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2/7/2013
Disclosure Statement of
Financial Interest
• I, (Jack Whitaker), DO have a financial
interest/arrangement or affiliation with one or more
organizations that could be perceived as a real or
apparent conflict of interest in the context of the
subject of this presentation, they are:
Grant/Research Support:
AstraZeneca
Boehringer Ingelheim
F.Hoffmann-La Roche
GlaskoSmithKline
Johnson and Johnson
Janssen
Lantheus Medical Imaging
Novartis
Schering-Plough Research Institute
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2/7/2013
Disclosure Statement of
Financial Interest
• I, (Jack Whitaker), DO have a financial
interest/arrangement or affiliation with one or more
organizations that could be perceived as a real or
apparent conflict of interest in the context of the
subject of this presentation, they are:
Speaker's Bureau:
Amarin
Boehringer Ingelhiem
Daiichi Sankyo
Lilly
Sanofi Aventis
Disclosure Statement of
Financial Interest
• I, (Jack Whitaker), DO have a financial
interest/arrangement or affiliation with one or more
organizations that could be perceived as a real or
apparent conflict of interest in the context of the
subject of this presentation, they are:
Employment:
Wellmont
Disclosure Statement of
Unapproved/Investigative Use
I, (Jack Whitaker),
DO anticipate discussing the
unapproved/investigative use of
a commercial product/device
during this activity or
presentation.
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LIPID
MANAGEMENT
CARDIOVASCULAR MORTALITY & MORBIDITY
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CARDIOVASCULAR MORTALITY & MORBIDITY
Explaining the Decrease in
U.S. Deaths from Coronary
Disease
1980 - 2000
• Reductions in Major Risk
Factors
• Evidence Based Therapies
N Engl J Med 2007 ; 356:2388-98
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Clinical Trials
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currently be
display ed.
CLARIT
Y
TIMI
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TIMI 28
PCI-
CU
RE
CAPRIE
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LIPID
MANAGEMENT
LIPID
MANAGEMENT
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JNC
ATP 4
GUIDELINES
“PROBABLY IN THE SPRING…”
National Heart, Lung, and Blood institute. Clinical practice guidelines aid reports in the development.
Available on website
NCEP - III
• < 100
mg / dL Optimal
• 100 - 129 mg / dL Near Optimal /
Above Optimal
• 130 - 159 mg / dL Borderline High
• 160 - 189 mg / dL High
• > 190
mg / dL Very High
Diabetic or other Risk Factors for Ischemic Heart
Disease VA/DOD Practice Guideline
Goal for LDL < 100
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LIPID
MANAGEMENT
• LDL CHOLESTEROL
• HDL CHOLESTEROL
• TRIGLYCERIDES
• Other
LDL
Cholesterol
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LDL Cholesterol
• HMG-CoA reductase
inhibitors ( “statins” )
• PCSK9 inhibitors (antibody
therapy)
• Microsomal Triglyceride
Transfer Protein inhibitors (
MTP )
LDL Cholesterol
HMG – CoA
Reductase Inhibitors
“Statins”
LDL Cholesterol
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LDL Cholesterol
• < 100
mg / dL Optimal
• 100 - 129 mg / dL Near Optimal /
Above Optimal
• 130 - 159 mg / dL Borderline High
• 160 - 189 mg / dL High
• > 190
mg / dL Very High
Trig > 400 dLDL Performed
Diabetic or other Risk Factors for Ischemic Heart
Disease VA/DOD Practice Guideline
Goal for LDL < 100
LDL Cholesterol
LDL Cholesterol
• HMG-CoA reductase
inhibitors ( “statins” )
• PCSK9 inhibitors (antibody
therapy)
• Microsomal Triglyceride
Transfer Protein inhibitors (
MTP )
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LDL Cholesterol
PCSK9 Inhibitors
Proprotein
Convertase Subtilisin Kexin
Type 9
LDL Cholesterol
PCSK 9 Inhibitors
LDL Cholesterol
PCSK 9 Inhibitors
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LDL Cholesterol
PCSK9 Inhibitors
Early trials
LDL Cholesterol
• HMG-CoA reductase
inhibitors ( “statins” )
• PCSK9 inhibitors (antibody
therapy)
• Microsomal Triglyceride
Transfer Protein inhibitors (
MTP )
LDL Cholesterol
Microsomal
Triglyceride
Transfer Protein
inhibitors ( MTP )
Familiar Hypercholesterolemia
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LDL Cholesterol
MTP
Inhibitors
Familiar Hypercholesterolemia
• Lomitapide
• Mipomersen
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HDL
Cholesterol
HDL Cholesterol
• < 40 mg / dL
Low
• > 60 mg / dL High
HDL Cholesterol
HDL
for
CVD PREVENTION:
HOPE or HYPE ?
