Transcript PACE Prague Sept 2011 HDL Master Class Modifying the

Diabetic dyslipidemia: The proatherogenic role of CETP and future use of
CETP inhibitors
Prof. John Betteridge
University College London
United Kingdom
Diabetes and Cardiovascular
Disease: Time To Act!
“With the rising tide of diabetes
around the globe, the double jeopardy
of diabetes and cardiovascular
disease is set to result in an explosion
of these and other complicationsunless preventive action is taken.”
Prof Sir George Alberti, IDF President.
International Diabetes Federation
Risk of Fatal and Non-fatal CHD in Men
with Type 2 Diabetes
Prospective follow-up of 4045 men 60 to 79 years
379 major CHD events
Comparison of late (>60 years) versus early onset diabetes (<60 years)
No
diabetes
No CHD
Diabetes and
CHD
Diabetes
Late onset
Early onset
Rate
8.7
15.7
21.7
25.7
Nb events
229
36
18
70
HR*
1
1.69 (1.182.41)
2.93 (1.74-4.64)
2.62 (1.99-3.44)
HR**
1
1.55 (1.082.21)
2.63 (1.56-4.42)
2.61 (1.96-3.49)
*Adjusted on age, smoking, alcohol consumption,social class, BMI, physical activity and previous stroke;
** Further adjustment on risk factors
Vannamethee SG et al. Arch Intern Med 2011.
Numbers of People (106) with
Diabetes for 2000 and 2010
26.5
14.2
32.9
17.5
24%
23%
84.5
132.3
9.4
57%
14.1
15.6
50%
22.5
1.0
44%
1.3
30%
Incidence in 2000
Incidence in 2010
% increase from 2000 to 2010
World
2000:151 million
2010:221 million (+46%)
Adapted from Amos AF et al Diabet Med 1997;14:S7-S85.
Survival Post-MI in Diabetic and
Non-diabetic Men and Women
Survival (%)
90
80
100
Men
(n=1628)
70
60
50
40
Women
90
(n=228)
Survival (%)
100
0
80
(n=568)
70
60
50
(n=156)
40
0
0 10 20 304050607080
Months post-MI
0 10 20 304050607080
Months post-MI
No diabetes
Diabetes
Sprafka JM et al Diabetes Care 1991;14:537.
Temporal Mortality Trends
Patients with and without Diabetes
Suffering a Myocardial Infarction
(a comparison of 1762 patients in 1995 with 1642 patients in 2003)
Cubbon RM et al. Eur Heart J 2007; 28: 540–545
Plaque Characteristics
Plaque burden increased in diabetic subjects
and distal burden increased in type 2
Mean percent necrotic core greater in type1
(p=0.05) and type 2 (p=0.004)
Macrophage plaque area and T cell infiltration
greater in diabetic subjects (p=0.03)
Mean number of fibrous cap atheromas
greater in type 2 ( p<0.02)
Healed plaque ruptures greatest in type 1
and type 2
Burke et al ATVB, 2004; 24: 1266
UKPDS:
Risk Factors for MI.
•
•
•
•
•
LDL cholesterol
HDL cholesterol
HbA1c
Systolic blood pressure
Smoking
Baseline Epidemiology Data
Turner et al BMJ 1998
Atherogenic Dyslipidaemia
( Metabolic Syndrome, Type 2
Diabetes)
Triglycerides
Insulin
resistance
Small, dense LDL
Remnants
HDL2
Clinical Manifestations
of Central Obesity
Type 2 diabetes
dysglycaemia
Insulin
resistance
FFAs
Adiponectin
Central
Obesity
Dyslipidaemia
low HDL
small, dense LDL
hypertriglyceridaemia
Hypertension
Endothelial dysfunction
Inflammation (hsCRP)
Impaired thrombolysis
 PAI-1
Courtesy of Selwyn AP, Weissman PN.
