Raul D. Santos MD, PhD Heart Institute-InCor

University of Sao Paulo Brazil

Agents to reduce LDL (and future developments)

Disclosure

• Honoraria for consulting and speaker activities on the last 2 years from

– Amgen, Aegerion, Astra Zeneca

– Biolab, BMS, Boehringer Ingelheim

– Genzyme, Merck, Praxis

– Pfizer, Eli Lilly, Novartis, Nestlé, Unilever

– Sanofi/Regeneron

2

• Epidemiology • Current options

– Statins – Ezetimibe – Resins – Niacin

• Recently approved and future treatments – Lomitapide – Mipomersen – CETP inhibitors – PCSK9 inhibitors

Agents do reduce LDL

3

Epidemiology

4

Cholesterol and CHD Mortality

Lancet 2007; 370: 1829–39

N=900,000

N=302.430

Non-HDL-cholesterol, CHD and Ischemic Stroke

CAD Stroke

N=173.312

JAMA 2009;302:1993-2000

Statins

Statins: Mechanism of Action

Statins inhibit HMG-CoA reductase

Intrahepatic cholesteorl pool reduction

Reduction of VLDL production

Less VLDL particles available to become LDL Incrementof LDL catabolsim

Increment on LDL receptor expression

Reduction of : LDL-C, TC, non-HDL-C and TG

HMG-CoA redutase

*P<0.002 vs ATV 10 mg; PRA 10 mg, 20 mg, 40 mg; SIN 10 mg, 20 mg, 40 mg. **P<0.002 vs ATV 20 mg, 40 mg; PRA 20 mg, 40 mg; SIN20 mg, 40 mg, 80 mg.

análise de 10-40 mg .

Jones PH et al. AJC. 2003;93:152-160.

RSV ATV SIN PRA

10 20 40 10 20 40 10 10 20 40

* -51

-55

-46

** ***

20 40 80 80

-46

-37

-43

-48

-28

-35

-20 -24

-30

-39

-60

-50

-40

-30

-20

-10

0

-52

Effects of Statins on LDL-C: STELLAR (% Changes vs. Baseline)

%

Impact of 1mmol/L reduction on LDL-C upon major

cardiovascular events and mortality

CTT 2010

Relative Risk (95% CI)

All cause mortality 0.90 (0.87-0.93), p<0.0001**

CHD mortality 0.80 (0.74—0.87); p<0.0001**

Other cardiac deaths 0.89 (0.81—0.98); p=0.002**

Stroke deaths 0.96 (0.84—1.09); p=0.5

Major vascular events 0.78 (0·76—0·80); p<0.0001

Non-fatal MI 0.73 (0.70 − 0.77); p<0.0001

Myocardial revascularization 0.75 (0.72 − 0.78); p<0.0001

Ischemic stroke 0.79 (0.74 − 0.85); p<0.0001

Cancer incidence 1.00 (0.96 − 1.04); p=0.9

Hemorrhagic stroke 1.12 (0.93 − 1.35); p=0.2

Adapted from The Lancet 2010.; 376:1670-81 **- CI 99%

Non-Lipid Lowering Effects of Statins

Jain MK, Ridker PM. Nature Rev Drug Discov, 2005

Statins: Side Effects

• Muscle

• Liver (??)

• Diabetes

• Hemorrhagic stroke (???)

• Cognitive functions ???????????

12

Ezetimibe

NPC1L1 Transports Intestinal Cholesterol and

Phytosterols: Inhibition of NPC1L1 by Ezetimibe for

Hypercholesterolemia and Sitosterolemia

Sitosterolemia

Cholesterol and

Plant Sterols

NPC1L1

Ezetimibe reduces cholesterol absorption in humans F

ra

ct

io

na

l C

ho

le

ste

ro

l A

bs

orp

tio

n

(%

)

0

20

40

60

80

0

20

40

60

80Mean = -54%

Range: 0 to -94%

LDL-C = - 20.4%

Sudhop et al. Circulation 106:1943, 2002

Mild Hypercholesterolemic Pure Vegetarians

Clarenbach JJ et al. J Lipid Res. 47:2820,2006

Mean = -58%

LDL-C = -17.3%

15

Farnier M et al. Atherosclerosis 2013; 229:415 - 422

Effects of ezetimibe, simvastatin and simvastatin/ezetimibe on pro-atherogenic lipids and

apoB

16

CTT/SHARP: Effects on ischemic events in CKD

Mean difference of LDL-C among treated groups (mg/dL)

Rel

ativ

e ri

sk r

edu

ctio

n

of

isch

emic

eve

nts

(9

5%

HF)

0%

5%

10%

15%

20%

25%

30%

0 20 40 10 30

Statins vs. control

(21 studies)

Intensive hypolipidemia

treatment vs.

Conventional

(5 studies)

SHARP

17%

risk

reduction

SHARP

32mg/dL

Baigent et al. Lancet 2011; 377;2181–2192. 17

IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit

CTT Collaboration.

Lancet 2005; 366:1267-78;

Lancet 2010;376:1670-81.

IMPROVE-IT

Cannon C. AHA Presentation 2014

Ezetimibe: Side Effects

• Gastro intestinal

19

Bile acid binding resins

Bile Acid Binding Resins

:Mechanism of Action

Gotto AM and Pownall HJ: Manual of Lipid Disorders. 1992

The first study showing that cholesterol

reduction prevents CVD was done with a

resin

JAMA 1984; 251:351

Bile Acid Resins: Side effects

• Gastro intestinal (much less with colesevelam)

• Increase in TG levels

• Binding to other medications

23

Niacin

24

Niacin: Mechanisms of Action

• Adipose tissue

– Hormone sensitive Lipase (GPR109A)

– FFA to the liver and TG and VLDL

– PPAR gamma – ABCA1

• Liver

– Production and Apo B degradation

– Apo A-I (?)

