Cardiovascular disease is a major global health burden. Large epidemiological studies and genetic studies have shown a causal relationship between LDL-C levels and cardiovascular risk. People with lifelong low LDL-C due to genetic mutations, such as loss-of-function mutations in PCSK9, have a significantly reduced risk of cardiovascular events. However, there remains unmet need as cardiovascular risk persists in many patients despite standard therapies due to difficulties achieving LDL-C treatment goals.

1. 1
Cardiovascular disease burden and
remaining unmet needs
Date of Preparation: December 2015
PROES008059

2. 2
Contents
• Burden of disease
• Causal relationship between LDL-C and CV risk
– Large epidemiological studies
– Genetic studies – PCSK9, Niemann-Pick C1-Like 1
– Large statin studies
– IMPROVE-IT study
• Unmet needs
– Persistent CV risk due to poorly controlled LDL-C despite standard of
care therapy
– Difficulties achieving LDL-C goals with current standard of care
• Diabetes

3. 3
Burden of disease

4. 4
CVD is the number one cause of non-
communicable death globally
• A summary of the leading causes of death globally; of the top 10 causes of death globally in 2012, CVD accounted
for 28% of all deaths1
• On average, one American dies from CVD every 40 seconds; equating to approximately 2,200 deaths
each day2
• Each year, CVD causes over 4 million deaths in Europe and over 1.9 million deaths in the European Union3
• >80% of CVD deaths take place in low- and middle-income countries and occur almost equally in men and women4
• By 2030, almost 23.3 million people globally will die from CVD annually, mainly from heart disease and stroke5
0
5
10
15
20
25
30
Percent
(%)
of
deaths
CVD (ischaemic heart disease, stroke and other cerebrovascular
disease)
Lower respiratory infections
Chronic obstructive pulmonary disease
Diarrhoeal disease
HIV/AIDS
Trachea, bronchus, lung cancers
Tuberculosis
The leading causes of death globally1
1. World Health Organization. Factsheet No. 310. http://who.int/mediacentre/factsheets/fs310/en/index.html. Accessed July 2014. 2. Go AS, et al. Circulation.
2013;127:e6–e245. 3. Nichols M, et al. European Cardiovascular Disease Statistics. 4th ed. Brussels, Belgium: European Heart Network; 2012. 4. World Health
Organization Media Centre. http://www.who.int/mediacentre/factsheets/fs317/en/index.html. Accessed February 12 2014. 5. Mathers CD, Loncar D. PLoS Med.
2006;3(11):e442. doi:10. 1371/journal.pmed.0030442.
CVD, cardiovascular disease.

5. 5
There is a high financial burden of CVD
• According to the 2012 European Cardiovascular Disease Statistics,
total costs to the EU economy as a result of CVD were estimated at
almost €196 (US $267) billion per year1
• Between 2010 and 2030, direct medical costs of CVD in the US are
projected to triple, from US $273 (€200) billion to US $818 (€588)
billion*2
– By 2030, the projected total direct and indirect costs of CVD in the US are
expected to exceed US $1 trillion (EU €736 billion)*3
• Direct costs of CVD in Asia are estimated to exceed US $120 (€88)
billion per year and are rapidly rising4
CVD is the number one cause of death globally, with a cost US
$700 (€515) billion in Europe and USA1,2
*Real (2008 US $)
1. Nichols M, et al. European Cardiovascular Disease Statistics. 4th ed. Brussels, Belgium: European Heart Network; 2012. 2. Heidenreich PA, et al. Circulation.
2011;123:933–944. 3. Go AS, et al. Circulation. 2013;127:e6–e245. 4. Asia-Pacific Heart Network (2009). Asia-Pacific heart charter. Available at:
http://www.world-heart-federation.org/fileadmin/user_upload/images/members_area/News/Asia%20Pacific%20HeartChart%20Consultation.pdf. Accessed February
2015.
CVD, cardiovascular disease.

6. 6
Low-density lipoprotein cholesterol and its
relationship to cardiovascular risk
Large epidemiological studies

7. 7
The causal relationship between cholesterol
levels and CV risk is well established
• A meta-analysis of 61 prospective observational
studies of vascular mortality, comprising of nearly
900,000 healthy participants
• Blood pressure and total cholesterol was measured at
baseline to determine the joint relevance of each of
these risk factors1
• There is a continuous positive relationship
between CV risk and serum total cholesterol
concentrations1
• There is a strong positive relationship between LDL-C
reduction with statins and the frequency of CVD
events2
– This is also observed in apparently healthy individuals
without hypercholesterolemia3
• Patients with heterozygous familial
hypercholesterolemia (HeFH) have life-long exposure
to very high LDL-C levels and typically develop CVD
relatively early in life4,5
Reprinted from The Lancet, 370, Prospective Studies
Collaboration, Blood cholesterol and vascular mortality by age,
sex, and blood pressure: a meta-analysis of individual data from
61 prospective studies with 55,000 vascular deaths, page 1831,
Copyright 2007, with permission from Elsevier.
Hazard
Ratio
(95%
CI)
256
128
64
32
16
8
4
2
1
0.5
4.0 5.0 6.0 7.0 8.0
Age at risk
(years)
80–89
70–79
60–69
50–59
40–49
Usual total cholesterol
(1 mmol/L)
Ischemic heart disease mortality
vs total cholesterol
155 193 232 270 309
(mmol/L)
(mg/dL)
1. Prospective Studies Collaboration. Lancet. 2007;370:1829–1839. 2. Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2010;376:1670–1681. 3. Ridker
PM, et al. for the JUPITER Study Group. N Engl J Med. 2008;359:2195–2207. 4. National Institute for Health and Care Excellence (2008). Identification and
management of familial hypercholesterolaemia: NICE clinical guideline 71. Available at: https://www.nice.org.uk/guidance/cg71. Accessed March 2013. 5. Stone NJ,
et al. Circulation. 1974;49:476–488.
CVD, cardiovascular disease

