LDL: Lower the Better

Expert Opinion
 LDL: Lower the Better

• Lower is Better: review of clinical trials

• Cardiovascular risk in South Asians
• Guidelines for cholesterol management
• Efficacy and safety of statin therapy in South
Asians
 Framingham: Low HDL-C and Elevated LDL-C
Are Independent Predictors of CHD Risk

3.0
Risk of CHD

2.0

1.0
25
45
65 HDL-C
0.0 85
(mg/dL)
100 160 220
LDL-C (mg/dL)
Slide Source
Gordon T et al. Am J Med 1977;62:707-714. Lipids Online Slide Library
www.lipidsonline.org
 Scandinavian Simvastatin Survival Study
(4S)
Proportion Alive
 Secondary prevention 1.00
Simvastatin
 4444 patients
 Cholesterol: 272 ± 23 mg/dL 0.95
 Simvastatin 20 mg/d
– 40 mg/d in 37% 0.90
Placebo
 LDL-C reduced 38%
0.85
 Survival and events
– 30% decreased death rate p=0.0003
0.80
– 34% decreased CHD events
 Subsequent secondary prevention
0.00
trials 0 1 2 3 4 5 6
Years Since Randomization
Scandinavian Simvastatin Survival Study Group. Lancet 1994;344: 1383-1389.
 AFCAPS/TexCAPS:
First Acute Major Coronary Event
0.07

0.06
Cumulative Incidence

37% Risk Reduction

0.05 (p = 0.00008)
Placebo
0.04

0.03

Lovastatin
0.02

0.01

0.00

0 1 2 3 4 5 5+ Years
Years of Follow-up
# At Risk
Lovastatin N=3304 N=3270 N=3228 N=3184 N=3134 N=1688
Placebo N=3301 N=3251 N=3211 N=3159 N=3092 N=1644
Downs JR, et al. JAMA 1998;279:1615-22.
 Statin Trials
• Meta-analysis of 14 statin outcome trials
– N=90,056 patients
– Range of duration of studies= 1.9-5.6 years
– 47% had pre-existing CHD
– 24% women
– 21% h/o DM
– 55% h/o HTN
– Range of baseline LDL-C= 118-193 mg/dL

Baigent C, et al. Lancet 2005;366(9493):1267-

 CTT Meta-analysis
For every 1.0 mmol/L (39 mg/dL) reduction in LDL-C…
Endpoint Treatment Control RR (CI)
(45 54)
0
(45 )
002

Non-fatal MI 2001 (4-4%) 2769 (6-2%) 0-74 (0.70-0.79)

CHD death 1548 (3-4%) 1960 (4-4%) 0-81 (0.75-0.87)
Any major coronary event 3337 (7-4%) 4420 (9-8%) 0-77 (0.74-0.80)
CABG 713 (1-6%) 1006 (2-2%) 0-75 (0.69-0.82)
PTCA 510 (1-1%) 658 (1-5%) 0-79 (0.69-0.90)
Unspecified 1397 (3-1%) 1770 (3-9%) 0-76 (0.69-0.84)
Any coronary revascularisation 2620 (5-8%) 3434 (7-6%) 0-76 (0.73-0.80)
Haemorrhagic stroke 105 (0-2%) 99 (0-2%) 1-05 (0.78-1.41)
Presumed ischaemic stroke 1235 (2-8%) 1518 (3-4%) 0-81 (0.74-0.89)
Any stroke 1340 (3-0%) 1617 (3-7%) 0-83 (0.78-0.88)
Any major vascular event 6354 (14-1%) 7994 (17-8%) 0-79 (0.77-0.81)
0.5 1.0 1.5
Treatment Control
better better
Baigent C, et al. Lancet 2005;366(9493):1267-1278 Effect p<0.0001
 1:1 Relationship of LDL-C Reduction and CHD Risk
Reduction Maintained between Statin and Non-Statin
Trials
London WOSCOPS
100 Oslo CARE
MRC LIPID
Nonfatal MI and CHD death

Los Angeles AF/TexCAPS

relative risk reduction, %

80 Upjohn HPS
LRC ALERT
NHLBI PROSPER
POSCH ASCOT-LLA
60 4S CARDS

40

20

–20

15 20 25 30 35 40
LDL-C reduction, %
MI = myocardial infarction.

Adapted with permission from Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.

