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Diabetic dyslipidemia: The pro-atherogenic role of CETP and future use of
CETP inhibitors
Prof. John BetteridgeUniversity 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 complications- unless preventive action is taken.”
Prof Sir George Alberti, IDF President.
International Diabetes Federation
Prospective follow-up of 4045 men 60 to 79 years379 major CHD eventsComparison of late (>60 years) versus early onset diabetes (<60
years)
Risk of Fatal and Non-fatal CHD in Men with Type 2 Diabetes
No diabetesNo CHD
Diabetes Diabetes andCHD
Late onset Early onset
Rate 8.7 15.7 21.7 25.7
Nb events 229 36 18 70
HR* 1 1.69 (1.18-2.41)
2.93 (1.74-4.64)
2.62 (1.99-3.44)
HR** 1 1.55 (1.08-2.21)
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
World2000:151 million2010:221 million (+46%)
Incidence in 2000Incidence in 2010% increase from 2000 to 2010
Adapted from Amos AF et al Diabet Med 1997;14:S7-S85.
14.2
17.5
23%
15.6
22.5
44%
9.4
14.1
50%
26.5
32.9
24%84.5
132.3
57%
1.0
1.3
30%
Survival Post-MI in Diabetic and Non-diabetic Men and Women
Sprafka JM et al Diabetes Care 1991;14:537.
Months post-MI
No diabetes Diabetes
Women
(n=568)
(n=156)Su
rviv
al (%
)
100
90
80
70
60
50
40
0
0 1020304050607080
Months post-MI
Su
rviv
al (%
)
Men
(n=1628)
(n=228)
100
90
80
70
60
50
40
0
0 1020304050607080
Cubbon RM et al. Eur Heart J 2007; 28: 540–545
Temporal Mortality Trends Patients with and without Diabetes
Suffering a Myocardial Infarction(a comparison of 1762 patients in 1995 with 1642 patients in 2003)
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 2Burke 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) Triglyceride
s
Small, dense LDL
Insulin resistance
Remnants HDL2
Clinical Manifestations of Central Obesity
Type 2 diabetes dysglycaemia Dyslipidaemia low HDL small, dense LDL hypertriglyceridaemia
Hypertension
Endothelial dysfunction Inflammation (hsCRP)
Impaired thrombolysis PAI-1
CentralObesity
Insulinresistance
FFAs
Adiponectin
Courtesy of Selwyn AP, Weissman PN.
Lipoprotein Metabolism in Insulin Resistance and Type 2 Diabetes
Small, dense LDL
Pattern B
Pattern A
LDL profile byelectrophoresis
Hepatic lipase
LDL
TG-rich
TG
CETP
NormalLDL
CELipoprotein lipase
ElevatedTRL
VLDL
Chylomicrons
Intestine
Adipose tissue
NEFA
TG CE
TG CE
44
2
0
241296420Hours
PlasmaTriglycerides(mmol/l)
Type 2 diabetes Controls
ADIPONECTIN
Characteristics of LDL Subclasses
Hurt-Camejo E et al Curr Opin Lipidol 2000;11:465
Large, buoyant LDL pattern A
Small, dense LDL pattern B
GAG-binding segments(3147–3157) (3359–3367)
apo B-100
Free cholesterolPhospholipids
• 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
Large, buoyantparticles
Small, denseparticles
Apo B More apo B
The Absolute Concentration of LDL-C Can be Misleading in Subjects with
Small, Dense LDL.
At the same LDL-C level, the number of LDL particles is increased, if small and denseEach LDL particle contains one molecule of apo BApo B concentration increases in direct relation to number of LDL particles
Sniderman AD et al Ann Intern Med 2001
LDL Subfractions “Control” vs Patient with Insulin
Resistance
Increasing densityDecreasing size
I
II
IIIDJB-TG 0.9 mmol/l
DM-TG 2.95 mmol/l
High-risk CHD patients (high cholesterol)
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)
Primaryprevention
Secondaryprevention
Statins:The Evidence Base.
WOSCOPS(pravastatin)
AFCAPS/TexCAPS(lovastatin)
4S(simvastatin)
CARE (pravastatin)
LIPID
(pravastatin)
Continuum of risk
22.6
12.9
8.44
7.9
2.8
Pla
ceb
o M
I ra
te p
er
10
0 s
ub
jects
per
5
years
HPS
304 events Expected completion 2005304 events Expected completion 2005
Atorvastatin 10 mg
2,838Patients2,838
Patients
d/b PBO
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
Primary EndpointTime to first major CVD event
Colhoun et al. Diabetic Med 2002; 32: 259-264.