8. 8
The Framingham Study: Relationship between
serum cholesterol levels and CVD mortality
• 30 years of follow-up from the Framingham Study, which investigated the relationship between serum
cholesterol values and cardiovascular disease (CVD) mortality, found that cholesterol levels were directly
related to 30-year CVD and all-cause mortality in individuals under the age of 50
– 5% increase in overall death and 9% increase in CVD death for each 10 mg/dL increase of cholesterol
CVD mortality was directly related to total cholesterol levels in the 30-year follow-up
from the Framingham study1
1. Anderson KM, et al. JAMA 1987;257(16): 2176–80.
†P<0.01 ‡P<0.01
Univariate proportional-hazards model coefficients for cholesterol level and mortality

9. 9
220
180
140 260
8
6
4
2
0
Serum cholesterol mg/dL
Age-adjusted
CHD
death
rate/1000
men/6
years
300
16
14
12
10
18
240
200
160 280
CHD mortality increased
progressively above the 20th
percentile for serum cholesterol
(>181 mg/dL [4.68 mmol/L])
MRFIT screening data: Association of serum
cholesterol and CHD death in 361,662 men
1. Martin MJ, et al. Lancet. 1986;2(8513):933–6.
CHD, coronary heart disease; MRFIT, Multiple Risk Factor Intervention Trial for the Prevention of Coronary Heart Disease.
20
th
percentile
• MRFIT was a large, multicentre cohort study of middle-aged men with high CV risk. Its aim was to determine the
risk relationship between serum cholesterol and CHD, and to compare it with the pattern observed between blood
pressure and CHD risk

10. 10
The Seven Countries Study: Relationship
of serum cholesterol to mortality
Adapted from 1. Verschuren WM, et al. JAMA. 1995;274(2):131–6.
CHD, coronary heart disease.
• This was a 25-year follow-up study of 12,467 men based in seven countries, and across six cohorts. The principal
aim was to determine the relative risk of CHD mortality in relation to cholesterol levels

11. 11
80 100 120 140 160 180
LDL-C (mg/dL)
4.50
2.85
1.80
1.15
0.75
Relative
Risk
of
CHD
Women
n=6907
Men
n=5432
Adjusted for age and race
10-year follow-up
ARIC Study:
Relationship of LDL-C to CHD in men and women
Adapted from 1. Sharrett AR, et al. Circulation. 2001;104(10):1108–13.
ARIC, Atherosclerosis Risk In Communities; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol
ARIC was a population-based sampling of 15,792 residents, 45 to 64 years old from 4
communities in NC, MS, MN, and MD

12. 12
Low-density lipoprotein cholesterol and its
relationship to cardiovascular risk
Genetic studies – PCSK9 and NPC1L1

13. 13
Life-long low LDL-C is associated with significant
reductions in cardiovascular risk
• Modern hunter-gatherer populations with life-long LDL-C levels of
approximately 50–75 mg/dL (1.3–1.9 mmol/L) show little evidence
of atherosclerosis1
• People with genetically determined low levels of LDL-C have shown
that life-long low LDL-C levels are associated with low CV risk2,3
• A meta-analysis of 312,321 subjects showed that long-term
exposure to naturally low levels of LDL-C, resulting from 9 different
polymorphisms in 6 genes, was associated with a 54.5% reduction
in the risk of CHD for each mmol/L lower of LDL-C2
– The latter study suggests a 3-fold greater reduction in the risk of CHD
per unit lower LDL-C than that observed during treatment with a statin
started later in life2
1. O’Keefe JH, et al. 2004;43(11):2142–2146. 2. Ference BA, et al. J Am Coll Cardiol. 2012;60:2631–2639. 3. Benn M, et
al. J Am Coll Cardiol. 2010;55:2833–2842.

14. 14
PCSK9 gain-of-function (GoF) and loss-of-function
(LoF) mutations and their effect on LDL-C
metabolism and CV risk
• PCSK9 GoF mutations are a rare cause of familial hypercholesterolemia
(FH)1
– PCSK9 GoF mutations first found in 2003 through genotype sequencing of
samples taken from the members of two French families with FH2
– Analysis of three genotyping studies and a review article reveals that patients
with PCSK9 GoF mutations have high levels of LDL-C, premature
atherosclerosis, coronary artery disease (CAD) and other CV complications1,3,4
• In contrast, PCSK9 LoF mutations are a rare cause of familial hypobeta-
lipoproteinemia (FHBL)4
– PCSK9 LoF mutations first found in 2005 in African Americans with FHBL
during genetic sequencing of 128 individuals with low LDL-C from the Dallas
Heart study5
– A large prospective study relating the incidence of CAD over 15 years with the
presence of PCSK9 LOF mutations, revealed that patients with LoF mutations
have low plasma LDL-C levels and a consistent reduction in CAD6
1. Abifadel M, et al. Atherosclerosis. 2012;223:394–400. 2. Abifadel M, et al. Nat Genet. 2003;34:154–156. 3. Norata GD, et
al. Atherosclerosi.s 2010;208:177–82. 4. Tibolla G et al, Nut Met Cardiovasc Dis. 2011;21:835–843. 5. Cohen J, et al. Nat
Genetics 2005;37:161–165. 6. Cohen J, et al. New Eng J Med. 2006;354:1264–72.

15. 15
PCSK9 mutations and effect on LDL metabolism
↓LDL-R levels
↓LDL clearance
↑LDL
High risk for atherosclerosis and coronary heart
disease (CHD)
↓LDL
Protection from atherosclerosis and CHD
↑LDL-R levels
↑LDL clearance
Gain of Function Loss of Function
Adapted from 1. Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1):18–28. 2. Soufi M, et al. Gene.
2013;521(1):200–3.
LDL, Low-density lipoprotein.

16. 16
PCSK9 LoF mutations provide genetic validation
for the potential role of PCSK9 inhibition in
LDL-C metabolism and clearance
• Subjects with loss-of-function mutations in PCSK9:
– Have naturally low levels of LDL-C and a reduced prevalence of CV
disease (CVD) relative to the general population (based on two large
prospective studies looking at the relation between CVD and LoF
mutations)1,2
– These LoF mutations are not associated with any detectable clinical
abnormalities1,2
PCSK9 mutation
LDL-C reduction
vs non-carriers
CAD reduction
vs non-carriers
Benn et al. JACC
20101 R46L 13% 30%
Cohen et al. NEJM
20062
R46L
Y142X or C679X
15%
28%
47%
88%
1. Benn M, et al. J Am Coll Cardiol. 2010; 55:2833–42. 2. Cohen JC, et al. N Engl J Med. 2006;354:1264–72.
CAD, coronary artery disease; LoF, loss-of-function.