Lipoprotein Metabolism in Insulin Resistance
and Type 2 Diabetes
Adipose tissue
LDL profile by
electrophoresis
ADIPONECTIN
NEFA
VLDL
Normal
LDL
Lipoprotein lipase
Elevated
TRL
Chylomicrons
Intestine
4
2
0
TG CE
Pattern A
CE
CETP
TG
TG-rich
LDL
TG CE
Plasma
Triglycerides
(mmol/l)
Small,
dense LDL
diabetes
Type 2
Controls
0 2 4 6 9 12 24
Hours
Hepatic lipase
Pattern B
Characteristics of LDL Subclasses
Large, buoyant LDL
pattern A
Phospholipids
Small, dense LDL
pattern B
GAG-binding segments
(3147–3157) (3359–3367)
Free cholesterol
apo B-100
• Polar lipids: 63.3%
• Accessible apo B-100: 36.7
• Low GAG affinity
• Polar lipids: 35.6%
• Accessible apo B-100: 64.4
• High GAG affinity
Hurt-Camejo E et al Curr Opin Lipidol 2000;11:465
The Absolute Concentration of LDL-C
Can be Misleading in Subjects with Small,
Dense LDL.
Large, buoyant
particles
Apo B
Small, dense
particles
More apo B
Sniderman AD et al Ann Intern Med 2001
At the same LDL-C level,
the number of LDL
particles is increased,
if small and dense
Each LDL particle
contains one molecule
of apo B
Apo B concentration
increases in direct
relation to number of
LDL particles
LDL Subfractions
“Control” vs Patient with Insulin Resistance
DM-TG 2.95 mmol/l
DJB-TG 0.9 mmol/l
III
I
II
Increasing density
Decreasing size
Statins:The Evidence Base.
Placebo MI rate per 100 subjects per 5 years
Continuum
of risk
22.6 Secondary
prevention
12.9
HPS
8.44
7.9
2.8
Primary
prevention
4S
(simvastatin)
High-risk CHD patients
(high cholesterol)
CARE
(pravastatin)
LIPID
(pravastatin)
WOSCOPS
(pravastatin)
AFCAPS/TexCAPS
(lovastatin)
Majority of
CHD patients
(broad range of
cholesterol levels)
Patients at high risk
of CHD (high
cholesterol)
Patients at low
risk of CHD
(low HDL-C)
CARDS:
Collaborative AtoRvastatin Diabetes
Study
Patient Population




Type 2 diabetes (40-75y)
No prior MI or CVD
Other risk factors +
Lipid profile:
 LDL-C <159 mg/dL
(4.14 mmol/L)
 TG <600 mg/dL
(6.78 mmol/L)
Collaboration in the UK
with Diabetes UK, NHS R&D
and Pfizer

2,838
Patients
d/b PBO
Atorvastatin 10 mg
304 events
Expected completion 2005
Actual termination June 2003 after
2nd interim analysis 210 events
Primary Endpoint
Time
to first major CVD event
Colhoun et al. Diabetic Med 2002; 32: 259-264.
Median Lipid Levels by Treatment
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
Average difference 26%
Average difference 40%
1.40 mmol/L (54mg/dL) p<0.0001
1.20 mmol/L (46mg/dL)
p<0.0001
6
4
3
4
2
2
1
0
0
0
1
2
3
4
4.5
0
Years of Study
Placebo
1
2
3
Years of Study
Atorvastatin
4
4.5
Median Lipid Levels by Treatment
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)
Average difference 1%
Average difference 19%
0.02 mmol/L,0.8mg/dL p=0.0002
0.39 mmol/L, 35mg/dL p<0.0001
1.4
2
1.2
1
.8
1
.6
.4
.2
0
0
0
1
2
3
4
4.5
0
Years of Study
Placebo
1
2
3
Years of Study
Atorvastatin
4
4.5
Cumulative Hazard for Primary
Endpoint
Cumulative Hazard (%)
15
Relative Risk -37% (95% CI: -52, -17)
Placebo
127 events
P=0.001
2.46/100
person yrs
10
Atorvastatin
83 events
1.54/100
person yrs
5
0
0
Number at risk
Placebo 1410
1
2
3
4
4.75
1351
1306
651
305
Atorva
1022
1392
1361
1074
694
328
1428
Years
Incidence of major vascular events (%)
Heart Protection Study
Diabetes Subgroups
With/Without CHD or Other CVD
50
Placebo
Simvastatin 40 mg
40
RRR
12%
RRR
22%
30
RRR
23%
20
RRR
19%
RRR
31%
10
1009
0
972
Diabetes
+ CHD
5683 5722
No diabetes
+ CHD
519
551
Diabetes
+ other CVD
1481 1449
1455 1457
No diabetes
+ other CVD
Diabetes
+ no CVD
HPS Collaborative Group. Lancet. 2003;361:2005
LDL-C and change in percent atheroma volume in
IVUS studies
2
REVERSAL5
1.5
pravastatin
CAMELOT4
placebo
Change in
Percent
Atheroma
Volume*
(%)
1
ACTIVATE1
placebo
0.5
50
60
70
80
90
Mean LDL-C (mg/dL)
-0.5
Progression
placebo
atorvastatin
0
-1
A-Plus2
REVERSAL5
100
110
120
Regression
ASTEROID3
rosuvastatin
†ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin
therapies but included placebo arms who received background statin therapy (62%, 80% and 84% respectively).
*Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT
1 Nissen S et al. N Engl J Med 2006;354:1253-1263. 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al.
JAMA 2006;295 (13):1556-1565 4 Nissen S et al. JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291:1071–1080
Objective:
To characterize IVUS defined coronary
atherosclerosis progression in diabetic patients
Methods:
Systematic analysis, 2,237 subjects in RCTs of
atherosclerosis progression, Reversal, Camelot,
Activate, Asteroid and Illustrate .
All patients had CAD, at least one lumen
narrowing >20% on diagnostic arteriogram.
The pattern of disease progression was compared
in subjects with and without diabetes
Diabetic patients had a greater percent atheroma
volume 40.2 ± 0.9% vs 37.5 ± 0.8% on multivariate
analysis, p<0.0001 at baseline.
Atherogenic Dyslipidaemia
( Metabolic Syndrome, Type 2
Diabetes)
Triglycerides
Insulin
resistance
Small, dense LDL
Remnants
HDL2
HPS Diabetic Cohort
Benefits of Simvastatin by Baseline LDL
and HDL-Cholesterol
35
27.9
30
25
20
31.1
23.3
20.9
25.9
21.3
15.7
16.8
15
10
5
0
2nd Qtr
3rd Qtr
4th Qtr
LDL-Cholesterol
HDL-Cholesterol
3mmol 3mmol 0.9mmol 0.9mmol
1st Qtr
Placebo
West
Simvastatin
North
Role of Cholesteryl Ester Transfer Protein
(CETP) in Lipoprotein Metabolism
HDL2
VLDL
Enrichment with
cholesteryl esters
CE
CETP
TG
Transient enrichment
with triglycerides (TG)
HL
Hepatic Lipase (HL)
small
dense
LDL
Formation of
small dense LDL
Facilitated modification of
LDL
Formation of small
HDL3 and lipid-poor
pre-HDL
HDL3
Pre  HDL
Regeneration of HDL
or removal from circulation,
e.g. by renal filtration
Von Eckardstein, Expert Review of Cardiovascular Therapy 2010, 8(3):345–58.
Dysfunctional HDL in Diabetes
A-I
CE
CE
TG
TG
A-I
Oxidation
CETP↑
Glu
A-I
A-I
CE
TG
PAF-AH
Glx
J
A-I
PAF-AH A-I
PAF-AH
SAA
•
ABCA1-mediated cholestrol
efflux↓
•
LCAT activation↓
•
PON1↓
•
Anti-oxidative activity↓
•
Protection against apoptosis↓
•
Stimulation of eNOS/NO↓
•
Inhibition of VCAM-1 and
ICAM-1
expression↓
•
Inhibition of neutrophil
infiltration↓
•
Stimulation of reendothelialisation↓
Nobecourt et al. Diabetologia 2005;48:529; 2007;50:243; 2008;51:1008; ATVB 2010;30:766;
DeSouza et al. Atherosclerosis 2008:197:84, Sorrentino et al. Circulation 2010, 121:110–122.