Actual termination June 2003 after 2nd interim analysis 210 events
Median Lipid Levels by Treatment
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
0 2 3 41 4.5 2 3 41 4.5
Years of Study
Years of Study
00
1
2
3
4
0
2
4
6
Placebo Atorvastatin
Average difference 26%
1.40 mmol/L (54mg/dL) p<0.0001
Average difference 40%
1.20 mmol/L (46mg/dL) p<0.0001
Median Lipid Levels by Treatment
HDL cholesterol (mmol/L)
Triglycerides (mmol/L)
0 2 3 41 4.5 2 3 41 4.5
Years of Study
Years of Study
00
1
21.4
0
.2
.4
.6
.8
1
1.2
Placebo Atorvastatin
Average difference 1%
0.02 mmol/L,0.8mg/dL p=0.0002
Average difference 19%
0.39 mmol/L, 35mg/dL p<0.0001
Cumulative Hazard for Primary Endpoint
Relative Risk -37% (95% CI: -52, -17)
P=0.001
Atorva
Placebo
Years
328
305
694
651
1074
1022
1361
1306
1392
1351
1428
1410
Placebo127 events 2.46/100 person yrs
Atorvastatin 83 events 1.54/100 person yrs
Cu
mu
lati
ve H
aza
rd (
%)
0
5
10
15
0 1 2 3 4 4.75Number at risk
Heart Protection Study Diabetes Subgroups With/Without CHD or Other CVD
Heart Protection Study Diabetes Subgroups With/Without CHD or Other CVD
HPS Collaborative Group. Lancet. 2003;361:2005
0
10
20
30
40
50
Inci
denc
e of
maj
or v
ascu
lar
even
ts (
%)
Placebo Simvastatin 40 mg
RRR12%RRR12%
RRR23%RRR23%
RRR22%RRR22%
RRR19%RRR19%
RRR31%RRR31%
Diabetes + CHD
Diabetes + CHD
No diabetes
+ CHD
No diabetes
+ CHD
Diabetes + other
CVD
Diabetes + other
CVD
No diabetes + other
CVD
No diabetes + other
CVD
Diabetes + no CVDDiabetes + no CVD
1009 972 5683 5722 519 551 1481 1449 1455 1457
-1
-0.5
0
0.5
1
1.5
2
50 60 70 80 90 100 110 120
ASTEROID3 rosuvastatin
A-Plus2 placebo
ACTIVATE1 placebo
CAMELOT4 placebo
REVERSAL5 pravastatin
REVERSAL5 atorvastatin
Mean LDL-C (mg/dL)
LDL-C and change in percent atheroma volume in IVUS studies
Change
in Percent
AtheromaVolume*
(%)
†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
Progression
Regression
Objective:To characterize IVUS defined coronary atherosclerosis progression in diabetic patients
Methods:Systematic analysis, 2,237 subjects in RCTs ofatherosclerosis 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) Triglyceride
s
Small, dense LDL
Insulin resistance
Remnants HDL2
HPS Diabetic CohortBenefits of Simvastatin by Baseline
LDL and HDL-Cholesterol
0
5
10
15
20
25
30
35
1st Qtr 2nd Qtr 3rd Qtr 4th Qtr
WestNorth
LDL-Cholesterol 3mmol 3mmol
20.9
15.7
27.9
23.3
HDL-Cholesterol 0.9mmol 0.9mmol
31.1
25.9
16.8
21.3
Vasc
ula
r Even
ts (
%)
PlaceboSimvastatin
Role of Cholesteryl Ester Transfer Protein (CETP) in Lipoprotein Metabolism
Facilitated modification of LDL
Enrichment with
cholesteryl esters
Formation of small dense LDL
Hepatic Lipase (HL)
smalldenseLDL
Transient enrichment with triglycerides (TG)
HL
Formation of small HDL3 and lipid-poor pre-HDL
Regeneration of HDL or removal from circulation,
e.g. by renal filtration
HDL3
Pre -HDL
VLDL
CETP TGCE
HDL2
Von Eckardstein, Expert Review of Cardiovascular Therapy 2010, 8(3):345–58.
PLTP J
A-I
SAA
A-II
LCAT
CETP
PON1PAF-AH
SAA
sPLA2
sPLA2
PLTP
A-I
A-I
A-I
A-IA-I
A-II
A-IILCAT
CETP
PON1
PAF-AH
PLTP
A-I
A-I
A-I
A-IA-I
A-II
A-IILCAT
CETP
PON1
PAF-AH
PLTP
A-I
A-I
A-I
A-IA-I
A-II
A-IILCAT
CETP
CETG
PON1PAF-AH
CE TG
CE TG
CETP↑ Oxidation
Glu Glx
Dysfunctional HDL in Diabetes
• 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 re-endothelialisation↓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.