17. 17
PCSK9 LoF mutations are associated with low
LDL-C and low prevalence of CAD events
From The New England Journal of Medicine, Cohen et al. Sequence Variations in PCSK9, Low LDL,
and Protection against Coronary Heart Disease, 354, 1268, 1270. Copyright © 2013 Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society.
*Nonsense mutations include PCSK9142X PCSK9679X. PCSK946L is a substitution mutation.
• This was a large prospective study investigating the incidence of CAD over 15 years in the Atherosclerosis Risk
in Communities study, in relation to the presence of PCSK9 LoF mutations
Nonsense mutation:
The presence of PCSK9 nonsense
mutations significantly reduces the risk
of coronary heart disease
1. Cohen JC, et al. N Engl J Med. 2006;354:1264–72.
CAD, coronary artery disease; LoF, loss-of-function.

18. 18
Loss-of-function mutations in PCSK9 are
associated with lower serum LDL-C and lower
incidence of CHD
PCSK9 mutations were associated with a 28% reduction
in mean LDL-C and an 88% reduction in the lifetime risk
of CHD (p=0.008 for the reduction; HR=0.11; 95% CI:
0.02, 0.81; p=0.03)
30
20
10
0
Frequency
(%)
1.3 2.6 5.2 6.5 7.8
Plasma LDL-C in black subjects (mmol/L)
0
No mutation
(n=3278)
50th percentile
30
20
10
0
1.3 2.6 3.9 5.2 6.5 7.8
0
PCSK9142X or PCSK9679X
(n=85)
3.9
12
8
4
0
No Yes
PCSK9142X or PCSK9679X
CHD
(%)
1. Cohen JC, et al. N Engl J Med 2006;354:1264–72.
CHD, coronary heart disease.
• This was a large prospective study investigating the incidence of CAD over 15 years in the
Atherosclerosis Risk in Communities study, in relation to the presence of PCSK9 LoF mutations

19. 19
Inactivating mutations of the NPC1L1 gene is
associated with lower LDL-C levels1
11
10
11
7
8
-24 (-50 to 2)
-6 (-30 to 18)
-11 (-33 to 10)
-13 (-27 to 1)
-22 (-53 to 10)
-2 (-29 to 25)
-10 (-31 to 10)
-12 (-23 to -1)
4,586
10,754
22,515
2,287
2,671
European ancestry
CHD-free controls
ARIC
WGHS
Subgroup total
African ancestry
CHD-free controls and JHS
ARIC
Subgroup total
All participants
Mean difference in LDL-C (mg/dL)
-45 25
-10
Subgroup
Number of participants Estimated
difference in
LDL-C (95% CI)
Total Carriers
1. The Myocardial Infarction Genetics Consortium Investigators. N Engl J Med 2014;371(22):2072–82.
ARIC, Atherosclerosis Risk in Communities study; CHD, Coronary heart disease; NPC1L1, Niemann-Pick C1-Like 1; JHS, Jackson Heart Study;
WGHS, Women’s Genome Health Study.
• This was a sequencing/genotyping cohort study of 113,094 people with or without CHD disease, to
identify inactivating mutations of the NPC1L1 gene and its relationship to CHD risk

20. 20
Inactivating mutations of the NPC1L1 gene are
associated with lower CHD risk
• A sequencing/genotyping cohort study of 113,094 people with or
without CHD identified inactivating mutations of the NPC1L1 gene
• Carriers of the 15 different inactivating mutations had, on average,
a 53% reduction in CHD risk compared with non-carriers
(OR=0.47; 95% CI: 0.25–0.87; p=0.008)
• Carriers of NPC1L1 mutations also had significantly lower levels of:
– Total cholesterol (mean adjusted difference, -13 mg/dL [-0.34 mmol/L];
p=0.03)
– LDL-C (mean adjusted difference, -12 mg/dL [-0.31 mmol/L]; p=0.04)
1. The Myocardial Infarction Genetics Consortium Investigators. N Engl J Med 2014;371(22):2072–82.
CHD, coronary heart disease; NPC1L1, Niemann-Pick C1-Like 1.

21. 21
Life-long low LDL-C reduces CHD risk
Life-long exposure to low LDL-C due to single nucleotide polymorphisms (SNPs)
reduces the risk of CHD by 54.5% for each mmol/L lower of LDL-C1
CHD = coronary heart disease
141,565
111,900
186,582
127,651
77,041
82,880
49,160
118,842
75,487
0.88 (0.86—0.90)
0.86 (0.86—0.91)
0.94 (0.92—0.96)
0.72 (0.62—0.84)
0.87 (0.83—0.92)
0.89 (0.86—0.93)
0.94 (0.90—0.98)
0.94 (0.92—0.96)
0.86 (0.83—0.89)
rs599839
rs646776
rs11206510
rs11591147
rs65111720
rs2228671
rs12916
rs4299376
rs4420638
SORT1
PCSK9
LDLR
HMGCR
ABCG8
APOE
(l-squared = 91.8%, p<0.001
0.70 0.80 0.90 1.0
Nearby
gene SNP
Sample
Size (n) OR (95% CI)
A meta-analysis of 312,321 subjects with long-term exposure to naturally low levels of LDL-C,
resulting from 9 different polymorphisms in 6 genes
1. Ference BA, et al. J Am Coll Cardiol. 2012;60:2631–9.
CHD, coronary heart disease.

