Target LDL• TLC
LDL mass may underestimate atherogenic risk
Cholesterolbalance
100 mg/dL 100 mg/dL
Up to 70%more particles
Adapted from Otvos JD, et al. Am J Cardiol 2002; 90 (suppl):22i-29i
• Increased susceptibility to oxidation
• Increased vascular permeability
• Decreased affinity for LDL receptor
• Association with insulin resistance syndrome
• Association with high TG and low HDL
Small Dense LDL and CHD: Potential Atherogenic Mechanisms
Austin MA et al. Curr Opin Lipidol 1996;7:167-171.
Statin Action
36
Time Course of Statin Effects
* Time course establishedDays Years
LDL-C lowered*
Inflammationreduced
Vulnerableplaquesstabilized
Endothelialfunctionrestored
Ischemicepisodesreduced
Cardiac eventsreduced*
37
Dual Inhibition
DuodenumDuodenum
JejunumJejunum
IleumIleum
CMapoB48
LiverLiver
CM RemnantapoB48
VLDLapoB100
Ezetimibe
X
LDLapoB100
XStatin
ColonColon38
Rosuva
Simva
Atorva
10 mg
Adapted from Jones P.H. et al. Am J Cardiol 2003;92:152–160
20 40 80
Prava Not achieved with maximum licenced dose
Statin Dose Required to Achieve 45–50% Reduction
Fluva Not achieved with maximum licenced dose
Jones PH, et al. Am J Cardiol. 2003;92:152–160.
-60%
-50%
-40%
-30%
-20%
-10%
0%
Mean
% C
han
ge in
LD
L-C
fro
m
Un
treate
d B
aselin
e V
alu
e Atorvastatin Rosuvastatin Simvastatin
14% with3 titrations
9% with2 titrations
18% with3 titrations
10 mg 20 mg 30 mg 40 mg
−28
−7−4−7
−46†
−6*−3*
−37
−6−5−3
The Initial Statin Dose is Important
The Initial Statin Dose is Important
40
Molecular pathway
EARLYHIGH DOSE
Lipophylic statins better
Additional sulphone binding site Arg568
Istvan and Deisenhofer Science 2001; 292:1160-1164
Rosuvastatin
Rosuvastatin: Additional binding site with HMG-CoA
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
Fluvastatin (20, 40, 80 mg)
Rosuvastatin (10, 20, 40 mg)
Lovastatin (20, 40, 80 mg)
Atorvastatin (10, 20, 40, 80 mg)
Simvastatin (40, 80 mg)
Occu
rren
ce o
f A
LT >
3
×ULN
(%
)
Persistent elevation is elevation to >3 x ULN on 2 successive occasionsBrewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
ALT >3 × ULN: Frequency by LDL-C reduction
Liver effects - Benefit versus Risk
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
Occu
rren
ce o
f C
K >
10 ×
ULN
(%
)
Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)
Rosuvastatin (10, 20, 40 mg)
Pravastatin (20, 40 mg)
Atorvastatin (10, 20, 40, 80 mg)
Simvastatin (40, 80 mg)
CK >10 x ULN: Frequency by LDL-C Reduction
Muscle effects - Benefit versus Risk
CHD All Patients
High RiskPati
ents
Ach
ievin
g G
oal
(%)
Inadequate Achievement of NCEP ATP III Treatment Goals, Especially among
Patients at Highest Risk
70%
Adapted from Pearson TA et al. Arch Intern Med 2000;160;459-467.
Low Risk
Drug therapy included statins (fluvastatin, lovastatin, pravastatin, simvastatin), gemfibrozil, bile acid sequestrants, niacin, psyllium fiber, and combination drug therapy.
