The case for intensive lipid management: The opportunities and issues for cardiologists Prof. John Betteridge University College London Slide lecture prepared and held by: Master Class: Advanced CV Risk management in cardiology June 17-18, 2011, London Presentation topic
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The case for intensive lipid management:The opportunities and issues for
cardiologists
Prof. John BetteridgeUniversity College London
Slide lecture prepared and held by:
Master Class: Advanced CV Risk management in cardiologyJune 17-18, 2011, London
Presentation topic
A Survey of 246 Suggested Coronary Risk Factors
Paul N. Hopkins and Roger R. Williams
Department of Internal Medicine, Cardiology Division, University of Utah
Medical Center, Salt Lake City, UT 84132 (USA)
Atherosclerosis 1981
BMJ 1975, 4 500-502
Down regulate HMGCoA reductaseReduce LDL receptor synthesis
Esterified by ACAT (storage)
The Fate of LDL
PCSK9 preventsLDLR recycling
LDLR
FH3: mutations in PCSK9Proprotein convertase subtilisin/kexin type 9
• PCSK9 is a protease which binds to LDL-R and directs them to lysosomes for degradation, rather than recycling to cell surface
• Loss of function (non-sense and some mis-sense) mutations lead to LDL levels– 2.6% of US blacks, LDL 28%, CHD 88%– 3.2% of US whites, LDL 15%, CHD 47%
• (Cohen et al. NEJM 2006;354:1264)• Rare gain of function (other mis-sense) mutations described
which lead to severe FH– D374Y accounts for 2% of FH in UK– phenotype generally more severe than HeFH due to LDLR mutations– true homozygotes not described?
• Statins increase PCSK9 as well as LDLR activity – counterproductive
• Potential therapeutic target
Tall, NEJM 2006;354:1310Horton et al. Trends Biochem Sci 2006;32:71Zhang et al. PNAS 2008;105:13045
Familial Hypercholesterolaemia
Autosomal dominant inheritanceXanthomataPremature vascular diseaseElevated low density lipoprotein levelsGenetic defect at the LDL receptor
COHEN et al. New Engl J Med 354:1264, 2006
P=0.003
No Yes
PCSK946L
Coro
nary
Heart
Dis
ease
( %
)
12
8
4
0
Freq
uen
cy (
% )
Plasma LDL Cholesterol in White Subjects ( mg/dL)
No PCSK946L Allele ( n=9223 )
30
20
10
0
30
20
10
0
0 50 100 150 200 250 300
0 50 100 150 200 250 300
50th Percentile
PCSK946L Allele ( n=301 )
LDL-C Distribution and CAD Incidence Presence or Absence of PCSK9 46L Allele
Dallas Heart Study
LDL and Atherogenesis
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel LumenLDL
LDL Readily Enter the Artery Wall Where They May be Modified
LDL
Intima
Modified LDL
Modified LDL are Pro inflammatory
Hydrolysis of Phosphatidylcholineto Lysophosphatidylcholine
Other Chemical Modifications
Oxidation of Lipidsand ApoB
Aggregation
LDL
LDLEndothelium
Vessel LumenMonocyte
Macrophage
AdhesionMolecules
Macrophages and Foam Cells Express Growth Factors and Proteinases
• Available drugs of limited efficacy, poorly tolerated or both.
small differences between control and treated groups
• Clinical trial science poorly developed. low end-point numbers poor data collection Lack of definitive outcomes: small reduction in CHD events (mainly non-fatal MI) no effect on overall mortality
Dietary cholesterol
Biliarycholesterol
Effects of Statins
Intestinal pool
LDL receptors
Hepaticcholesterol
Synthesis
Plasma LDL
Statins
High-risk CHD patients (high cholesterol)
Majority of CHD patients (broad range of cholesterol levels)
PROVE-IT TrialIntensive and Moderate Lipid-Lowering
after Acute Coronary SyndromesPopulation:4162 patients within 10 days of acute coronary syndromeTreatment:Standard: Pravastatin 40mg/day mean LDL 2.46mmol/l Intensive: Atorvastatin 80mg/day mean LDL 1.6mmol/lPrimary endpoint:Death , MI, unstable angina requiring hospitalisation, revascularisation and strokeFollow-up:18-36 months (mean 24 months)
Cannon et al N Engl J Med April 8th 2004
Pravastatin 40mg 26.3%
16% reduction p=0.005C
VD
En
dp
oin
ts
24 3018
Months126
Atorvastatin 80mg 22.4%
Intensive Lipid Lowering with Atorvastatin in Patients with Stable
Coronary DiseaseTreat to New Targets Trial (TNT)
Population: 10,001 patients with CHD: previous MI, angina with objective evidence of atherosclerotic CHD, coronary revascularization.
Protocol: 15464 CHD patients, LDL-C 130-250mg/dl (3.4-6.5mmol/l) 8 week run-in treatment with atorvastatin 10 mg/day. 5461 excluded. If LDL -C <130mg/dl randomised to either atorvastatin 10mg/dl or 80mg/day. Median follow-up 4.9yrs.
Primary end point: Occurrence of first CVD event; CHD death, non-fatal, non procedure - related MI, resuscitation after cardiac arrest, fatal or non fatal stroke.
.
La Rosa et al NEJM March 2005
La Rosa et al NEJM March 2005
Treat to New Targets: Lipid Effects
Primary Efficacy Outcome Measure: First Major Cardiovascular Event*