22. 22
Low-density lipoprotein cholesterol and its
relationship to cardiovascular risk
Large statin and ezetimibe studies

23. 23
Statin trials have also demonstrated that
lowering LDL-C reduces CV risk
• In addition to large epidemiological and genetic studies, the relationship
between LDL-C and CV risk is supported by large statin studies
• The degree of LDL-C reduction is strongly associated with reduced risk of
CV events1–6
– Lowering LDL-C levels with statins in patients with (secondary prevention) or
without (primary prevention) prior CV events has been shown to significantly
improve CV outcomes
– A lower limit of LDL-C below which there is a definite safety problem and/or no
further benefit has not yet been determined2
– Clinical trials with statins have shown increased benefit of reducing LDL-C to low
levels (<50 mg/dL)4,5
• Lowering LDL-C to <70 mg/dL has been recommended as an optional
target for high-risk patients in the latest European guidelines7
1. LaRosa JC, et al. Am J Cardiol. 2012;111:1221–9. 2. O’Keefe JH, et al. J Am Coll Cardiol. 2004;43(11):2142–6. 3. Ference BA, et al. J Am
Coll Cardiol. 2012;60:2631–9. 4. Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2010;376:1670–81. 5. Hsia J, et al. JACC.
2011;56(16):1666–75. 6. Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2012;380:581–90. 7. Reiner Z, et al. Eur Heart J.
2011;32:1769–818.

24. 24
Lowering LDL-C levels in patients with or
without prior CV events has been shown
to significantly improve CV outcomes
25
20
15
10
5
60 100 120 140 160 180
80 200
Event
Rate
(%)
LDL-C Achieved (mg/dL)
30
1
3 4
5
6
8
9 1
2
4
7
Treatment Arm
Control Arm (Placebo)
Control Arm (Active Comparator)
Secondary Prevention
1. POSCH (1990)
2. 4S (1994)
3. CARE (1996)
4. LIPID (1998)
5. MIRACL (2001)
6. HPS (2002)
7. A to Z (2004)
8. ALLIANCE (2004)
9. PROVE-IT (2004)
10. IDEAL (2005)
11. TNT (2005)
Primary Prevention
1. WOSCOPS (1995)
2. AFCAPS (1998)
3. ASCOT (2003)
4. CARDS (2004)
5. MEGA (2006)
6. JUPITER (2008)
7. SHARP (2011)
5
7
10
3
1
7
4
2
3
11
2
9
6
4
7
3
6
5
2
8
610
11
1
5
LDL-C vs CV events
• From a meta-analysis of randomized controlled trials of statins used in primary (N=7) and secondary (N=11)
prevention, produced by the NIH/ACC/AHA Task Force1
Lowering LDL-C levels in patients with (secondary prevention) or without (primary
prevention) prior CV events has been shown to significantly improve CV outcomes
Adapted from 1. Raymond C, et al. Clev Clin J Med. 2014;81:11–19.

25. 25
There is a linear relationship between
reduction in major CV events and LDL-C
reduction in statin trials
LDL-C vs. major CV events
Adapted from CTT
Collaborators, Efficacy and
safety of cholesterol-
lowering treatment
Proportional
reduction
in
CV
event
rate
(SE)
50%
40%
30%
20%
10%
0%
-10%
0.5 1.0 1.5 2.0
Reduction in LDL cholesterol
21%
39
(mmol/L)
(mg/dL)
58 77
19
A later meta-analysis of 26 RCTs involving 170,000 participants demonstrated that with every 1 mmol/L (39
mg/dL) reduction in LDL-C, statins produce a relative risk reduction in major CV events of 22% at 1 year
(standard statin dose vs. control)2
1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2005;366:1267–78. 2. Cholesterol Treatment Trialists’
(CTT) Collaboration. Lancet. 2010;376:1670–81.
• A meta-analysis of data from 14 randomized controlled trials (RCT) of statins including 90,056 participants.
Weighted estimates were obtained of effects on different clinical outcomes per 1.0 mmol/L reduction in LDL-C1

26. 26
Effect of statins in reducing LDL-C and CV events:
The CTT meta-analysis
With every 1 mmol/L (39 mg/dL) reduction in LDL-C, statins produce an approximate
relative risk reduction in major CV events of 22% at 1 year (standard statin dose vs. control)
Adapted from 1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2010;376:1670–81.

27. 27
Very low levels of atherogenic lipoproteins and
the risk for cardiovascular events
Hazard
ratio
LDL-C
Percent
(%)
1.00
50
0.75
0.50
0.25
0
0 100 150 200 250
10
20
30
40
0
(mg/dL)
1.3 2.6 3.9 5.2 6.5 (mmol/L)
30
Risk of major CV
events
Distribution of
achieved on-
statin LDL-C
levels
Patients who achieve very low LDL-C levels (<50 mg/dL) have a lower
risk for major cardiovascular events than those achieving moderately low
levels1
• A meta-analysis including individual patient data (N=38,153) from 8 randomized controlled statin trials –
conventional lipids and apolipoproteins were determined for each participant at baseline and at 1-year follow-up
1. Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485–94.

28. 28
Effect of the addition of ezetimibe to statin
therapy in reducing CV risk:
IMPROVE-IT study design
Patients stabilized post ACS ≤ 10 days:
LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
(N=9067)
Simvastatin
40 mg
(N=9077)
Follow-up visit Day 30, every 4 months
Duration: Minimum 2½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Uptitrated to
simvastatin 80 mg
if LDL-C > 79 mg/dL
90% power to detect
~9% difference
1. Cannon CP, et al. American Heart Association Scientific Sessions, Session LBCT.02 November 17, 2014, Chicago.
*3.2mM **2.6mM
ACS, acute coronary syndrome; CV, cardiovascular; MI, myocardial infarction; UA, unstable angina

29. 29
IMPROVE-IT: Mean LDL-C at 1 year, ITT and OT
1. Cannon CP, et al. American Heart Association Scientific Sessions, Session LBCT.02 November 17, 2014, Chicago.
ITT, intent to treat; OT, on-treatment.
Simva OT: LDL-C 69.5 mg/dL
EZE+Simva OT: LDL-C 52.5 mg/dL
Simva ITT : LDL-C 69.9 mg/dL
EZE+Simva ITT: LDL-C 53.2 mg/dL
LDL-C values at 1 year
ITT
OT
OT: ΔLDLC 17.0 mg/dL ITT: ΔLDLC 16.7 mg/dL
ITT
OT
4
mo
1
yr
Randomization
2
yrs
3
yrs
4
yrs
5
yrs
6
yrs
7
yrs
8
yrs
Time since randomization
40
80
50
60
70
90
100
LDL-C
(mg/dL)
QE
Simvastatin
Ezetimibe/Simvastatin

