Lipid Targets

1. 1
What Should be the Lipid Targets in
Patients with Diabetes and the Metabolic
Syndrome?
Michael Davidson M.D. FACC,
Diplomate of the American Board of
Lipidology
Clinical Professor, Director of Preventive
Cardiology
The University of Chicago
Pritzker School of Medicine

2. DISCLOSURES
Michael H. Davidson, MD
Consulting Fees
– Abbott Vascular, AstraZeneca, GlaxoSmithKline
Honoraria
– Abbott Vascular, AstraZeneca, GlaxoSmithKline,
Schering-Plough Corp. / Merck & Co., Inc.
Grants/Contracted Research
– Abbott Vascular, AstraZeneca

3. 3
Attributable Declines in CHD Deaths Between
1980 and 2000
2˚ prevention: 11%
47%
Net 44%
Therapies Lifestyle/
Risk Factors
Attributable
reduction
in
CHD
deaths
(%)
Ford ES et al. N Engl J Med. 2007;356:2388-2398.
9%
Unexplained
Initial Rx MI/UA: 10%
Rx for HF: 9%
Revasc for angina: 5%
Other Rx: 12%
∆ Phys. Activity: 5%
∆ Smoking: 12%
∆ Systolic BP: 20%
∆ Cholesterol: 24%
∆ BMI: -8%
∆ Diabetes: -10%
9%

4. 4

5. 6
*Meta-analysis of 14 statin trials (CTT collaborators)
Reduction in LDL-C level (mg/dL)
Relation Between Proportional in Incidence of Major CVD
Events & Mean Absolute LDL-C Reduction at Year 1*
Proportional
Reduction
in
CHD
Event
Rate
0%
10%
20%
30%
40%
50%
60%
0 ~ 20 ~ 40 ~ 60 ~ 80
N= >90,000
>45,000 on statin
>45,000 on placebo
Baigent C, et al. Lancet. 2005;366:1267-1278.
1 mmol/L reduction in LDLc results in 20% reduction in CVD risk at 1 yr

6. 7
Is it statins or LDL-c?

7. 8
The young Nikolai N.
Anitschkow ca.1904, at
the time a student at the
Military Medical Academy
in St. Petersburg.
His drawing of a
typical foam cell-
rich lesion in a
rabbit
Linking Cholesterol to Atherosclerosis

8. 9
Rationale for therapeutic lowering of Apo B lipoproteins: decrease the
probability of inflammatory response to retention
Blood
Apo B lipoprotein
particles
Modification
Macrophage
Monocytes bind to
adhesion molecules
Tabas I et al. Circulation. 2007;116(16):1832–1844. Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15(5):551–
561.
Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25(8):1536–1540. Hoshiga M et al. Circ Res. 1995;77(6):1129–
1135.
Merrilees MJ et al. J Vasc Res. 1993;30(5):293–302. Nakata A et al. Circulation.1996;94(11):2778–2786.
Steinberg D et al. N Engl J Med. 1989;320(14):915–924.
Smooth muscle
Cardiovascular Risk Increases With Increased
Plasma Apo B Lipoproteins
Foam cell
Inflammatory
response

9. 10
A. Non-Human Mammals B. Humans - US
-
-
-
-
-
-
0
50
100
150
200
300
700
LDL
Levels
Rat
Lio
n
Pig
Camel
Guinea
Pig
Sheep
Cow
Rabbit
Cat
Newborns
Normal Adults
FH Heterozygotes
FH Homozygotes

10. 11
What Is Desirable Cholesterol?
50 70 90 110 130 150 170 190 210
Adult American
San
Pygmy
!Kung
Inuit
Hazda
Hunter-
gatherer
humans
Mean total cholesterol, mg/dL
Cholesterol Levels Among Different Human
Populations
Adapted from O’Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142–2146.

