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