30. 30
IMPROVE-IT: Primary endpoint on-treatment
1. Cannon CP, et al. American Heart Association Scientific Sessions, Session LBCT.02 November 17, 2014, Chicago.
Simvastatin — KM 32.4%
2079 events
Ezetimibe/Simvastatin — KM 29.8%
1932 events
HR=0.924 CI: 0.868, 0.983
p=0.012
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (> 30 days after randomization), or stroke
7.6% Treatment effect
Time since randomization (years)
7
6
5
4
3
2
1
0
0
10
20
30
40
Event
rate
(%)
CV event rate

31. 31
IMPROVE-IT: Summary
• Key findings:
– Lowering LDL-C with non-statin agent (i.e. ezetimibe) on top of
simvastatin (-17 mg/dL treatment difference vs. simvastatin alone)
reduces the risk of cardiac events in post-ACS patients by a further 7.6%
(HR=0.924; 95% CI: 0.868, 0.983; p=0.012)
– Lowering LDL-C levels (even modestly) beyond those achieved by statins
reduces CV event rates further1
When added to statin therapy, ezetimibe achieves greater LDL-C and major CV
event reductions than statins alone
1. Cannon CP, et al. American Heart Association Scientific Sessions, Session LBCT.02 November 17, 2014, Chicago.

32. 32
Unmet needs
Persistent CV risk due to poorly controlled LDL-C despite treatment
with standard of care

33. 33
Patients with high CV risk face challenges in
achieving LDL-C goals (predominantly US data)
• Statins are the standard of care for HC management
• However, many patients are not reaching their recommended
LDL-C goal with statin therapy1-3
High risk patients1 HeFH patients2,3
23% not
at goal
76% not at
goal
~80% not
at goal
LDL-C Goal <100 mg/dL LDL-C Goal <70 mg/dL LDL-C Goal <100 mg/dL
1. Jones PH, et al. J Am Heart Assoc. 2012;1:e001800. doi: 10.1161/JAHA.112.001800. 2. Stein EA, et al. Am J Cardiol.
2003;92:1287–1293. 3. Pijlman AH, et al. Atherosclerosis. 2010;209:189–194.
HC, hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia.

34. 34
Despite statin therapy, many high-risk patients
have marked LDL-C elevations (EU)
Despite statin therapy, 46.8% high risk patients have LDL-C levels
≥2.5mmol/L (≥100 mg/dL)
Density
Non high-risk
High-risk
0.6
0.5
0.4
0.3
0
0.2
0.1
0
1 2 3 4 5 7
6
LDL-C (mmol/L)
LDL-C 2.5 mmol/L
(100 mg/dL)
46.8%
1.8 mmol/L
(70 mg/dL)
• Cross-sectional, observational study of statin-treated patients (N=22,063) to assess the prevalence of persistent
dyslipidemia in relation to CV risk factors. European Society of Cardiology recommendations were used to classify
patient risk, and to define LDL-C goal and normal levels for HDL-C and triglycerides1
1. Gitt AK, et al. Eur J Prev Cardiol. 2012;19:221–30.

35. 35
Only a small proportion of patients with HeFH reach
the LDL-C treatment target of <2.5mmol/L
• A large cross-sectional study of 1,249 lipid clinic outpatients with known HeFH that recorded data on the use of lipid-
lowering therapy, plasma lipids and lipoprotein levels, safety, and reasons for not achieving treatment goals
Only 21% of patients with HeFH reach the treatment target for LDL-C of
<2.5mmol/L1
Proportion of HeFH patients at LDL-C target for different treatment goals
LDL-C Target (mmol/L)
Attainment
of
Target
(%)
1 2 3 4 5 5 7 8 9 10
0
20
40
60
80
100
2.5
1. Pijlman AH, et al. Atherosclerosis. 2010;209(1):189–194.
HeFH, heterozygous familial hypercholesterolemia.

36. 36
Key patient populations may need additional
LDL-C lowering therapies
Patients who could benefit from
additional lipid lowering therapy
Magnitude of impact
High-risk patients with poorly controlled
LDL-C despite treatment with standard of
care1
Up to 76% of high risk patients fail to
reach their LDL-C goal of less than
70mg/dL1
Those who cannot or will not take statins
due to adverse effects2,3
10–20% of patients treated with high
dose statins show some degree of statin
intolerance2,7,8
40–50% of patients are non-adherent at
1 year9,10
Familial hypercholesterolemia
• at high risk of premature coronary disease4
and who fail to reach their LDL-C goal5,6
Approximately 80% of patients with
familial hypercholesterolemia failed to
reach an LDL-C target <100mg/dL11
1. Jones PH, et al. J Am Heart Assoc. 2012;1:e001800. doi: 10.1161/JAHA.112.001800. 2. Bruckert E, et al. Cardiovasc Drugs Ther. 2005;19(6):403–14.
3. Cohen JD, et al. J Clin Lipidol. 2012;6:208–15. 4. Rees A. Eur Heart J. 2008;29:2583–4. 5. Stein EA, et al. Am J Cardiol. 2003;92:1287–93.
6. Pijlman AH, et al. Atherosclerosis. 2010;209:189–94. 7. Arca M, et al. Diabetes Metab Syndr Obes. 2011;4:155–66. 8. Betteridge DJ, et al. Nat Rev Endocrinol.
2013;doi:10.1038/nrendo.2012.254. 9. Avorn J, et al. JAMA. 1998;279(18):1458–62. 10. Casula M, et al .Patient Preference and Adherence 2012;6:805–14.
11. Stein E, et al. Am Heart J. 2004;148: 447–55.

37. 37
International guidelines recommend lowering LDL-C is the
primary treatment objective in patients with
hypercholesterolemia, with or without a history of CVD
High
CV
risk
ESC/EAS 2011 guidelines for the
management of dyslipidemias2
<70 mg/dL <100 mg/dL
Very
high
CV
risk
LDL-C
target
Approx. LDL-C
relative
reduction from
baseline
ACC/AHA 2013 guidelines on the treatment of
blood cholesterol to reduce ASCVD in adults1
Treat level of ASCVD risk based
on age and tolerability
≥50% 30%–50%
High
intensity
statin
Moderate
intensity
statin
1. Stone NJ, et al. ACC/AHA Guidelines. J Am Coll Cardiol. 2014;63(25):2889–934. 2. Reiner Z, et al. ESC/EAS Guidelines.
Eur Heart J. 2011;32:1769–818. 3. Grundy SM, et al. Circulation. 2004;110:227–39.
ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease.

