Lowering LDL cholesterol provides significant cardiovascular benefits and reduces risk, even in those with low baseline LDL levels or who achieve very low LDL levels with treatment. While residual risk remains even with intensive statin therapy to lower LDL well below current target levels, risk continues to decrease as LDL is further lowered. The lower the achieved LDL level, the lower the long-term risk of major cardiovascular events and atherosclerotic progression.

1. LDL Cholesterol Target :“ Lower the Better ”
Dr. Arindam Pande
MBBS (Hons), MD, DM, FSCAI(USA), FESC, FACC (USA), FRCP (Glasg)
Consultant Interventional Cardiologist,
Medica SuperSpeciality Hospital, Kolkata
www.drarindampande.com
https://www.facebook.com/DrPandeCardiologist/

2. Sharlayne Tracy

3. * Premature death = under age 70
DALY = Disability Adjusted Life Years; NCDs = noncommunicable chronic diseases.
1. WHO. 2011. Global atlas on cardiovascular disease prevention and control. Geneva: World Health Organization in collaboration with the
World Heart Federation and the World Stroke Organization. 2. WHO. 2016. World Health Statistics 2016: Monitoring health for the SDGs.
Geneva: World Health Organization.
Global Burden of Cardiovascular Disease
Leading cause of death
in the world
• > 17.3 million deaths per year globally
• 10% of the global disease burden
(DALYs)
• Cardiovascular diseases claim
more lives than all forms of cancer
combined
Cardiovascular (CV) Disease1
Top Leading Causes of
Premature Death Globally2*
CVD
Cancer, 27%
Other NCDs, 23%
Respiratory
diseases, 8%
Diabetes, 4%

4. *”Diseases of the Heart” is defined by the NCHS classification used in compiling the leading causes of death. Includes acute
rheumatic fever/chronic rheumatic heart diseases (I00–I09), hypertensive heart disease (I11), hypertensive heart and renal
disease (I13), CHD (I20–I25), pulmonary heart disease and diseases of pulmonary circulation (I26–I28), heart failure (I50),
and other forms of heart disease (I29–I49, I50.1–I51). “Diseases of the heart” are not equivalent to “total cardiovascular disease,”
which the AHA prefers to use to describe the leading causes of death. Source: National Center for Health Statistics.
1. Mozaffarian D, et al. Circulation. 2015;133(4):e38-360. 2. Vanuzzo D. Intern Emerg Med. 2011;6 Suppl 1:45-51.
Despite Recent Reductions,
Deaths Due to Heart Disease Remain High1
Year
DeathsinThousands
Deaths Attributable to
Diseases of the Heart* (US, 1900-2013)
Deaths due to diseases of
the heart have declined
dramatically over the past 2
decades,
yet the number of deaths
remains high and residual
risk remains1
Residual risk is the risk for
incident CV events or the
progression of CV disease
that persists even with
current standard of care2

5. 1. Keenan TE, et al. Curr Cardiol Rep. 2013;(9):396. 2. WHO. 2011. Global atlas on cardiovascular disease prevention and control. Geneva:
World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization. 3. Sharifi M, et al. Heart.
2016;102(13):1003-1008. 4. Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78. 5. Roger VL, et al. Circulation. 2012;125:e2-e220. 6.
Stone NJ, et al. J Am Coll Cardiol. 2014;63:2889-2934. 7. Vanuzzo D. Intern Emerg Med. 2011;6 Suppl 1:45-51.
Multiple Modifiable and Non-modifiable Factors
May Contribute to Cardiovascular Risk
CV = cardiovascular; HeFH = Heterozygous Familial Hypercholesterolemia; HDL = high density lipoproteins; HoFH = Homozygous Familial
Hypercholesterolemia; LDL = low-density lipoproteins; Lp(a) = lipoprotein(a); TG = triglycerides.
Age, Race, Sex4,5
Increased
Cardiovascular
Risk
History of
CV Event6
Smoking2
Lipid Disorders1
(LDL-C, HDL-C, TG, Lp(a))
Type 2 Diabetes,
Metabolic Syndrome2
Obesity2
Genetics3
(e.g., HeFH, HoFH)
Physical Inactivity and
Diet2
Hypertension2
Residual CV risk includes risk from modifiable and non-modifiable risk factors7