 Log-Linear Relationship Between LDL-C
Levels and Relative Risk for CHD
• This relation is consistent with
3.7
a large body of epidemiologic
2.9 data available from clinical
Relative Risk trials of LDL-lowering therapy
for CHD 2.2
(Log Scale) 1.7 • These data suggest that for
1.3 every 30-mg/dL change in
LDL-C, the relative risk for
1.0 CHD is changed in proportion
by about 30%
40 70 100 130 160 190
LDL-C (mg/dL) • The relative risk is set at 1.0
for LDL-C = 40 mg/dL

Grundy SM et al. Circulation. 2004;110:227–239.

 Clinical Outcome Trials Testing
Intensive vs Standard Statin Therapy
Trial Population Yrs  LDL-C, RR in 1° RR for
mg/dL End CHD death
Point, % or MI, %
PROVE ACS 2 33 16 16
-IT TIMI (N=4162)
A-to-Z ACS 2 14 11 15
(N=4497)
TNT Stable CAD 5 24 22 22
(N=10 001)
IDEAL Stable CAD 5 23 11 12
(N=8888)
Cannon, C. P. JAMA 2005;294:2492-2494.
Correction JAMA 2005;294:2973.
Copyright restrictions may apply.
 PROVE-IT Substudy: Primary
End Point* and Achieved LDL-C Levels
Achieved LDL (mg/dL)

Hazard Ratio†
>80–100 Referent

>60–80 0.80 (0.59, 1.07)

>40–60 0.67 (0.50, 0.92)‡

£40 0.61 (0.40, 0.91)‡

0 1 2
Lower Better Higher Better

*All-cause mortality, myocardial infarction, coronary revascularization, unstable

angina, and stroke.
†
Adjusted for multiple baseline characteristics, including LDL-C level.
‡
Significantly lower than the referent group.
Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.
 Treating to New Targets (TNT):
First Major Cardiovascular Event*
0.15 Atorvastatin 10 mg, mean
LDL-C 101 mg/dL
Proportion Experiencing Major

Atorvastatin 80 mg, mean Relative

Cardiovascular Event

Risk
0.10 LDL-C 77 mg/dL Reduction
= 22%

P=0.0002
0.05

0.00
0 1 2 3 4 5 6
Time (years)

* Coronary heart disease death, nonfatal non-procedure-related myocardial infarction, resuscitated

cardiac arrest, fatal or nonfatal stroke
LaRosa et al. N Engl J Med 2005;352:1425–1435.
 Intensive LDL-C Goals for High-
Risk Patients
Recommended LDL-C treatment goals

ATP III AHA/ACC guidelines 2006

Update 20041 for patients with CHD*,2 Update
<100 mg/dL: <100 mg/dL:
Patients with Goal for all
CHD or CHD risk <100 mg/dL patients with CHD†,2
equivalents
(10-year risk >20%)1 <70 mg/dL:
A reasonable
<70 mg/dL: goal for all patients
Therapeutic with CHD†,2
option for very
high-risk patients1 <70 mg/dL

• If it is not possible to attain LDL-C <70 mg/dL

because of a high baseline LDL-C, it generally is
possible to achieve LDL-C reductions of >50% with
more intensive LDL-C─lowering therapy, including
drug combinations.
* And other forms of atherosclerotic disease. 2
†
Factors that place a patient at very high risk: established cardiovascular disease (CVD) plus:
multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic
syndrome (triglycerides [TG] ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and acute coronary
syndromes.1
1. Grundy SM et al. Circulation. 2004;110:227–239.
2. Smith SC Jr et al. Circulation, 2006; 113:2363–2372.
 AFCAPS/TexCAPS: RR of Acute Coronary
Events—LDL-C and CRP Level*
No. Patients No. Needed
with Events to Treat†
Lovastatin (L) Placebo (P)
L P better better
LDL-C < median, 19 17 ---
CRP < median (n=1,448)

LDL-C < median, 22 37 48

CRP > median (n=1,428)

LDL-C > median, 15 37 33

CRP < median (n=1,420)

LDL-C > median, 29 40 58

CRP > median (n=1,446)

0.0 0.5 1.0 1.5 2.0 2.5

RR with 95% CI
*Median TC:HDL-C ratio=5.96; median CRP=0.16 mg/dL.
†
Calculated on 5 patient-years at risk to prevent one event.
RR=relative risk; CRP=C-reactive protein; CI=confidence interval.

Adapted from Ridker PM et al. N Engl J Med. 2001;344:1959-1965.