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Relationship Between Changes in
LDL-C and HDL-C Levels and CHD
Risk
1% decrease
in LDL-C reduces
CHD risk by
1%
1% increase
in HDL-C reduces
CHD risk by
1%
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation.
2002;106(25):3143-3223; Barter et al. Eur Heart J. 2004;6(suppl A):A19-A22.
Framingham Heart Study: CHD Risk
CHD Risk After 4 Years
3
2
25 (0.7)
45 (1.2)
65 (1.7)
85 (2.2)
1
0
100 (2.6)
160 (4.1)
220 (5.7)
LDL-C, mg/dL (mmol/L)
Men aged 50-70; Castelli. Can J Cardiol. 1988;4(suppl A):5A-10A.
HDL Cholesterol
Current Approaches to Raising HDL - C
• Diet and exercise up to 10%
• Fibrates 5 – 20%
• Statins 3 – 15%
• Niacin up to 30%
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HDL Cholesterol
• Is niacin ineffective? Or
did AIM-HIGH miss its
target?
• HPS – 2 THRIVE study
HDL Cholesterol
Is niacin ineffective?
Or did AIM-HIGH miss its target?
• Perhaps niacin is no good as a preventative agent
• Perhaps raising raising HDL-C is flawed as a
preventive strategy
• Perhaps AIM-HIGH had methodological flaws
• Perhaps statins are so good that, once you prescribe
one, anything else you do will not make much of a
difference
Cleveland Clinic Journal of Medicine January 2012 vol. 79 1 38-43
HDL Cholesterol
HPS – 2 THRIVE study
• After nearly four years of follow-up , the
combination of extended-release niacin /
laropiprant added to statin therapy did not
significantly reduce the risk of CV events
compared to statin therapy but did significantly
increase the risk of nonfatal but serious side
effects
Merck. Merck announces HPS-THRIVE study of Tredaptive (extended-release niacin / laropiprant) did not
achieve primary endpoint. December 20, 2012.
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HDL Cholesterol
NOVEL Approaches to Raising HDL - C
• Cholesteryl Ester Transfer
Protein (CETP) Inhibition
• Infusions of ApoA1
• LXR Antagonists
HDL Cholesterol
CETP inhibition
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Effect of CETP Inhibition on Plasma
Cholesterol Transport
Liver
LDL-R
CE
CE
SR-B1
SR-B1
VLDL-C/
LDL-C
FC
CETP
Bile
HDL-C
CE
LCAT
FC
Extrahepatic
tissues
FC
Adapted from Barter et al. Arteriosclerosis Thromb Vasc Biol.
2003;23(2):160-167.
Relationship Between CETP and
Atherosclerosis
Animal Studies (Rodents)
• Rodents naturally deficient in CETP
• Rodents naturally resistant to
development
of atherosclerosis
• Expression of CETP in transgenic mice
and rats increases atherosclerosis in
most (but not all) models
Barter et al. Arterioscler Thromb Vasc Biol. 2003;23(2):160-167.
Relationship Between CETP and
Atherosclerosis
Animal Studies (Rabbits)
• Rabbits have high level of activity of
CETP
• Rabbits naturally highly susceptible to
the development of atherosclerosis
• Inhibition of CETP in rabbits decreases
atherosclerosis in all models
Barter et al. Arterioscler Thromb Vasc Biol. 2003;23(2):160-167.