11. 12
Non-HDL-C lowering predicts CVD risk
reduction
Robinson JG, et al. JACC 2009; 53: 316-322

12. 13
499 American Indian men and women
with type 2 diabetes and no CVD
≥40 yrs old
SBP>130 mmHG, LDL-C >100 mg/dL
Standard Targets
LDL-C ≤100 mg/dL; SBP ≤ 130 mmHg
non-HDL-C ≤ 130 mHg
N=247
Aggressive Targets
LDL-C ≤70 mg/dL; SBP ≤ 115 mmHg
non-HDL-C ≤ 100 mmHg
N=252
Measure CVD using carotid
and cardiac ECHO at baseline,
18 months, 36 months intervention
Primary outcome—change in CIMT
Study Design
Fleg JL et al. J Am Coll Cardiol. 2008;52: 1-8.

13. 14
-0.04
-0.03
-0.02
-0.01
0
0.01
0.02
0.03
0.04
0.05
ITT Sensitivity*
Aggressive Standard
Changes in IMT
mm
*Pts (N=129) who maintained LDL-C<73; Group differences for each P<0.001
Howard BU et al. JAMA. 2008;299:1678-1689.

14. 15
Change in Lipid and CRP at 36 Months:
Standard vs Aggressive Therapy Subgroups
Values are mean (95% confidence interval). The P values were determined using the ANOVA F Test.
aSignificant difference between S an E+.
bSignificant difference between S and E- (based on logorithim of CRP).
Fleg JL et al. J Am Coll Cardiol. 2008;52: 1-8.
P=0.0001
P=0.987
P=0.0001 P=0.11 P=0.008
ab
ab
Change
in
Parameter
(mg/dl)
-0.7 -6
11
2.7
0.9
-31.1
-34
-12
-24
2.7 2.5
-26
-15
-36.6
-32.3
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
LDL-C HDL-C Non-HDL-C Triglcerides CRP
Standard group (S) Ezetimibe group (E+) No ezetimibe group (E-)

15. 16
Change in CIMT at 36 Months:
Standard vs Aggressive Therapy
Subgroups
aP<0.001 vs standard group.
Fleg JL et al. J Am Coll Cardiol. 2008;52: 1-8.
0.039
-0.025
-0.012
-0.05
-0.04
-0.03
-0.02
-0.01
0
0.01
0.02
0.03
0.04
0.05
Standard group (S)
Ezetimibe group (E+)
No ezetimibe group (E-)
CIMT
(mm)
a
a

16. 17
Is LDL-c or LDL-p/ApoB/non-HDL?

17. 18
Event-free survival stratified by LDL-C and
LDL-P in the Framingham Offspring Study

18. 19
IDEAL: Added* Predictive Value
for Major Coronary Events
10.1
13.0
16.6
19.8
22.1
29.8
4.3
6.7
21.0
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
Added
Chi
Square
Statistic
P<0.0001
P<0.0001
P<0.0001
P=0.04
P<0.0001 P<0.0001
P<0.0001
P<0.0001
P=0.01
TC LDL-C Non-HDL-C Apo B HDL-C Apo A-1 LDL-C/ TC/HDL-C Apo B/
HDL-C Apo A-1
*Predictive value added over and above age, gender, and smoking status.
Holme et al. Ann Med. 2008;40:456.

19. 20

20. ADA/ACC 2008 Consensus Statement:
Treatment Goals in Patients With Cardiometabolic
Risk and Lipoprotein Abnormalities
“In individuals on statin therapy who continue to have low HDL-C or elevated
non–HDL-C, especially if apoB levels remain elevated, combination therapy is
recommended. The preferred agent to use in combination with a statin is nicotinic acid…”
aMajor risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD.
Brunzell JD, et al. Diabetes Care. 2008;31(4):811-822. Copyright © 2008 American Diabetes Association.
Goals
LDL-C Non-HDL-C ApoB
Highest-risk patient
• Known CVD
• Diabetes plus ≥1 additional
major CVD risk factora
<70 mg/dL <100 mg/dL <80 mg/dL
High-risk patients
• No diabetes or known CVD
but ≥2 major CVD risk
factorsa
• Diabetes but no other
major CVD risk factorsa
<100
mg/dL
<130 mg/dL <90 mg/dL