1,352 4,1371,924861
40%
18%
39%
n =
0%
20%
40%
60%
80%
100%
34.9
24.8
29.6
19.4
0
10
20
30
40
Diabetes No Diabetes
ControlTreatmentc
Maj
or V
ascu
lar
Eve
nt R
ateb
, %
CVD Risk Higher Than Patients With No Diabetes on Placebo
Residual Risk
Diabetes No Diabetes
Residual Risk
CTT Collaborators. Lancet. 2008;371:117-125.
a4.3-year mean follow-up of 18 686 patients with diabetes; n = 71 370 patients with no diabetesbNonfatal MI, CHD death, stroke, or coronary revascularizationcEvent rate per 1 mmol/L (39 mg/dL) reduction in LDL-C
Statin Therapy Residual CVD Events
CTT Meta-Analysis of 14 Statin Trialsa
• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion
Bays H. Expert Rev Cardiovasc Ther 2004;2:89-105.
HL
TGRemnants
Smalldense LDL
HL
TG
Renal clearance
Smalldense HDL
TG
HL
Atherogenic Dyslipidemia
CETP
TG
CE
CETPCE
TG
LPL
TG
Apo E
TG
High
ApoCIII
Apo B
TGRL
TG
CE
TGpool
Adiposity High carbohydrate
diet Insulin resistance Genetic
predisposition
TGTG
CE
30-D
ay R
isk
Dea
th,
MI,
Or
Rec
urre
nt A
SC
(%)
Role of Triglycerides: PROVE IT-TIMI* Trial1
• Elevated triglyceride level ≥200 mg/dL increases the risk of death, myocardial infarction or acute coronary syndrome
significantly
LDL-C <70 mg/dL,on statins
1. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.
On – Treatment (mg/dL)
TGL/HDL RATIO
• BELOW 3.8 FOR ASIANS 3.0• GOOD USEFUL RATIO IN DIABETICS,
METABOLIC SYNDROME • ABNORMAL RATIO INDICATES
INCREASE IN SMALL DENSE LDL ALTHOUGH BLOOD LEVELS OF LDL IS NORMAL OR LOW
JACC 2005
• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion
LDL-C & HDL-C v/s CAD RiskFramingham Heart Study
Reprinted from Castelli WP. Can J Cardiol. 1988;4:5A–10A, with permission from Pulsus Group Inc.
0
1
2
3
220 160 100 mg/dL85
6545
25
HDL Chol
este
rol (
HDL-C)
LDL Cholesterol (LDL-C)
Coro
nary
Art
ery
Dis
ease
(
CA
D)
Rela
tive R
isk
mg/d
L
59
Antioxidative Activity
AntithromboticActivity
ReverseCholesterolTransportCellular
CholesterolEfflux
AntiapoptoticActivity
Anti-inflammatoryActivity
HDL-CAnti-infectious
Activity
Adapted from Chapman MJ et al. Curr Med Res Opin. 2004,20:1253-1268, with permission from LibraPharm, Ltd.Assmann G et al. Annu Rev Med. 2003,54:321-341.
EndothelialRepair
VasodilatoryActivity
Antiatherogenic Actions of HDL-C
Relationship Between Changes in
LDL-C and HDL-C Levels and CHD Risk
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670. 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
1% decreasein LDL-C reduces CHD risk by 1%
1% increasein HDL-C reduces CHD risk by 3%
Nicotinic Acid – Mechanism of Action
Liver CirculationHDL
Serum VLDL results in reduced lipolysis to LDL
Serum LDL
VLDL
Decreases hepatic production of VLDL and of apo B
VLDL secretion
Apo B
Hepatocyte Systemic Circulation
Mobilization of FFA
TG synthesis
VLDL
LDL
Lipid Effects of Niacin Extended-Release (ER)
Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U.