-NH-CH2 -C-CH-CH-CH-CH
2 OH
OH
OH
OH
O
SAA
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
• 6661 patients with DM: in torcetrapib/atorvastatin arm vs. atorvastatin arm– significant lower plasma glucose levels: 0.34
mmol/L– significant lower HbA1c levels: 0.1% vs. 0.3%
increase– significant lower insulin levels: 11.7 µU/ml– significant lower HOMA: increase in atorvastatin
arm
Barter et al, Circulation 2011; 124: 555–562.
Mechanism?
ILLUMINATE: Recent Post Hoc Analysis:
“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) reductionscalculated with random effects model.18 trials, 45058 participants, 2870 major CVD events, 4552 coronary eventsand 3880 deathsResults: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 eventsNo 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%
10.0%
20.0%
PROACTIVE CHICAGO PERISCOPE
Triglycerides
HDL- Chol
Dormandy et al Lancet, 2005; 366: 1279 Mazzone T et al. JAMA, 2006; 296: 2572Nissen et al JAMA, 2008; 299: 1562
Intravascular Ultrasound of Coronary Arteries
Determining the Atheroma Area
EEM Area
LumenArea
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
(EEM Area — Lumen Area)
Precise planimetry of EEM and lumen bordersallows calculation of atheroma cross-sectional area
On multivariate analysis the only parameter independently associated with slowing of disease progression in the Pioglitazone group was Triglyceride/HDL-C ratio P=0.03
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
Pre Treatment
Post Treatment for 1 month with Pioglitazone
Plaque echo lucency using carotid ultrasound with integrated back scatter
Aleglitazar Balanced Activation of PPAR- and -
Roche data on file.
0
8
16
24
32
–11 –10 –8 –6–9 –7 –5 –4
↑
Fold
acti
vati
on
of
PPA
R-
Fold
activ
atio
n
of P
PA
R-
Henry et al. Lancet 2009; 374:126.
The SYNCHRONY Study Effects of Aleglitazar on HbA1c
Change in HbA1c from baseline
Henry et al. Lancet 2009; 374:126.
Change inHbA1cfrom baseline
HDL-Chol
Apo B
Trigs
LDL-Chol
The SYNCHRONY Study Effects of Aleglitazar on Lipids and Lipoproteins
Henry et al. Lancet 2009; 374:126.
Aleglitazar Summary of Cardiometabolic Effects
Inflammation and thrombinolysis/ fibrinolysis
↓ hs-CRP 40%↓ Fibrinogen 10%↓ PAI-1 6%
Hypertension
↓ Blood pressure
1 to 3 mmHg
Glycemic control
↓ HbA1c 0.85%↓ FPG –2.16
mmol/L↓ HOMA-IR 35%
Dyslipidemia
↑ HDL 21%↓ Triglycerides
43%↓ LDL 16%
Henry et al. Lancet 2009; 374:126.
Aleglitazar 150 µg
Placebo
Treatment Period (until 950 events)at least 2.5 years
Run-in Period2–6 weeks
Follow-upFollow-up
Scr
eened
Pa
tients
Ind
ex A
CS
Even
t
4 weeks
Standard of care (diabetes and other CV risk factors)
Double-blind, placebo-controlled
7,000 patients
Primary Endpoint cardiovascular death, non-fatal myocardial infarction and stroke
Known or recently diagnosed type 2 diabetes Acute coronary syndrome 2-6 weeks prior to randomisation Excludes Class II-IV heart failure eGFR < 45 mL/min/1.73m2
Aleglitazar Ongoing Trial – ALECARDIO
Low HDL (small dense)
Small,dense LDL
CE-richremnants
AtheromaCE
CE
CE
Remnant
Small,dense LDL
Small, denseHDL
The Atherogenic Lipid Profile
Mixed lipaemia as in Metabolic Syndrome,Type 2 diabetes,Familial Combined Hyperlipidaemia, Renal impairment Dysbetalipoproteinaemia
Adapted from Am J Med 1977;62:707-714
LDL (mg/dL)
HDL (mg/dL)
High LDL-C and low HDL-C Are Associated With Increased CHD Risk
0.0
1.0
2.0
3.0C
H
D
R
I
S
K
100 160 220 8565
4525
Framingham Study: Lipids and CHD Risk
Intensive LDL a
nd HDL