6. LDL-C is involved at every stage of atherosclerotic plaque
formation
dysfunction
Plaque
Vulnerable
plaque Rupture Thrombus
Obstructive atherosclerotic
disease
Acute event
 Cardiac vessels − MI
 Brain vessels − stroke
 Peripheral vessels − critical limb ischaemia
Increasing
foam cell
formation2
High concentration of
lipid-filled macrophages,
thin fibrous cap, necrotic
core2
LDL-C reduces eNOS
activity1
LDL and macrophages within the
vessel wall form foam cells2 Foam cell
necrosis 2
Endothelial Fatty acid
streaks
Coagulation and platelet recruitment on exposure
to tissue factor2
Lesion enlarges,
arterial lumen narrows,
blood flow hampered3
Pro-coagulant
pathways may
dominate, leading to
occlusive blood clot3

7. Increasing Age
Non-modifiable risk
age, sex, genetics
Primordial
prevention
of atherogenesis
Total
modifiable risk
Residual
modifiable risk
Gain in event free years
Postponement of coronary event
Plaque
ruptureAsymptomaticphase
Clinical event horizon
Statin Statins + other therapies
Theoretical Disease Trajectories in Coronary Heart Disease Prevention1
1. Adapted from Packard CJ, et al. Vascul Pharmacol. 2015;71:37-39.
Not All CVD Risk Is Modifiable
Probability of a clinical event
without prevention
with first-line statins
Statins + other therapies
with optimal risk factors
”Other therapies” refers to any treatment or lifestyle modification that could further reduce residual risk.
CVD = cardiovascular disease.
Statin modifiable
risk

8. Residual CV Risk Remains Despite Treatment with Lipid
Lowering Agents
CV = cardiovascular.
1. Sampson UK, et al. Curr Atheroscler Rep. 2012;14(1):1-10.
CV Event Rates in Large Prospective Treatment Studies1
PatientsThatSuffered
MajorCVEvents(%)
Secondary Prevention Primary Prevention
28
13
16
12
16
15
11
3
8 8
6
9
19
10
12
9
14 14
9
2
7
6
4
6
0
5
10
15
20
25
30
Control Statin
4S
4,444
CARE
4,159
LIPID
9,014
HPS
20,536
PROSPER
5,804
ASPEN
2,410
TNT
10,001
ASCOT
-LLA
10,305
ALLHAT
10,355
WOSCOPS
6,595
AFCAPS/Te
xCAPS
6,605
CARDS
2,838
Statin Trial
Name
N

9. * Mean or median LDL-C after treatment.
CV = cardiovascular; CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol.
1. Cannon CP, et al. N Engl J Med. 2004;350:1495-1504. 2. Pederson TR, et al. JAMA. 2005;294:2437-2445. 3. LaRosa JC, et al. N Engl Med.
2005;352:1425-1435.
Incidence of Major CVD Events and Levels of LDL-C in Patients Receiving
Moderate- or High-Intensity Statin Therapy1-3
Residual CV Risk Remains Even in Those Receiving
Treatment with High-Intensity Statins
26.3
13.7
10.9
22.4
12
8.7
0
5
10
15
20
25
30
35
40
PatientsExperiencing
MajorCVDEvents(%)
N 4,162 8,888 10,001
LDL-C,* mg/dL 95 62 104 81 101 77
PROVE IT-TIMI 221 IDEAL2
TNT3
Moderate-intensity Statin Therapy
High-intensity Statin Therapy
LDL-C,* mmol/L 2.46 1.60 2.69 2.09 2.61 1.99

10. LDL-C is a major contributor to CV risk
aEvent rates for HPS, CARE, and LIPID are for death from CHD and nonfatal MI. Event rates for 4S and the TNT study also
includes resuscitation after cardiac arrest. CARE, Cholesterol and Recurrent Events Trial; CHD, coronary heart disease; CV,
cardiovascular; HPS, Heart Protection Study; LDL-C, low-density lipoprotein cholesterol; LIPID Long-term Intervention with
Pravastatin in Ischaemic Disease; MI, myocardial infarction; 4S Scandinavian Simvastatin Survival Study; TNT, Treating to
New Targets.
LaRosa JC, et al. N Engl J Med 2005;352:1425–35.
LDL-C levels and event ratesa in secondary prevention statin studies
EventRate(%)
30
25
20
15
10
5
0
0 70 90 110 130 150 170 190
Statin
Placebo
4S
4S
LIPID
LIPID
CARE CARE
HPS HPS
TNT (less-intense LDL-C management)
TNT (intense LDL-C management)
Mean LDL-C (mg/dL)