• Lipid effects
– Most potent agent for HDL: 20%+; nonlinear– Favorable effects on LDL-particle density– LDL (linear), TG, and Lp(a)
• Tolerability with concomitant statin therapy
– No change in rate of liver adverse effects or myositis versus statin monotherapy
302010
0-10-20-30-40-50
mg500 1000 1500 2000 2500 3000
Ch
an
ge f
rom
Base
line
(%)
-8-13
-22 -21-16
293024
2116
10
-21
-32
-44-39
-14
-5
-26
-3
-12
-30-25
-17
HDL-C
LDL-C
Lp(a)
TG
0%
20%
40%
60%
80%
100%
4 wk 8 wk 12 wk 24 wk 1 y
Pe
rce
nt
Us
ers
Average Daily Dose of ER Niacin Prescription Refills at Fixed Time Intervals Niaspan discontinuation rate high, adherence rate low, dose less optimal. Only 47% of all ER niacin users reached recommended maintenance dose of 1000 mg or higher, and only 77% reached the dose of 2000 mg during follow-up. Clinical evidence showed that nonadherence for medication leads to the prevalence of the disease and discontinuation from medication increases patient mortality risk.
1. Retrospective cohort study using administrative claims data from 2000 to 2003 Ingenix Lab/Rx Database™. Kamal-Bahl et al. Abstract presented at AHA 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, Washington, D.C., May, 2006. 2. Ho PM, et al. Arch Intern Med. 2006;466:1836–1841. 3. Ho PM et al. Arch Intern Med. 2006;166:1842–1847.
N=14,386 N=6,349 N=5,277 N=5,402 N=2,104
>1500 mg
1001-1500 mg
751-1000 mg
501-750 mg
≤500 mg
Niacin-Induced Flushing Limits Niacin Utilization
AIM-HIGH
3300 patients
Primary End PointComposite of CHD death, nonfatal MI, ischemic stroke, or hospitalization for high-risk ACS with objective evidence of ischemia
Key Secondary End PointsComposite of CHD death, nonfatal MI, or ischemic stroke
4 year follow-up
Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes
ClinicalTrials.gov Identifier: NCT00120289
DUAL PATHOGEN
ATHEROGENIC
THROMBOGENIC
RISK:2-4 FOLDWTH LOW HDL:8 FOLDWITH HIGH LDL:12 FOLDALL THREE:25 FOLD
RESIDUAL RISK DUE TO
• LOW HDL• HIGH TRIGLYCERIDES• SMALL DENSE LDL• NON HDL CHOLESTEROL• Hs CRP• LIPOPROTEIN (a)
*P<0.002 RSV 20 mg vs ATV 20, 40 & 80 mg; RSV 40 mg vs ATV 40 & 80 mg
Jones P.H. et al. Am J Cardiol 2003;92:152–160
0
2
4
6
8
10
12
Mean
ch
an
ge in
HD
L-C
from
baselin
e (
%)
7.7%
9.6%*
Rosuvastatin*
10 20 40 80
Dose, mg (log scale)
3.2%
5.6%
Pravastatin6.8%
Simvastatin
5.3%
2.1% Atorvastatin
5.7%
Rosuvastatin achieves significantly greater increase
in HDL-C
RESIDUAL RISKTHE ISSUES
• Whether treating residual risk is really needed when LDL goal is achieved ?
• How to treat it?• Is there evidence that treating
residual risk decreases clinical events?
4 major statin benefit groups were identified for whom the ASCVD risk reduction clearly outweighs the risk of adverse events.
1) with clinical ASCVD, 2) primary elevations of LDL–C >190 mg/dL, 3) diabetes aged 40 to 75 years with LDL– C 70
to189 mg/dL and without clinical ASCVD, or 4) without clinical ASCVD or diabetes with LDL–C
70 to189 mg/dL and estimated 10-year ASCVD risk >7.5%.
• Lipoprotein metabolism • LDL • TGL• HDL• Current guidelines • Case discussion
Major recommendations for statin therapy for ASCVD prevention
Major recommendations for statin therapy for ASCVD prevention (Conti.... from prev.
page)
Initiating statin therapy in individuals with clinical ASCVD
Initiating statin therapy in individuals without clinical ASCVD
Initiating statin therapy in individuals without clinical ASCVD (Conti.... from prev.
page)
Statin Therapy: Monitoring therapeutic response and adherence
Guidelines that aren’t
implemented never workNow, we have an unparalleled
opportunity to prevent ASCVD
– but, only if we act !!
80