38. 38
Patients with persistent CV risk despite treatment with standard of care
therapy may benefit from additional lipid-lowering options1,2
Persistent CV risk despite treatment with
standard of care therapy
• Persistent CV risk due to elevated lipids may be reduced by
the additional lowering of:
– LDL-C2,3
– Non-HDL-C3
– ApoB3
– Lp(a)4,5
1. Pöss J, et al. Current Pharmaceutical Design. 2011;17:861–70. 2. Wiviott SD, et al. J Am Coll Cardiol. 2005;46:1411–6.
3. Boekholdt SM, et al. JAMA. 2012;307:1302–9. 4. Kamstrup PR, et al. JAMA. 2009;301:2331–9. 5. Nordestgaard BG, et
al. Eur Heart J. 2010;31:2844–53.

39. 39
Unmet needs
Difficulties achieving LDL-C goals with current standard of care

40. 40
Difficulties achieving LDL-C
goals with statins
• Increasing the statin dose can lower LDL-C further and improve CV
outcomes1-3
– However, high statin doses are underutilized4 and are generally
associated with decreased tolerability1-3,5
• Even with high-potency statin therapy*, only 33% of high-risk
patients with the most difficult to treat hypercholesterolemia are
able to adequately control their LDL-C levels4
• Statin resistance, which is not well defined, also prevents patients
from reaching their LDL-C goal
– Patients do not always respond to statin therapy4
• Beyond statins, therapeutic options are limited6-8
*High potency statins defined as atorvastatin (40 mg or 80 mg), rosuvastatin (20 mg or 40 mg), or simvastatin 80 mg.
1. Cannon CP, et al. N Engl J Med. 2004:350(15):1495–504. 2. LaRosa JC, et al. N Engl J Med. 2005;352:1425–35. 3. Pedersen TR, et al. JAMA. 2005;294:2437–
45. 4. Karalis DG, et al. Cholesterol. 2012; doi:10.1155/2012/861924. 5. Bruckert E, et al. Cardiovasc Drugs Ther. 2005;19(6):403–14. 6. HPS2-THRIVE
Collaborative Group. Eur Heart J. 2013;34:1279–91. 7. The AIM-HIGH Investigators. N Engl J Med. 2011;365:2255–67. 8. Reiner Z, et al. ESC/EAS Guidelines. Eur
Heart J. 2011;32:1769–818.

41. 41
Patients who poorly tolerate statin therapy may
have difficulty achieving LDL-C goals
• 10%–15% of patients treated with high-dose statins show some
degree of statin intolerance1
• Some patients on statin therapy are unable to achieve their LDL-C
goal because of adverse events2
– In the Prediction of Muscular Risk in Observational (PRIMO) study
population, 10.5% of patients on high-dose statin therapy
complained of muscle pain3
– Recent trials have reported the incidence of statin-related muscle
symptoms to be as high as 16%4
Due to statin intolerance, limited and variable efficacy of statin
therapies, some high-risk patients may remain at elevated CV risk5
1. Arca M, et al. Diabetes Metab Syndr Obes. 2011;4:155–66. 2. Karalis DG, et al. Cholesterol. 2012;1–7. 3. Abd TT.
Expert Opin Drug Saf. 2011;10(3):373–87. 4. Ridker PM, et al. N Engl J Med. 2008;359(21):2195–207. 5. Reiner Z, et al.
Eur Heart J. 2011;32:1769–818.

42. 42
Identifying true statin intolerance
• Prevalence of statin intolerance is difficult to define and there is no
universally accepted definition
• Some patients can be successfully rechallenged, questioning the diagnosis
• Patient preference also plays a role
Statin intolerance is a clinical syndrome that is:
i. Characterized by inability to use statins long-term due to
significant symptoms and/or biochemical abnormalities
ii. Either ‘complete’ (intolerant to any statin at any dose) or ‘partial’
(intolerant to some statins at some doses)
iii. Not attributable to established predispositions such as drug-drug
interactions, untreated hypothyroidism, febrile illness, etc1
1. Mancini GB, et al. Can J Cardiol. 2013;29(12):1553–68.

43. 43
PRIMO: Risk of muscle symptoms
with high-dose statins
Statin Dosage
Percentage of patients
with muscular
symptoms*
Odds ratio†
(95% CI)
p-value‡
Pravastatin 40 mg/day 10.9%
Atorvastatin 40–80 mg/day 14.9%
1.28 (1.02,
1.60)
0.035
Simvastatin 40–80 mg/day 18.2%
1.78 (1.39,
2.29)
<0.0001
Fluvastatin 80 mg/day 5.1%
0.33 (0.26,
0.42)
<0.0001
* % values relative to the total number of patients with or without muscular symptoms
† Odds ratios were calculated using pravastatin as the reference
‡ p values were determined by Pearson’s Chi-squared test
1. Bruckert E, et al. Cardiovascular Drugs and Therapy. 2005;19:403–14.

44. 44
Clinical trials and muscle-related adverse effects
Why the low incidence in clinical trials?
• Patients highly selected
• Often have pre-randomization ‘run-in’
• Definitions of muscle adverse effects differ
• Motivated trial patients may minimize symptoms
• Muscular aches and pains are common in placebo group1
1. Mancini GB, et al. Can J Cardiol. 2011;27:635–62.