11. LDL-C is a major contributor to atherosclerotic progression
A-Plus, Avasimibe and Progression of Lesions on Ultrasound; ASTEROID, A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived
Coronary Atheroma Burden; CAMELOT, Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis; LDL-C, low-density lipoprotein
cholesterol; REVERSAL, Reversal of Atherosclerosis With Aggressive Lipid-Lowering; IVUS, intravascular ultrasound.
Sipahi I, et al. Cleve Clin J Med 2006;10:937–44; Nissen SE, et al. JAMA 2006;295:1556–65.
LDL-C levels and atherosclerosis progression in coronary artery IVUS studies
50 60 70 80 90 100 110 120
Mean LDL-C (mg/dL)
ASTEROID
A-PLUS
ACTIVATE
REVERSAL
CAMELOT
MedianChangein
AtheromaVolume(%)
r2=0.95
P<0.001
1.8
1.2
0.6
0
–0.6
–1.2
REVERSAL
Statin
Placebo

12. Clinical benefit of lower LDL is determined by absolute exposure to lower LDL
Ference et al. J Am Coll Cardiol 2015;65:1552–1561.

13. Consistent CV risk reduction independent of baseline LDL-C level
CI, confidence interval; CTT, Cholesterol Treatment Trialists; CV, cardiovascular; LDL-C,
low-density lipoprotein cholesterol; RR, relative risk.
CTT Collaboration. Lancet 2010;376:1670–81.
CTT meta-analysis, N=169,138 in 26 trials
Baseline LDL-C
Events (% per annum)
Statin/Higher Control/Lower RR (CI) per 39 mg/dL reduction in LDL-C
All trials combined
<77 mg/dL 910 (4.1%) 1012 (4.6%) 0.78 (0.61, 0.99)
77 to <97 mg/dL 1528 (3.6%) 1729 (4.2%) 0.77 (0.67, 0.89)
97 to <116 mg/dL 1866 (3.3%) 2225 (4.0%) 0.77 (0.70, 0.85)
116 to <135 mg/dL 2007 (3.2%) 2454 (4.0%) 0.76 (0.70, 0.82)
135 mg/dL 4508 (3.0%) 5736 (3.9%) 0.80 (0.76, 0.83)
Total 10,973 (3.2%) 13,350 (4.0%) 0.78 (0.76, 0.80)
Statin/higher dose better
0.45 0.75 1.0 1.3
Control/lower dose better

14. JUPITER trial: consistent risk reduction
also at low baseline LDL-C
*Overall in the trial, rosuvastatin reduced LDL-C by 50%, suggesting achieved LDL-C of ≤30 mg/dL in this
subgroup. CI, confidence interval; LDL-C, low-density lipoprotein cholesterol.
Hsia J et al. J Am Coll Cardiol 2011;57:1666–75.
Baseline LDL-C N
HR (95% CI) for
Primary Endpoint
≤130 mg/dL 17,802
≤120 mg/dL 13,972
≤110 mg/dL 9784
≤100 mg/dL 6269
≤90 mg/dL 3687
≤80 mg/dL 2033
≤70 mg/dL 1022
≤60 mg/dL* 511
0.20 0.50 1.00 2.00
Rosuvastatin Superior Rosuvastatin Inferior