JUPITER Ridker et al NEJM 2008

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

HR 0.56, 95% CI 0.46-0.69 Placebo 251 /

0.08
P < 0.00001 8901

Number Needed to Treat (NNT5) = 25

0.06

- 44 %
Cumulative Incidence
0.04

Rosuvastatin 142 / 8901

0.02
0.00

0 1 2 3 4

Number at Risk Follow-up (years)

Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
JUPITER Ridker et al NEJM 2008

Secondary Endpoint – All Cause Mortality

HR 0.80, 95%CI 0.67-0.97
P= 0.02
0.06 Placebo 247 / 8901

- 20 %
0.05
Cumulative Incidence
0.04
0.03

Rosuvastatin 198 / 8901

0.02
0.01
0.00

0 1 2 3 4

Number at Risk Follow-up (years)

Rosuvastatin 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227
Placebo 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246
JUPITER
Dual Target Analysis: LDLC<70 mg/dL, hsCRP<1 mg/L
0.08

Placebo
HR 1.0 (referent)
0.06
Cumulative Incidence

LDL > 70 mg/dL

and / or
hsCRP > 1 mg/L
0.04

HR 0.59 (0.46-0.75)

LDL < 70 mg/dL

0.02

and
hsCRP < 1 mg/L
HR 0.21 (0.09-0.51)
0.00

0 1 2 3 4

Number at Risk Follow-up (years) P < 0.0001

Rosuvastatin 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145
Placebo 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168
 New Indication for Rosuvastatin
(2010)

For primary prevention “in individuals without clinically

evident coronary heart disease but with an increased
risk of cardiovascular disease based on age ≥50 years
old in men and ≥60 years old in women, hsCRP ≥ 2
mg/L, and the presence of at least one additional CVD
risk factor”
 Statin Therapy and Diabetes
CTT Meta-analysis— Meta-analysis on Risk of Incident
2008 Diabetes Update Diabetes (2010)
Major coronary event
Diabetes
No diabetes ASCOT-LLA
Any HPS
JUPITER
Revascularization WOSCOPS
Diabetes LIPID
CORONA
No diabetes
PROSPER
Any MEGA
AFCAPS/TexCAPS
Stroke 4S
Diabetes ALLHAT
No diabetes GISSI HF
Any GISSI PREV
OR 1.09
Major vascular event (1.02-1.17)
Diabetes RR 0.79 (0.72-0.86)
No diabetes RR 0.79 (0.76-0.82) 0.5 1.0 1.5
Any RR 0.79 (0.76-0.81) 1 additional case of incident diabetes per
255 patients on statins for 4 years
0.5 1.0 1.5
Treatment Control
CTT Collaborators. Lancet 2008;371:117-25; Sattar N, et al. Lancet 2010;375:735-42.
 LDL: Lower the Better

• Lower is Better: review of clinical trials

• Cardiovascular risk in South Asians
• Guidelines for cholesterol management
• Efficacy and safety of statin therapy in South
Asians
Estimated Trends in CHD Cases in
India By Age Group
61.5M

47M

35.9M

27M

NCMH Burden of Disease in India, WHO, 2005

 Characteristics of the Metabolic
Syndrome
Risk Factor (≥3) Defining Level
Abdominal obesity Waist circumference*
Triglycerides ≥150 mg/dl
<40 mg/dl in men;
HDL-C
<50 mg/dl in women
Blood pressure ≥130/85 mm Hg
Fasting glucose ≥110 mg/dl

*In US: men >40 in (102 cm); women >35 in (88 cm)
Modified WHO/IDF criteria in India: men ≥90 cm, women ≥80 cm
Expert Panel. JAMA. 2001;285:2486-2497;
Enas EA, et al. JCMS 2007;2:267-75.
CHD and Metabolic Syndrome in India
• Average age for first MI is 10 years earlier in South
Asians compared to Europeans and Chinese
(INTERHEART)
• Estimated 11% prevalence of CHD in India (Chennai
Urban Population Study)
• 29% of Indian men and 46% of women have MetS
• MetS develops 10 years earlier in Indian men and 20
years earlier in women, compared to whites
• Indians have at least 2x the risk of CHD compared to
whites, after adjusting for MetS and diabetes

Yusuf S, et al. Lancet 2004;364:937-52;