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Relationship Between CETP and
Atherosclerosis
CV Risk in Human Population Studies
• Presence of CETP deficiency
associated with elevated HDL-C levels
• Genetic CETP mutations are highly
prevalent in individuals with HDL-C >
100 mg/dl
• CETP deficiency associated with less
vascular events only when
accompanied by higher HDL-C levels
CETP Inhibitor
Differentiation
• CETP inhibitors differ by:
–Their chemical structures
–Physicochemical properties
–Binding site on CETP
Stroes et al. Poster presented at: ACC Annual Scientific Session. March 29 - April 1, 2008; Chicago, Illinois.
CETP Inhibitors
• Torcetrapib
• Dalcetrapib
• Anacetrapib
• Evacetrapib
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Relationship Between CETP and
Atherosclerosis
Human Studies
• Torcetrapib inhibits CETP and raises HDL-C
by about 60 to 70% and lowers LDL-C by
more than 20 to 25%
• In human studies torcetrapib had no effect
on atherosclerosis in 3 imaging trials
• In human studies torcetrapib increased
both mortality and major CV events in a
large endpoint trial
Barter et al. N Engl J Med. 2007;357:2109-2122.
Off-Target Pharmacological Effects
of Torcetrapib
• Torcetrapib has off-target (non-CETP inhibitor) effects
– In patients receiving torcetrapib in the ILLUMINATE
trial there was a significant:
• Increase in blood pressure
• Decrease in serum potassium
• Increase in serum bicarbonate
• Increase in serum sodium
• Increase in serum aldosterone
• The adverse outcome in the ILLUMINATE trial may thus
have been the consequence of off-target actions of
torcetrapib and not related to CETP inhibition
Barter et al. N Engl J Med. 2007;357:2109-2122.
CETP Inhibitors
• Torcetrapib
• Dalcetrapib
• Anacetrapib
• Evacetrapib
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Dalcetrapib
Dalcetrapib
N ENGL J MED 367:22
Dalcetrapib
N ENGL J MED 367:22
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Dalcetrapib
N ENGL J MED 367:22
Relationship Between CETP and
Atherosclerosis
Human Studies
• Dalcetrapib inhibits CETP and raises HDL-C
by about 31 to 40% and had minimal effect
on LDL-C
• Dalcetrapib had no significant effect on any
component of the primary endpoint or total
mortality in a large endpoint trial (halted
due to futility)
• Dalcetrapib had a generally acceptable
side-effect profile
Schwartz et al. N Engl J Med. 2012;367:2089-2099.
CETP Inhibitors
• Torcetrapib
• Dalcetrapib
• Anacetrapib
• Evacetrapib
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TRIGLYCERIDES
TRIGLYCERIDES
• 40 - 160 mg / dL
TRIGLYCERIDES
“the association between triglyceride levels
and cardiovascular disease is more uncertain”
Lars Berglund, John D. Brunzell, Anne C.
Goldberg, Ira J. Goldberg, Frank Sacks,
Mohammad Hassan Murad, and Anton F. H.
Stalenhoef
Clinical Practice Guideline: Evaluation and
Treatment of Hypertriglyceridemia: An Endocrine
Society Clinical Practice Guideline
JCEM 2012 97: 2969-2989;
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TRIGLYCERIDES
• FIBRATES
• NIACIN
• OMEGA - 3 FATTY ACIDS
TRIGLYCERIDES
ICOSAPENT
ETHYL
Indications and Usage
VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet
to reduce triglyceride (TG) levels in adult patients with severe
(≥ 500 mg/dL) hypertriglyceridemia.
• The effect of VASCEPA on the risk for pancreatitis in patients
with severe hypertriglyceridemia has not been determined.
• The effect of VASCEPA on cardiovascular mortality and
morbidity in patients with severe hypertriglyceridemia has not
been determined.
TRIGLYCERIDES
Indications and Usage
VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet
to reduce triglyceride (TG) levels in adult patients with severe
(≥ 500 mg/dL) hypertriglyceridemia.
• The effect of VASCEPA on the risk for pancreatitis in patients
with severe hypertriglyceridemia has not been determined.
• The effect of VASCEPA on cardiovascular mortality and
morbidity in patients with severe hypertriglyceridemia has not
been determined.