45. 45
Summary: Why are cholesterol targets not
achieved?
• Over-reliance on diet and lifestyle changes
• Insufficient starting doses of statins
• Inability to reach more aggressive targets even with high dose
statin
• Lack of follow-up for uptitration
• Complacency/inertia with sub-optimal cholesterol values achieved
• Confusion around recommended lipid targets
• Fear of side effects of statins
• Statin intolerance

46. 46
New treatment options in development

47. 47
Non-statin alternative therapies in development:
Emerging options
• PCSK9 inhibitors to increase LDL receptor levels1–4
• Apolipoprotein B (apoB) inhibitor5
• Microsomal triglyceride transfer protein (MTP) inhibitor5
• Cholesterol transport (CETP) inhibitors – increase HDL and
decrease LDL6
*Investigational products
1. McKenney JM, et al. JACC. 2012;59(25):2344–53. 2. Robinson JG. J Manag Care Pharm. 2013;19(2):139–49. 3.
Giugliano RP, et al. Lancet 2012;380:2007–15. 4. Koren MJ, et al. J Am Coll Cardiol. 2014;63(23):2531–40. 5. Rader DJ,
et al. Circulation 2014; 29(9):1022–32. 6. Mabuchi H, et al. Mol Cells. 2014;37(11):777–84.

48. 48
Overview of PCSK9-directed therapies
in development1–7
Company Drug Agent Indication Phase
Inhibition of PCSK9 binding to LDL-R
Sanofi/Regeneron Alirocumab Fully Human mAb Hypercholesterolemia 3
Amgen Evolocumab Fully Human mAb Hypercholesterolemia 3
Pfizer/Rinat
Neuroscience
Bococizumab mAb Hypercholesterolemia 3
Novartis LGT209 mAb Hypercholesterolemia 2
Roche/ Genentech RG7652 mAb Hypercholesterolemia 2
Eli-Lilly LY3015014 mAb Hypercholesterolemia 2
PCSK9 protein binding fragment
BMS/Adnexus BMS-962476 Adnexins Hypercholesterolemia 1
Inhibition of PCSK9 synthesis (gene silencing)
Alnylam ALN-PCS02 siRNA oligonucleotides Hypercholesterolemia 2
Idera TBD
Antisense
oligonucleotide
Hypercholesterolemia Preclinical
Inhibition of PCSK9 autocatalytic processing
Seometrix SX-PCK9 Small peptide mimetic Hypercholesterolemia Preclinical
Shifa Biomedical TBD Small molecule Metabolic Disorders Preclinical
Cadila Healthcare TBD Small molecule Preclinical
mAb: monoclonal antibody
1. Rhainds D, et al. Clin Lipidol 2012;7:621–40. 2. Lambert G, et al. J Lipid Res. 2012;53:2515–24. 3. Clinicaltrials.gov. RUTHERFORD-2, NCT01763918. 4.
Clinicaltrials.gov. SPIRE-HR, NCT01968954. 5. Nature Reviews: Drug Discovery. Selected PCSK9-targeted agents in development. Available at:
http://www.nature.com/nrd/journal/v11/n5/fig_tab/nrd3699_T5.html. Accessed Feb 2015. 6. Clinicaltrials.gov. LY3015014, NCT01890967. 7. Stein EA, Swergold
GR. Curr Atheroscler Rep. 2013:15:310.
mAB, monoclonal antibody; siRNA, short interfering RNA.

49. 49
Alirocumab Evolocumab Bococizumab
DB Trials
ODYSSEY
N
Length
(M)
Patient
Exposure
(Y)
Min
LDL-C
(mg/dL)
DB
Trials
N
Length
(M)
Patient
Exposure
(Y)
Min
LDL-C
(mg/dL)
DB Trials N
Lenght
(M)
Patient
Exposure
(Y)
Min
LDL-C
(mg/dL)
HeFH
FH I 471 18 496 ≥100
RUTHERFOR
D-2
300 3 46 ≥100 SPIRE-HF 300 12 200 ≥70
FH II 250 18 250.5 ≥100
HIGH FH 105 18 106.5 ≥160
Combo Tx
COMBO I 306 12 210 ≥ 70
LAPLACE-2 1700 3 231 ≥80
SPIRE-HR 600 18 600 ≥70
COMBO II 660 24 960 ≥70
OPTIONS I 350 6 50 ≥70
SPIRE-LDL 1600 18 1600 ≥70
OPTIONS II 300 6 50 ≥70
Mono Tx MONO 100 6 25.5 ≥100 MENDEL-2 600 3 92 ≥100
Statin
Intolerant
ALTERNATIVE 250 6 50 ≥70
GAUSS-2 300 3 46 None
PLANNED
GAUSS-3 500 3 NA NA
Long term LONG-TERM 2100 18 2340 ≥70 DESCARTES 905 12 602 ≥75 SPIRELL 939 12 626 >100
Total N of
Patients
4892
~4538 patient-yrs
in DB controlled
trials
Total N of Patients
4305
~1017 patient-yrs
in DB controlled
trials
Total N of Patients
3439
~3000 patient-yrs
(assumes 2:1
randomization, final N
likely to be larger as
anticipate additional
trials)
Most advanced PCSK9 monoclonal antibodies
in development: Phase III programmes
ClinicalTrials.gov. available at: http://clinicaltrials.gov. Accessed August 10, 2014.
DB, double blind; min, minimum

50. 50
CETP inhibitors in development: Impact on
HDL-C and LDL-C
• Greatest impact on HDL-C, some effect on LDL-C as either monotherapy or
in combination with statin therapy
Anacetrapib1–3 Evacetrapib4 Dalcetrapib1,5 Torcetrapib1
Effect on CETP Complete inhibition No data
Modulation
(selective
inhibition)
Complete inhibition
HDL increase
24 weeks: 138%
2-yr extension:
153%
12 weeks: 129% 31% 72%
LDL decrease
24 weeks: 40%
2-yr extension: 40%
12 weeks: 36% No change 25%
Clinical status
Phase III
DEFINE
DEFINE-extension
Phase III
REVEAL (outcome)
Phase II
Primary prevention
Phase III
ACCELERATE
(outcome)
Discontinued -lack
of clinical outcome
benefit
dal-OUTCOMES
Discontinued -
increases in
cardiovascular
events and total
mortality
ILLUMINATE
1. Shinkai H. Vasc Health Risk Manag 2012;8:323–31. 2. Cannon CP, et al. N Engl J Med. 2010;363:2406–15. 3. Gotto AM Jr, et al. J
Cardiovasc Pharmacol Ther. 2014;19(6):543-9. 4. Nicholls SJ, et al. JAMA 2011;306(19):2099–109. 5. Schwartz GG, et al, dal-OUTCOMES
Investigators. N Engl J Med. 2012;367(22):2089–99.
CETP, Cholesteryl Ester Transfer Protein