How to Increase HDL?
Acute:
Reconstituted HDL: eg A1 Milano (Arg 173 Cys) (IVUS)
Delipidated HDL (IVUS)
Apo A1 mimetics (?)
Chronic:
Diet and lifestyle: Weight reduction, diet, alcohol,
exercise, smoking cessation
Statins
PPAR alpha agonists: fibrates (HHS; VAHIT; BIP; FIELD
ACCORD)
PPAR gamma agonists: TZDs (PROactive, CHICAGO,
PERISCOPE) Dual PPAR Agonist aleglitazar
Nicotinic acid (ER form; MK0524) (CDP, Numerous
regression trials)
CETP inhibitors eg torcetrapib, (ILLUMINATE),
dalcetrapib, anacetrapib
ILLUMINATE: Recent Post Hoc Analysis:
• 6661 patients with DM: in
torcetrapib/atorvastatin arm vs. atorvastatin
arm
–
–
–
–
significant
significant
significant
significant
lower plasma glucose levels: 0.34 mmol/L
lower HbA1c levels: 0.1% vs. 0.3% increase
lower insulin levels: 11.7 µU/ml
lower HOMA: increase in atorvastatin arm
Mechanism?
Barter et al, Circulation 2011; 124: 555–562.
“If treatment with dalcetrapib and
anacetrapib is found to be both antidiabetic
and cardioprotective, there will be a
compelling case for considering CETP
inhibition as a treatment of choice in
patients with type 2 diabetes mellitus”.
Barter et al, Circulation 2011: (Aug) 124:555-562
How to Increase HDL?
Acute:
Reconstituted HDL: eg A1 Milano (Arg 173 Cys) (IVUS)
Delipidated HDL (IVUS)
Apo A1 mimetics (?)
Chronic:
Diet and lifestyle: Weight reduction, diet, alcohol,
exercise, smoking cessation
Statins
PPAR alpha agonists: fibrates (HHS; VAHIT; BIP; FIELD
ACCORD)
PPAR gamma agonists: TZDs (PROactive, CHICAGO,
PERISCOPE) Dual PPAR Agonist aleglitazar
Nicotinic acid (ER form; MK0524) (CDP, Numerous
regression trials)
CETP inhibitors eg torcetrapib, (ILLUMINATE),
dalcetrapib, anacetrapib
Background;
Several clinical trials have reported inconsistent findings for the effects
of fibrates on CVD risk
Methods:
Systematic search 1950-2010. Included RCTs assessing the effects of
fibrates on CVD outcomes. Summary estimates of relative risk (RR) reductions
calculated with random effects model.
18 trials, 45058 participants, 2870 major CVD events, 4552 coronary events
and 3880 deaths
Results:
Fibrate therapy associated with
10% RR reduction (95% CI 0-18; p=0.048) major CVD events
13% RR reduction (95% CI 7-19; p<0.0001 Coronary events
No impact on all-cause mortality, CVD mortality or sudden death
How to Increase HDL?
Acute:
Reconstituted HDL: eg A1 Milano (Arg 173 Cys) (IVUS)
Delipidated HDL (IVUS)
Apo A1 mimetics (?)
Chronic:
Diet and lifestyle: Weight reduction, diet, alcohol,
exercise, smoking cessation
Statins
PPAR alpha agonists: fibrates (HHS; VAHIT; BIP; FIELD
ACCORD)
PPAR gamma agonists: TZDs (PROactive, CHICAGO,
PERISCOPE) Dual PPAR Agonist aleglitazar
Nicotinic acid (ER form; MK0524) (CDP, Numerous
regression trials)
CETP inhibitors eg torcetrapib, (ILLUMINATE),
dalcetrapib, anacetrapib
Long term Effects of Pioglitazone
on HDL-Cholesterol and Triglycerides
in CVD Trials
20.0%
10.0%
0.0%
Triglycerides
HDL-Chol
-10.0%
-20.0%
PROACTIVE
CHICAGO
PERISCOPE
Dormandy et al Lancet, 2005; 366: 1279 Mazzone T et al. JAMA, 2006; 296: 2572
Nissen et al JAMA, 2008; 299: 1562
Intravascular Ultrasound of Coronary Arteries
Determining the Atheroma Area
Precise planimetry of EEM and lumen borders
allows calculation of atheroma cross-sectional area
EEM Area
Lumen
onlyArea
parameter
On multivariate analysis the
independently associated with slowing of disease
progression in the Pioglitazone group was
Triglyceride/HDL-C ratio
P=0.03
(EEM Area — Lumen
Area)
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
Nicholls et al JACC 57 No 2 2011
Objective:
Will pioglitazone stabilize carotid artery vulnerable plaque in patients with
acute coronary syndromes (ACS) and type 2 diabetes.
