LIPID LOWERING IN T2D (The Lower the Better?) CONS… TARGETING HARD CVD END POINTS Charles SAAB MD...

LIPID LOWERING IN T2DLIPID LOWERING IN T2D(The Lower the Better?)(The Lower the Better?)

CONS…CONS…TARGETING HARD CVD END POINTSTARGETING HARD CVD END POINTS

Charles SAAB MDCharles SAAB MD

Consultant EndocrinologistConsultant Endocrinologist

DCRP Sacre-Coeur University Hospital-LebanonDCRP Sacre-Coeur University Hospital-Lebanon

MGSD-CASABLANCA April 2011MGSD-CASABLANCA April 2011

WHAT IS THE BEST WAY TO AVOID

INJURIES IF A CAR ACCIDENT OCCURES???

BEST IS NOT TO LET ACCIDENTS

HAPPENS

AVOID INJURIES

"The growth of knowledge depends entirely on

disagreement“

Karl R. Popper (28 juillet 1902 à Vienne, Autriche - 17 septembre 1994 à Londres

DIABETES AND STATIN TTTDIABETES AND STATIN TTTIS IT FOR ALL??IS IT FOR ALL??

YES THE EARLIER THE BETTERYES THE EARLIER THE BETTERINDEPENDENTLY OF LDL LEVELSINDEPENDENTLY OF LDL LEVELS

24% SE 2.6reduction(P<0.00001)

Baseline STATIN PLACEBO Risk ratio and 95% CIfeature (10269) (10267) STATIN better STATIN worse

Het =0.8c 2

3

0.4 0.6 0.8 1.0 1.2 1.4

LDL (mg/dL)

<100 285 360

100 < 130 670 881

1087 1365130

ALL PATIENTS 2042 2606

(19.9%) (25.4%)

Simvastatin: Vascular Event by LDL

Heart Protection Study: Lancet 2002

IS CVD ONLY AN LDL MATTER??

1.00

0.99

0.98

0.97

0.96

0 0 2 4 6 8Years of follow-up

Low CRP-low LDL

Low CRP-high LDL

High CRP-low LDL

High CRP-high LDL

Ridker et al. N Engl J Med 2002;347:1157–65

Pro

bab

ilit

y o

f ev

ent-

free

su

rviv

al

Median LDL 124 mg/dLMedian CRP 1.5 mg/L

CV Event-free Survival Using Combined CRP and LDL-C Measurements

IDEAL

The Incremental decrease in Endpoints through Aggressive

Lipid Lowering Trial

IDEAL Study: IDEAL Study: Effect of Treatment on LDL-CEffect of Treatment on LDL-C

Mean LDL-C = 104 mg/dL

Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445.

0

70

80

90

100

110

120

130

BaselineWeek 12Year 1 Year 2 Year 3 Year 4 Year 5

LD

L-C

(m

g/d

L)

Atorvastatin 80mg

Simvastatin 20mg

Mean LDL-C = 81 mg/dL

99.8 mg/dl

80 mg/dl

102 mg/dl

79.1 mg/dl

Copyright restrictions may apply.

`NS

NS

NS

0

2

4

6

8

10

12

14

16

Barter PJ et al. J Am Coll Cardiol 2006;47:492–499. | Waters DD et al. J Am Coll Cardiol 2006;48:1793–1799.

Major Cardiovascular Events Major Cardiovascular Events According to On-treatment HDL-C: According to On-treatment HDL-C: Treating to New Targets (TNT) TrialTreating to New Targets (TNT) Trial

%

Atorvastatin 10 mgAtorvastatin 10 mg Atorvastatin 80 mgAtorvastatin 80 mgMean LDL-C73 mg/dL

Mean LDL-C99 mg/dL

On-treatment HDL-C (mg/dL)

<40 <40>40-50 >40-50 >50-60 >60>60>50-60

Major coronary events

50

40

30

20

10

0

0.5(19)

1.0(38)

1.5(58)

2.0(77)

-10

Major vascular events

Reduction in LDL-C mmol/L (mg/dL)

50

40

30

20

10

-10

0

0.5(19)

1.0(38)

1.5(58)

2.0(77)

Reduction in LDL-C mmol/L (mg/dL)

Pro

port

ion

al re

du

cti

on

in

even

t ra

te (

%

SE)

Pro

port

ion

al re

du

cti

on

in

even

t ra

te (

%

SE)

CTT Collaborators. Lancet 2005;366:1267–1278.

Relationship Between Proportional Reduction in Events and Mean LDL-C Reduction at 1 Year

90056 PATIENTS

a = Statin trials. Adapted from Robinson JG, et al. J Am Coll Cardiol. 2005;46(10):1855–1862.

Non

fata

l MI a

nd C

HD

Dea

th

Rel

ativ

e R

isk

Red

uctio

n, %

–20

100

80

60

40

20

0

LDL-C Reduction, %

25 3015 35 4020

LondonOsloMRCLos AngelesUpjohnLRC NHLBIPOSCH4Sa

WOSCOPSa

CAREa

LIPIDa

AF/TexCapsa

HPSa

ALERTa

PROSPERa

ASCOT-LLAa

CARDSa

Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis

Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis

National heart lung blood institute

Goals for Management of LDL in Patients With Diabetes

Guidelines

LDL-C Goal

Diabetes With CVDa Diabetes Without CVD

ESC/EASD 2007

<70 mg/dL(<1.8 mmol/L)


ADA/AHA/ACC 2007


<100 mg/dL(<2.6 mmol/L)

JBS2 2005 <77 mg/dLb

(<2.0 mmol/L)<77 mg/dLb

(<2.0 mmol/L)

NCEP ATP III 2004


<100 mg/dL(<2.6 mmol/L)