51. 51
Diabetes

52. 52
Diabetes and CVD risk
• Diabetes mellitus independently raises the risk of CVD1
– The UKPDS23 demonstrated that, in T2DM, patients with high LDL-C were >2x as
likely to develop CAD compared with those with low LDL-C2
• CVD is the most common cause of death in patients with diabetes
– 44% in type 1 diabetes and 52% in type 2 diabetes3
• Patients with diabetes are also more prone to dyslipidemias in the form of:
– Hypertriglyceridemia – approximately 18% of patients with T2DM vs. 8.5% in those
without diabetes
– Low HDL-C levels – twice as high as in patients without diabetes4
• Insulin resistance may also lead to higher levels of small dense LDL-C4
• Type 2 diabetes increases the risk of both micro- and macrovascular
complications3
– Data from the 1999–2004 NHANES indicate that the prevalence of microvascular
complications is significantly higher than that of macrovascular complications5,6
• A prospective observational study of 4,585 patients with type 2 diabetes from
the UKPDS study found that, for every 1% reduction in HbA1c, there was a:
– 37% decreased risk of microvascular complications (33–41%, p<0.0001)
– 14% decreased risk of combined fatal and non-fatal myocardial infarction (8–21%,
p<0.0001)7
1. Reiner Z, et al. Eur Heart J. 2011;32(14): 1769–818. 2. Turner RC, et al. BMJ .1998;316:823–8. 3. Morrish NJ, et al. Diabetologia. 2001;44(suppl 2):S14–S21.
4. Moodarian AD, et al. Nat Clin Pract Endocrinol Metab. 2009;5(3):150–9. 5. Deshpande AD, et al. Phys Ther. 2008;88:1254–64. 6. American Association of Clinical
Endocrinologists. State of diabetes complications in America. Available at: https://nfb.org/images/nfb/publications/vod/images/complications_press_release.doc.
Accessed Feb 10, 2015. 7. Stratton IM, et al. BMJ. 2000;321:405–12.
CAD, coronary artery disease; UKPDS, UK prospective diabetes study; T2DM, type 2 diabetes mellitus; NHANES, National Health and Nutrition Examination

53. 53
-5
Lipid lowering is effective in type 2 diabetes
• The effect of statin therapy in 18,686 individuals with type 2 diabetes was evaluated
from 14 randomized statin trials (≥1,000 participants; treatment duration ≥2 years).
The mean duration of follow-up was 4.3 years
Major vascular events All-cause mortality
Reductions per 1.0 mmol/L
Percentage
(%)
There was a 21% reduction in major CV events per mmol/L reduction in LDL-C in
patients with T2DM treated with statins
0
-10
-15
-20
-25
-21%
-9%
Adapted from 1. Cholesterol Treatment Trialists’ (CCT) Collaborators, et al. Lancet 2008; 371(9607):117–25.
T2DM, type 2 diabetes mellitus

54. 54
LDL-C goal achievement by diabetes status in a
UK primary-care database (2008–2011; N=2999)
• Only half of atorvastatin-treated patients with diabetes achieved LDL-C <2.0
mmol/L
• Goal achievement was highest on atorvastatin 80 mg, yet only 12% of patients
received this maximum dose
1. Jameson K, et al. Curr Med Res Opin. 2014;30:655–65.
DM, diabetes mellitus; CHD, coronary heart disease; AVD, atherosclerotic vascular disease
80
100
40
0
Patients
with
LDL-C
<2.0
mmol/L
(%)
CHD/AVD + DM
20
60
Atorvastatin 10 mg
DM
49.7
49.9 50.9
58.8
50.9
53.9
56.9
43.9
66.2
54.5
CVD risk group
All doses
Atorvastatin 80 mg
Atorvastatin 40 mg
Atorvastatin 20 mg

55. 55
Prevalence of meeting ABC goals among adults
with diagnosed diabetes (NHANES 1988–2010)
*p<0.01 vs 2007–2010 data
† p<0.05 vs 2007–2010 data
50
60
30
0
Patients
(%)
BP <130/80 mmHg
20
40
1988–1994
1999–2002
2003–2006
2007–2010
A1C <7.0%
*
†
*
*
†
ABC
LDL-C <2.6 mmoI/L
*
*
*
*
†
10
Adapted from 1. Stark Casagrande S, et al. Diabetes Care 2013;36:2271–9.
NHANES, National Health and Nutrition Examination Survey; BP, blood pressure; ABC = HbA1c (A), Blood pressure (B) and LDL-C (C)

56. 56
Summary of recent international guideline
recommendations on lipid management
in patients with diabetes
Recommended treatments and LDL-C goals
ADA
20151
• Moderate-intensity statin:
• Diabetes aged <40 y with additional CV risk factors
• Diabetes aged 40–75 y without additional CV risk factors
• High-intensity statin:
• Diabetes aged <40 y with CVD
• Diabetes aged 40–75 y with additional CV risk factors
ACC/AHA
20132
T1/T2DM aged 40-75 y:
• Moderate-intensity statin: diabetes aged 40–75 y
• High-intensity statin: diabetes and estimated 10-year ASCVD risk ≥7.5%
ESC/EASD
20133
• T1/T2DM at very high-risk (overt CVD, severe CKD or ≥1 CV RFs): LDL-C
<1.8 mmol/L
(<70 mg/dL) or at least a ≥50% LDL-C reduction if goal cannot be
reached
• T2DM at high risk (without any CV RFs): LDL-C <2.5 mmol/L (<100
mg/dL)
1. ADA. Diabetes Care. 2015;38 (suppl 1):S49–57. 2. Stone NJ, et al. ACC/AHA Guidelines. J Am Coll Cardiol.
2014;63(25):2889–934. 3. Ryden L, et al. ESC/EASD Guidelines on diabetes. Eur Heart J. 2013;34(39):3035–87.
CVD, cardiovascular disease; CKD, chronic kidney disease; RF, risk factor; T2DM, type 2 diabetes mellitus.

57. 57