Population:
61 patients with type 2 diabetes, age 63yrs, approx 70% male and echo lucent
carotid plaques within 5 days of ACS. Random allocation to
pioglitazone 15-30mg/day or matching placebo.
Methods:
Vulnerable carotid plaques were assessed by measuring plaque echolucency
using carotid ultrasound with integrated back scatter (IBS)
An increase in IBS reflects an increase in plaque echogenicity.
Echolucent plaques with low IBS represent identify lipid and macrophage-rich lesions,
unstable plaques
Plaque echo lucency using carotid
ultrasound with integrated
back scatter
Pre Treatment
Post Treatment for 1 month with Pioglitazone
Aleglitazar
Balanced Activation of PPAR- and -
Fold activation of
PPAR-
Fold activation of
PPAR-
32
24
16
8
0
–11
–10
–9
–8
↑
–7
–6
–5
–4
Roche data on file.
Henry et al. Lancet 2009; 374:126.
The SYNCHRONY Study
Effects of Aleglitazar on HbA1c
Change in
HbA1c
from baseline
Change in HbA1c from baseline
Henry et al. Lancet 2009; 374:126.
The SYNCHRONY Study
Effects of Aleglitazar on Lipids and Lipoproteins
Trigs
HDL-Chol
LDL-Chol
Apo B
Henry et al. Lancet 2009; 374:126.
Aleglitazar
Summary of Cardiometabolic Effects
Dyslipidemia
↑ HDL 21%
↓ Triglycerides 43%
↓ LDL 16%
Inflammation and
thrombinolysis/
fibrinolysis
↓ hs-CRP 40%
↓ Fibrinogen 10%
↓ PAI-1 6%
Glycemic control
Hypertension
↓ HbA1c 0.85%
↓ FPG –2.16
mmol/L
↓ HOMA-IR 35%
↓ Blood pressure
1 to 3 mmHg
Henry et al. Lancet 2009; 374:126.
Aleglitazar
Ongoing Trial – ALECARDIO
Screened Patients
Index ACS Event
Run-in Period
2–6 weeks
Treatment Period (until 950 events)
at least 2.5 years
Aleglitazar 150 µg
Placebo
4 weeks
Follow-up
Standard of care (diabetes and other CV risk factors)
Known or recently diagnosed
Double-blind, placebo-controlled
type 2 diabetes
Acute coronary syndrome
7,000 patients
2-6 weeks prior to randomisation
Primary Endpoint
Excludes
cardiovascular death, non-fatal
Class II-IV heart failure
myocardial infarction and stroke
eGFR < 45 mL/min/1.73m2
The Atherogenic Lipid Profile
Low HDL (small dense)
CE
Remnant
CE
Small, dense
HDL
Small,
dense LDL
Atheroma
Small,
CE-rich
dense LDL
remnants
Mixed lipaemia as in Metabolic Syndrome,Type 2 diabetes,
Familial Combined Hyperlipidaemia, Renal impairment
Dysbetalipoproteinaemia
CE
High LDL-C and low HDL-C Are
Associated With Increased CHD Risk
Framingham Study: Lipids and CHD Risk
C
3.0
H
D 2.0
R
I 1.0
S
K
0.0
100
220
160
85
65
45
25
HDL (mg/dL)
LDL (mg/dL)
Adapted from Am J Med 1977;62:707-714