TTCT/CC CT CC p-value*

n 342 219 211 11

chd present 81 71 70 1 0.033

BMI (kg/m²) 22.1±1.5 22.9±1.3 22.9±1.1 23.1±1.1 0.023

Cholesterol (mg/dl) 270.5±51.2 266.2±89.4 266.4±93.2 262±64.5 ns

LDL 183±46.8 189±54.8 194±53.9 174.6±62.5 ns

HDL 65.5±20.6 53.5±16 54±16 58.2±17.8 0.004

VLDL 22±13.2 23±8.8 23.4±8.8 19.2±4.8 ns

Triglycerides (mg/dl)

112±115.4 118±181.6 118.9±84.5 96.4±23.8 ns

Apo B (mg/dl) 100±22.6 103.3±21.1 103±11.1 111.5±9.8 ns

Apo A1 (mg/dl) 159±26.8 161±24.3 161.1±13.3 159±22.1 ns

Lp(a) (mg/dl) 6±4.2 12±14.1 12.1±8.8 10.7±3.4 ns

ROLE OF GENOTYPE IN CHD

Link E, et al, for the SEARCH Collaborative Group. N Engl J Med 2008;359:789–799. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Estimated Cumulative Risk of Myopathy Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of SimvastatinAssociated with Taking 80 mg of Simvastatin

Cumulative No. and Percentages with Myopathy

Year 1 Year 5

GenotypePopulationFrequency no. %

Attributable to genotype no. % of total no. %

Attributable to genotype no. % of total

TT 0.730 12 0.34 0 0 21 0.63 0 0

CT 0.249 17 1.38 12.8 75 32 2.83 24.9 78

CC 0.021 16 15.25 15.6 98 19 18.55 18.4 97

All genotypes 1.000 45 0.91 28.4 63 72 1.56 43.3 60

0

5

10

15

20C

um

ula

tive P

erc

enta

ge o

f Pati

ents

Who H

ave H

ad

a

Myop

ath

y

0 1 2 3 4 5 6

Years since Starting 80 mg of Simvastatin

CC genotype

CT genotype

TT genotype

Link E, et al, for the SEARCH Collaborative Group. N Engl J Med 2008;359:789–799. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Slide SourceLipids Online Slide Librarywww.lipidsonline.org

SMOKER EATERNO SPORTHTNOBESEMULTIPLE STROKESSTATIN= 0..DEATH AT WHAT AGE?

DEATH = 91 YO

NO SMOKING !!!!!!LEANJOGGING EVERY DAYHTN=0NO CVD NO DIABETESFIRST MI AT WHAT AGE???

FIRST MI = 50 YO

1874-1965

Slide Source:Lipids Online Slide Librarywww.lipidsonline.org

WHAT ELSE?? IN T2D LIPID WHAT ELSE?? IN T2D LIPID PROFIL????PROFIL????

CONTROVERSIES IN ACCORD (study)

BP/??

GLUCOSE/??

LIPIDS/??– HDL SHOULD BE INCREASED?– TG SHOULD BE DECREASED?

Baseline lipids – mg/dLSimvastatin + Fenofibrate

(n=2,765)

Simvastatin(n=2,753)

Overall(n=5,518)

Mean total cholesterol 174.7 175.7 175.2

Mean LDL-C 100.0 101.1 100.6

Mean HDL-C 38.0 38.2 38.1

Median TG 164 160 162

Baseline Characteristics – Lipids

ACCORD Study Group. N Engl J Med March 14, 2010. Epub.

ACCORD LipidACCORD Lipid

Results Results LDL-C target levels were achieved

in both groups



0 1 2 3 4 5 6 7

No. of PatientsFenofibratePlacebo

Mean

LD

L C

hole

stero

l (m

g/d

L)

Years

LDL-C

27472735

25932591

25052484

24172375

23612364

14771480

796801

248243

0

60

80

100

120

Placebo

Fenofibrate

Lipid levels at study close

Lipid levels at study closeSimvastatin + Fenofibrate

(n=2,765)


p value

Mean LDL-C (mg/dL) 81.1 80.0 p=0.16

RESULTS RESULTS There was a significant improvement

in TG and HDL-C in the combination group



0 1 2 3 4 5 6 7


Mean

HD

L C

hole

stero

l (m

g/d

L)

Years

HDL-C

27472735

25932591

25052484

24172375

23612364

14771480

796801

248243

037

38

39

40

41

42

43

Placebo

Fenofibrate

0 1 2 3 4 5 6 7


Med

ian T

rig

lyce

rides

(mg

/dL)

Years

Triglycerides

27472735

25932591

25052484

24172375

23612364

14781480

796801

248243

0100

120

140

160 Placebo

Fenofibrate

Lipid levels at study closeSimvastatin + Fenofibrate

(n=2,765)


p value

Mean HDL-C (mg/dL) 41.2 40.5 p=0.01

Median triglycerides (mg/dL) 122.0 144.0 p=0.001

RESULTS Primary endpoint

Major CV events (overall population)



0

20

40

60

80

100

Pro

port

ion w

ith E

vent

(%)

0 1 2 3 4 5 6 7 8

27652753

26442634

25652528

24852442

19811979

11601161

412395

249245

137131

No. At RiskFenofibratePlacebo

Years

0.92 (95% CI 0.79-1.08),p=0.32

0

10

20

0 1 2 3 4 5 6 7 8

Placebo

Fenofibrate

Major CV events defined as CV death, nonfatal MI and nonfatal stroke

MY TAILOR IS RICH

LIPID LOWERING SHOULD TARGET EACH T2D PATIENT RISK THE EARLIEST AND NOT TO THE LOWEST

LIPID LOWERING IN T2D (The Lower the Better?) CONS… TARGETING HARD CVD END POINTS Charles SAAB MD...

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