Mohan V, et al. JACC 2001;38(3):682-7.
Enas EA, et al. JCMS 2007;2:267-75.
 Dyslipidemia in South Asians
Lipid Variable South Asians
Compared to
Whites*
Total Cholesterol Similar or lower
LDL cholesterol Similar or lower
HDL cholesterol Lower
Triglycerides Higher
Non-HDL cholesterol Similar
Lipoprotein(a) Higher
Small dense HDL Higher
Small dense LDL Similar
Apo B/Apo A ratio Higher
Total Chol/HDL ratio Higher
Triglyceride/HDL Higher
ratio
*data compiled from multiple studies Enas EA, et al. JCMS 2007;2:267-75.
 Jaipur Heart Watch Studies:
Trends in Lipid Measures in Urban India

 LDL-C
  Triglycerides
  HDL-C


P<.001 P=.027
158±72
127±39 125±53 144±71
122±44 43±14
106±40 130±57
119±31 39±8 42±6
37±6

P=.001

1993-95 1999-01 2001-02 2004-05 1993-95 1999-01 2001-02 2004-05 1993-95 1999-01 2001-02 2004-05

(mg/dL)

Gupta R, et al. Lipids Health Dis 2008;7:40.

Chennai Urban Rural Epidemiology
Study (CURES)
• CURES is a large epidemiological study begun in
2001 in southern India
• In 150 subjects from CURES:
– hsCRP was strongly associated with CAD (OR
1.649, p=0.040) and diabetes (OR 2.264,
p=0.008) after adjusting for age and gender
– hsCRP levels significantly increased with
increases in tertiles of body fat and HbA1c

Mohan V, et al. Diabet Med 2005;22(7):863-70.

CRP Levels Are Associated with Traditional
CV Risk Factors in Asian Indians in UK
SD for % Increase in CRP
Predictor per 1 SD Increase in
Predictor Variable Variable Predictor Variable P
Age, y 6.70 17 <0.001
BMI (kg/m2) 3.79 41 <0.001
Waist-hip ratio 0.069 30 <0.001
Systolic BP, mm Hg 20.0 18 <0.001
Diastolic BP, mm Hg 11.7 19 <0.001
Glucose, mmol/L 1.83 11 0.01
Tg, mmol/L 1.23 22 <0.001

CRP levels are measured infrequently in India—

traditional risk factors, especially obesity, predict elevated
CRP
Chambers JC, et al. Circulation 2001;104(2):145-50.
 LDL: Lower the Better

• Lower is Better: review of clinical trials

• Cardiovascular risk in South Asians
• Guidelines for cholesterol management
• Efficacy and safety of statin therapy in South
Asians
 Dietary and Lifestyle Guidelines

• Include a variety of fruits, vegetables, grains, low-fat or nonfat

dairy products, fish, legumes, poultry, lean meats
• Limit foods high in saturated fat and cholesterol; instead
substitute unsaturated fat from vegetables, fish, legumes, nuts
• Limit excess salt and alcohol consumption
• Engage in aerobic exercise, stop smoking, and lose weight when
needed
Krauss et al. Circulation 2000;102(18):2284-99
ATP 2004 Update: LDL-C Therapy by Risk Categories
Based on Recent Clinical Trial Evidence
Risk Category LDL-C Goal Initiate Therapeutic Consider Drug Therapy
Lifestyle Changes
(TLC)
High risk: CHD or <100 mg/dL ≥100 mg/dL ≥100 mg/dL
CHD risk equivalents
(10-year risk >20%)
Optional goal of <70
Very high risk mg/dL

Moderately high risk: <130 mg/dL ≥130 mg/dL ≥130 mg/dL (consider
≥2 risk factors drug options if LDL-C
(10-year risk (optional goal 100–129 mg/dL)
10%–20%) <100 mg/dL)

Moderate risk: <130 mg/dL ≥130 mg/dL >160 mg/dL

≥2 risk factors
(10-year risk <10%)
Low risk: ≤1 risk <160 mg/dL ≥160 mg/dL ≥190 mg/dL (consider
factor drug options if LDL-C
160–189 mg/dL)

Adapted from Grundy SM et al. Circulation. 2004;110:227–239; http://lww.com

Effects of Drug Classes on Serum Lipids

Drug Class TC LDL HDL TG

Resins  20% 15%–30%  3%–5% Variable

CAI  13%  19%  3%  8%

Nicotinic acid  25% 5%–25%  15%–35% 20%–50%

Fibrates  15% Variable  10%–20% 20%–50%

n-3 fatty acids <--> <--> <-->  35-50%

Statins  15%–60% 18%–60%  5%–15% 7%–30%

Adapted from Gotto AM Jr, Pownall HJ, eds. Manual of lipid disorders. 3rd ed. Baltimore:
Williams & Wilkins; 2003.
 HO CO2Na
HO O HO CO2Na HO O
OH
O OH O
O H3C O
O H F
O O H3C O
H H N
H H
CH3 CH3