21. • Statin + fibrate (fenofibrate)
• Statin + niacin
• Glycemic control +
high-dose statin
Combined (mixed)
dyslipidemia
• Niacin
• Fibrates (fenofibrate, gemfibrozil)
• Omega 3 FA
• TLC
• Glycemic control
TG lowering
Goal: <150 mg/dL
Desirable but not targeted:
HDL-C raising
Goal: >40 mg/dL (men)
>50 mg/dL (women)
LDL-C lowering
1. Overt CHD or >40 yr with ≥1 major RF,
regardless of baseline LDL-C
Goal <70 mg/dL option
2. Without CVD and <40 yr but ≥2 RF
Goal <100 mg/dL
Second Priority
• Niacin, ezetimibe, bile acid
sequestrants, or fenofibrate
• TLC
• Statins
First Priority
American Diabetes Association (ADA)
Standards of Medical Care in Diabetes
Data from ADA. Diabetes Care. 2010;33(suppl 1):S11-S61.
Dyslipidemia Management

22. Hs-CRP=high-sensitivity C-reactive protein; Lp-PLA2=lipoprotein-associated phospholipase AS; RBP4=retinol
binding protein 4; NT-proBNP=N-terminal prohormone brain natriuretic peptide; MPO=myeloperoxidase;
GFR=glomerular filtration rate; Cr=creatinine; Lp(a)=lipoprotein (a)
Bibbins-Domingo K, et al. JAMA. 2007;297:169-176.
Emberson JR, et al. J Am Coll Cardiol. 2007;49(3):311-319.
Wang TJ, et al. N Engl J Med. 2006;355(25):2631-2639.
Folsom AR. Arch Intern Med. 2006;166(13):1368-1373.
Corson MA, et al. Am J Cardiol. 2008;101(Suppl 12A):41-50F.
Zethelius B, et al. N Engl J Med. 2008;358(20):2107-2116.
Biomarkers and/or Lipid Measurements
Useful in Determining Additional Risk
Biomarkers
• hs-CRP
• Lp-PLA2
• Adiponectin, RBP4
• NT-proBNP
• MPO
• Cystatin C
• GFR, Cr
• Microalbumin
Lipid Markers
• LDL particle number
• ApoB
• ApoAI, apoCIII
• Lp(a)
• Particle size

23. 24
0
0.02
0.04
0.06
0.08
0.10
0 0.5 1.0 1.5 2.0 2.5
LDL-C ≥70 mg/dL, CRP ≥2 mg/L
Follow-up (years)
LDL-C <70 mg/dL, CRP ≥2 mg/L
LDL-C ≥70 mg/dL, CRP <2 mg/L
LDL-C <70 mg/dL, CRP <2 mg/L
LDL-C <70 mg/dL, CRP <1 mg/L
Ridker et al. N Engl J Med. 2005;352:20.
Clinical Relevance of Achieved LDL-C and
CRP: Post-hoc Analysis of PROVE-IT TIMI-22

24. 25
Should LDL be lowered regardless of the
baseline in high risk patients?

25. 26
JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 /
8901
Rosuvastatin 142 /
8901
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Number Needed to Treat (NNT5) = 25
- 44 %
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
Cumulative
Incidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

26. LOW/HIGH
hs-CRP <2.0 mg/L
LDL-C ≥130 mg/dL
(n=1,132)
Males (n=649)
Females (n=483)
Eligible for
JUPITER
Primary
Prevention
(n = 5,513)
LDL-c <130 mg/dL
(n=3,235)
LDL-c ≥130 mg/dL
(n=2,278)
LOW/LOW
hs-CRP <2.0 mg/L
LDL-C <130 mg/dL
(n=1,614)
Males (n=1,054)
Females (n=560)
“JUPITER-Eligible”
hs-CRP ≥2.0 mg/L
LDL-C <130 mg/dL
(n=1,621)
Males (n=683)
Females (n=938)
HIGH/HIGH
hs-CRP ≥2.0 mg/L
LDL-C ≥130 mg/dL
(n=1,146)
Males (n=533)
Females (n=613)