15. The lower the LDL-C achieved, the lower the risk of CV
events
aRCT in patients with stable coronary disease. Major CV Events = death from CHD, nonfatal non-procedure-related MI, resuscitation after cardiac
arrest, or fatal or nonfatal stroke. bRCT of patients with LDL-C <130 mg/dL, high-sensitivity C-reactive protein ≥2.0 mg/L, and no history of CVD
or diabetes mellitus. Major CV events = CV death, MI, stroke, arterial revascularization, or hospitalized UA. ‡post randomization LDL-C. cRCT in
patients with stabilized ACS. Primary composite endpoint of death, MI, stroke, revascularization, and UA requiring hospitalization.
ACS, acute coronary syndrome; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; LDL-C, low-density lipoprotein
cholesterol; MI, myocardial infarction; RCT, randomized controlled trial; UA, unstable angina.
1. LaRosa JC, et al. J Am Coll Cardiol 2007;100:747–52.
2. Hsia J, et al. J Am Coll Cardiol 2011;57:1666–75.
3. Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411–6.
TNT1,a
Rate of major CV events
JUPITER2,b
Time to occurrence of major CV events
PROVE-IT3,c
Hazard ratio of primary endpoint
P for trend <0.0001
0 1 2 3 4
Follow-up (Years)
0.00
0.02
0.04
0.06
0.08
CumulativeIncidence
Placebo
LDL-C >50 rosuvastatin
LDL-C <50 rosuvastatin
*P value for trend across LDL-C
≤40
>40–60
>60–80
>80–100
0.80 (0.59, 1.07)
0.67 (0.50, 0.92)
0.61 (0.40, 0.91)
Lower Better Higher Better
Referent
0 1 2
AchievedLDL-C(mg/dL)
LDL-C (mg/dL)
0
<64
2
4
6
8
10
12
14
64–<77
77–<90
90–<106
≥106
P<0.0001*
%ofPatientsWithMajorCVEvents

17. LAI 2016: Treatment Goal

18. Clinical Studies – Evolocumab achieving unprecedented
low levels

19. Safety issues???

20. Cells Acquire Cholesterol from Various Sources
• Cholesterol for cellular physiologic functions can be from intra and/or
extracellular pathways
HDLR = high-density lipoprotein cholesterol receptor; LDL-C = low-density lipoprotein cholesterol; LDL-R = LDL receptor;
LDLRP = LDLR protein; SR-B1 = scavenger receptor class B type 1.
Mc Auley MT, et al. BMC Syst Biol. 2012;6:130. Xie C, et al. J Lipid Res. 2006;47:953-963. Hu J, et al. Nutr Metab (Lond).
2010;7:47. Orth M, Bellosta S. Cholesterol. 2012;2012:292598. Dietschy JM, Turley SD. J Lipid Res. 2004;45:1375-1397.
Figure adapted from Dietschy 2004.
Intracellular concentrations of
cholesterol are tightly regulated
and cells are not dependent on
circulating plasma LDL-C for
cholesterol synthesis.3

21. The Central Nervous System Synthesizes
Cholesterol De Novo
• The central nervous system
synthesizes cholesterol de
novo1,2
• The blood–brain barrier
prevents the uptake of
systemic lipoprotein
cholesterol1,2
• This segregation ensures that
cholesterol metabolism within
the brain is isolated from
changes in the circulating lipid
levels2
Cholesterol
Brain
SRE-regulated
gene products
Transcription
Acetyl-CoA
Cholesterol
Blood–brain
barrier Blood
Regulation of
neuronal function
Small GTP-binding
proteins
Isoprenoids
Prenylation
Cholesterol
24-hydroxylase
24S-hydroxycholesterol
24S-hydroxycholesterol
SRE
1. Björkhem I, Meaney S. Arterioscler Thromb Vasc Biol. 2004;24:806-815. 2. Katsuno M, et al. Nat Med. 2009;15:253-254.
Figure adapted from Katsuno M et al. 2009.

22. Safety Events
0
5
10
Neurocog
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
AST/ALT↑ CK↑
LDL-C (mgdL)at 4wks
Non-CV death Hem stroke
Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017
Adj P-values for trend >0.10
for each comparison
% pts
<20
20-49
50-69
70-99
>100
No safety concerns even with LDL <20mg/dl

23. A Quarter of a Century of Treating LDL-C
LDL‐C(mg/dL)
200
180
160
140
120
100
80
60
40
20
0
1994 1996‐2002 2004‐2005 2015 2017
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School

24. A Quarter of a Century of Treating LDL-C
LDL‐C(mg/dL)
200
180
160
140
120
100
80
60
40
20
0
1994 1996‐2002 2004‐2005 2015 2017
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School

25. If we can eradicate Polio………. why not
LDL?