HO
H3C
LOVASTATIN PRAVASTATIN SIMVASTATIN FLUVASTATIN

HO HO CO2- HO CO2-
CO2-
OH OH
OH
F F
H
F
Ca2+ Ca2+ Ca2+
N N N N

NH N
O S
O O
2 2 2
ATORVASTATIN ROSUVASTATIN PITAVASTATIN
 Rosuvastatin in Asian Patients
Study found significantly higher exposure to rosuvastatin (40
mg) in Asian subjects living in Singapore compared to white
subjects in the same environment.

Ratio of AUC
N Compared to Whites
Chinese 36 2.3
Malay 35 2.0
Asian Indians 35 1.6
White 36 1.0

Rosuvastatin labeling revised in 2005 to recommend starting

doses of 5 mg/day in Asian patients.

Lee E, et al. Clin Pharmacol Ther 2005;78:330-

 LDL: Lower the Better

• Lower is Better: review of clinical trials

• Cardiovascular risk in South Asians
• Guidelines for cholesterol management
• Efficacy and safety of statin therapy in South
Asians
 Investigation of Rosuvastatin in
South Asians (IRIS)

• 6-week open-label trial conducted in US and Canada

• All lipid-lowering treatments discontinued during 6-
week dietary lead-in
• Eligible participants were South Asians above their lipid
targets (n=740)
• Randomization to rosuvastatin 10 or 20 mg, or
atorvastatin 10 or 20 mg
• Safety outcomes
– All treatments were well tolerated
– No serious treatment-related adverse events

Deedwania PC, et al. AJC 2007;99(11):1538-

IRIS: Effects on LDL-C and HDL-C
Mean % LDL-C Reduction Mean % HDL-C Increase
Rosuva Atorva Rosuva Atorva
10 mg 10 mg 20 mg 20 mg

P=0.0023 Rosuva Atorva Rosuva Atorva

10 mg 10 mg 20 mg 20 mg

Deedwania PC, et al. AJC 2007;99(11):1538-

IRIS: LDL-C Goal Attainment in High-
Risk Patients (n=485)
% Achieving LDL-C <100mg/dL % Achieving LDL-C <70mg/dL

Rosuva Atorva Rosuva Atorva Rosuva Atorva Rosuva Atorva

10 mg 10 mg 20 mg 20 mg 10 mg 10 mg 20 mg 20 mg

Deedwania PC, et al. AJC 2007;99(11):1538-

 Similar Effects of Statin Therapy on
South Asian and White CHD Patients
in Canada

Effects on LDL-C and HDL-C since Initiation of Statin Monotherapy

Atorvastatin (Median 20 mg) Simvastatin (Median 20 mg)

South
South Asians Whites Whites
p Asians p
(n=48) (n=75) (n=41)
(n=26)
% Change
-43 -41 0.3 -35 -37 0.6
LDL-C
% Change
19 12 0.2 12 12 0.9
HDL-C

Gupta M, et al. J Clin Pharmacol 2009;49(7):831-837.

 JUPITER: Safety of Lowering LDL-C <70 mg/dL
140

120
LDL (mg/dL)

100
LDL decreased 50% at 12
80
months in the rosuvastatin
60
group, to a median 55 mg/dL,
40
with no increase in adverse
20
events.
0
0 12 24 36 48
Months
Adverse Events RosuvastatinPlacebo P

Any SAE 1,352 (15.2) 1,337 (15.5) 0.60

Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34
Myopathy 10 (0.1) 9 (0.1) 0.82
Rhabdomyolysis 1 (0.01)* 0 (0.0) --
Incident Cancer 298 (3.4) 314 (3.5) 0.51
Cancer Deaths 35 (0.4) 58 (0.7) 0.02
Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44
*Occurred after trial completion, trauma induced. Ridker et al NEJM 2008
 Conclusion
• Lowering LDL-C reduces cardiovascular risk. There
does not appear to be a lower threshold beyond
which LDL-C reduction ceases to confer clinical
benefit.
• South Asian patients are at increased risk for CHD,
and CHD and MetS develop at a younger age in
Indians compared to other populations.
• Although few trials have been conducted, statin
therapy has been shown to be safe and effective in
South Asians.
• High-risk individuals should be treated to LDL-C <100
mg/dL, preferably <70 mg/dL.
THANK YOU