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TRIGLYCERIDES
ICOSAPENT ETHYL
INFLAMMATION
and
ATHEROSCLEROSIS
INFLAMMATION and ATHEROSCLEROSIS
• Cardiovascular Inflammation
Reduction Trial (CIRT)
• Canakinumab Antiinflammatory Thrombosis
Outcomes study (CANTOS)
• The Stabilization of Plaques
using Darapladib ( SOLID
TIMI 52 )
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INFLAMMATION
and
ATHEROSCLEROSIS
Cardiovascular
Inflammation Reduction
Trial (CIRT)
INFLAMMATION and ATHEROSCLEROSIS
Cardiovascular Inflammation
Reduction Trial (CIRT)
• Methotrexate
• Trial to evaluate efficacy in preventing
recurrent cardiovascular events in
patients with MI prior to study entry
INFLAMMATION
and
ATHEROSCLEROSIS
Canakinumab
Anti-inflammatory
Thrombosis Outcomes
study (CANTOS)
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INFLAMMATION and ATHEROSCLEROSIS
Canakinumab
Anti-inflammatory Thrombosis
Outcomes study (CANTOS)
• Anti- IL -1B monoclonal antibody
• Trial to evaluate efficacy in
preventing recurrent cardiovascular
events in patients with MI prior to
study entry and elevated hsCRP
INFLAMMATION
and
ATHEROSCLEROSIS
The Stabilization of Plaques
using
Darapladib
( SOLID TIMI 52 )
INFLAMMATION and ATHEROSCLEROSIS
The Stabilization of Plaques using
Darapladib
( SOLID TIMI 52 )
• Selective inhibitor of lipoprotein - associated
phospholipase A2 ( Lp – PLA2 )
• Trial to evaluate the efficacy in preventing
cardiovascular death, nonfatal MI and
nonfatal stroke in patients following acute
coronary syndrome
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Case History:
A 69 year old man is referred to your service for routine evaluation.
He has a history of hypertension, dyslipidemia, prior 25 pack year
Tobacco use, obesity, and non-insulin dependent diabetes mellitus.
He admits to poor dietary compliance. He has a prior history of
stable exertional angina and underwent cardiac catherization six
years ago , which revealed an 90% mid-LAD occlusion that was
treated with a percutaneous coronary intervention and bare metal
stenting. Current medications consist of aspirin, lisinopril,
metformin, and metopropol. On examination his BP is 155/95
mmHg, pulse is 85 bpm and regular. Cardiovascular exam is
unremarkable. On laboratory testing, he is found to have a
creatinine of 0.6 mg/dl, fasting glucose of 112 mg/dl, liver function
test within normal limits, and a fasting lipid panel of triglycerides
194 mg/dl, HDL 42 mg/dl, and a calculated LDL of 158 mg/dl. He
inquires as to the benefit of cholesterol lowering therapy?
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Lowering this patient’s LDL-C level from
158 mg/dl (4.0 mmol/L) to 116 mg/dl (3.0
mmol/L) with a statin medication would
result in which of the following?
A. No change in this patient’s
long-term future cardiovascular
risk
B. 20% - 25% decrease in relative
risk of future CV events
C. 12% increase in risk of
worsening glucose intolerance
D. 10% decrease in relative risk of
future CV event
E. It is unknown whether statin
medication alters the risk of
major CV events in patients
with known coronary artery
disease
answer
There is clear evidence that in patients with underlying
coronary disease, the use of statin medications results
in substantial reduction in risk of future cardiovascular
events due to lowering of LDL cholesterol levels. Prior
work has suggested that lowering LDL cholesterol on
average 1 mmol/L (~40 mg/dL), reduces the relative risk
of cardiovascular events 20-30% (CTT Collaboration,
Lancet, 2010; LaRosa, NEJM, 2005). While a slight
increase in risk of glucose intolerance has been
observed in patients treated with statin medications,
this overall risk is quite low (Sattar N, et al. Statins and
risk of incident diabetes: a collaborative meta-analysis
of randomized statin trials. Lancet. 375: 735–42. 2010)
Thank you!
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