27. Variable
Low CRP/
Low LDL
“JUPITER-
Eligible”
p-value
(comparing
Group 1, 2)
Low CRP/
High LDL
High CRP/
High LDL
p-value
(comparing
Group 3,4)
Age (years) 64.1 (0.12) 64.3 (0.12) 0.17 63.8 (0.15) 64.4 (0.15) <0.002
Males (%) 64 (0.012) 43 (0.012) <0.0001 56 (0.014) 48 (0.014) <0.0001
Whites (%) 84 (0.009) 78 (0.010) <0.0001 84 (0.011) 78 (0.012) 0.0001
Hypertensive (%) 35 (0.012) 47 (0.012) <0.0001 39 (0.014) 43 (0.014) 0.03
Smoker (%) 13 (0.008) 17 (0.010) 0.0002 10 (0.009) 21 (0.012) <0.0001
Metabolic
Syndrome (%)
19 (0.010) 33 (0.012) <0.0001 25 (0.013) 40 (0.014) <0.0001

28. 29
Clinical Characteristics (cont.)
Variable
Low CRP/
Low LDL
“JUPITER-
Eligible”
p-value
(comparing
Group 1, 2)
Low CRP/
High LDL
High CRP/
High LDL
p-value
(comparing
Group 3,4)
Triglyceride
(mg/dL)
114.6
(1.54)
133.4
(1.54)
< 0.0001
129.6
(1.83)
145.6
(1.82)
<0.0001
HDL-c (mg/dL) 54.6
(0.38)
50.8
(0.38)
< 0.0001
49.9
(0.45)
45.8
(0.44)
<0.0001
Calculated LDL-C
(mg/dL)
103.2
(0.52)
101.8
(0.52)
0.06
155.3
(0.62)
156.0
(0.61)
0.46
Glucose (mg/dL) 97.5
(0.22)
99.4
(0.22)
< 0.0001
98.7
(0.27)
100.7
(0.26)
<0.0001
hs-CRP (mg/L)*
0.9 4.7 1.0 4.4

29. 30
Predicted 10-Year CHD Risk
Variable
Low CRP/
Low LDL
“JUPITER-
Eligible”
p-value
(comparing
Group 1, 2)
Low CRP/
High LDL
High CRP/
High LDL
p-value
(comparing
Group 3,4)
Mean
Framingham
10-Year Risk
(FRS)
5.0% 4.7% <0.0001 6.3% 7.1% <0.0001

31. Taylor AJ, et al. N Engl J Med. 2009;361(22):2113-2122. Copyright © 2009 Massachusetts Medical Society.
Months
0 8 14
0.006
0.004
0.002
0.000
-0.002
-0.004
-0.006
-0.008
-0.010
-0.012
-0.014
-0.016
-0.018
-0.020
Change
From
Baseline
in
Mean
Carotid
Intima-Media
Thickness
(mm)
Ezetimibe
Niacin
P=0.003

32. - Statin monotherapy
The Lower
The Better
TARGET
HDL-C TG
LDL-C
ATP I, ATP II
ATP III
- Combination therapy
TARGET
Comprehensive
is the Best
HDL-C TG
LDL-C
ATP III update, IDF
ESC, EASD, ADA,NICE
ATP IV ??
(FIELD, JUPITER
ACCORD, etc…..)
LIKELY TO:
Confirm Top Priority:
intensive LDL-C reduction to
achieve goals
Reinforce:
HDL and TG as secondary
therapeutic targets
(i.e. in T2DM, MetS)
 New Markers of High CV Risk:
Apo B?
Hs-CRP?.....

33. 34
Conclusions
 Achievement of LDL-C and Non-HDL-C should be
the primary goal of lipid therapy for patients with
diabetes and metabolic syndrome and the lower the
better
 Lifetime low LDL levels are associated with a marked
reduction of CVD events
 In the US population with a growing prevalence of
metabolic syndrome and obesity, non-HDL/ApoB is
more predictive of CVD than LDL-c
 In patients at high risk (CVD, diabetes, elevated
CRP), LDL reduction with statins has proven outome
benefits regardless of baseline LDL-c levels