Digby JE ATVB 2012;32:582-8

Lamon-Fava S et al . ATVB 2008;28:2672-8

Extended release Niacin

Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U Guyton JR et al. Am J Cardiol 1998;82:82U-84U

Changes vs. baseline (Mean %)

ER Niacin +

Statins

ER Niacin

320 Week 48 -12 -18 +26 -30 -16 -27

225 Week 96 -13 -20 +28 -40 -17 -28

723 V. Baseline – – – – – –

120 Week 48 -27 -36 +28 -36 -30 -33

122 Week 96 -27 –36 +27 -41 -30 -35

Treatment n Duration TC LDL-c HDL-c Lp(a) ApoB TG

All changes significant

Coronary Drug Project: Long term mortality reduction in post

AMI patients with niacin

Niacin

Placebo

P = 0,0012

100

90 80

70

60 50

40 30 20 10

0 2 4 6 8 10 12 14 16

Years of follow-up

Surv

ivia

l (%

)

Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

HPS 2 THRIVE: Niacin/Laropiprant not effective in patients with well controlled LDL-C

The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203-212.

Niacin-ER: side effects

• Flushing

• Glucose intolerance/Diabetes

• Skin infections

• Gout

• Peptic Ulcer

Recently Approved Drugs for Homozygous Familial Hypercholesterolemia

30

MTP inhibitors

Lomitapide

Lomitapide: Mode of Action

32 p0300 Lomitapide causes a higher rate of gastrointestinal sideeffects and aminotransferase elevations than does ezeti-mibe. However, all adverse events disappeared after drugdiscontinuation.

s0145 Phase 3 Studyp0305 Research has shown that HoFH patients given an average

dose of 40 mg/day of lomitapide had reductions in LDL-C,apoB, and TG concentrations of 50%, 49%, and 45%, respec-tively, after 26 weeksof treatment. Similarly, Lp(a) and HDL-C levels were reduced at week 26, but these levels returnedto baseline by week 78 (Table 38-7). Of 29 HoFH patientswho took lomitapide, 3 were able to discontinue LA, and3 others permanently increased the time interval betweenLA treatments.133

s0150 Safetyp0310 Phase 3 studies indicate that the most common side effects

(seen in 28%of patients) of lomitapide are diarrhea, nausea,vomiting, dyspepsia, and abdominal pain.133Approximatelyone third of study participants had an elevation in at least

one liver enzyme to greater than or equal to three timesthe upper limit of normal. Approximately 14% of studypatients had elevated liver enzymes at greater than or equalto five times the upper limit of normal. Dose reduction ortemporary drug discontinuation resulted in normalizationof liver enzymes. No clinically significant changes in biliru-bin, prothrombin time, or alkaline phosphatase occurred.As expected, because of lomitapide's mechanism ofaction,130mean hepatic fat content increased approximately7.6%on average (range 0%–30%) by week 26, but no furtherincreases were reported at week 78. Longer term hepaticsafety studies of lomitapide still need to be conducted.

p0315Because individuals taking lomitapide must consume alow-fat diet, and because lomitapide causes fat malabsorp-tion, patientsshould concomitantly be given vitamin E, lino-leic acid, alpha-linolenic acid, eicosapentaenoic acid, anddocosahexaenoic acid supplementation.134 As with mipo-mersen, because lomitapide can cause adverse events suchas liver toxicity, it is available in the United States onlythrough a risk evaluation and mitigation strategy program.

Comp. by: GAsokpandian Stage: Revises1 Chapter No.: 38 Title Name: BallantyneDate:22/8/14 Time:14:40:34 Page Number: 11

TABLE 38-7t0040 Effects of Lomitapide 5 to 60 mg (Average Dose 40 mg/day) on Plasma Lipids, Apolipoprotein B, andLipoprotein(a)

PATIENT POPULATION(BASELINE: N =29)

% CHANGE INLDL-C

% CHANGE INAPOB

% CHANGE INTRIGLYCERIDES

% CHANGE INLP(A)

% CHANGE INHDL-C

Week 26 (n¼26) –50* –49* –45* –15* –12*

Week 56 (n¼26) –44* –45* –29* –19* 1

Week 78 (n¼26) –38* –43* –31* –1 –5

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Baseline lipid levels (n¼29): LDL-C¼336 mg/dL; apoB¼259 mg/dL; triglycerides¼92 mg/dL; HDL-C¼43 mg/dL; Lp(a)¼67 mg/dL.*Significant change versus baseline.

Data from reference 133

Lower VLDL, LDL,chylomicrons, and

chylomicron remnants

Blood vessel

Intestinal epithelial cell

Cytoplasm

ER

Luman

ApoB48degraded

MTP

TG

Liver cell

Cytoplasm

ER

Luman

ApoBdegraded

MTP

FIGURE 38-9f0050Au1 Effects of microsomal triglyceride transport protein (MTP) inhibit ion by lomitapide. ApoB, apolipoprotein B; LDL, low-density lipoprotein; TG, triglyceride;VLDL, very-low-density lipoprotein. (Modified from references 130,132,134,135.)

B978-0-323-28786-9.00038-4, 00038

Ballantyne, 978-0-323-28786-9

11

38Sp

ecia

lPatie

nt

Po

pu

latio

ns:

FH

an

dO

the

rSev

ere

Hy

perch

ole

stero

lem

ias

To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier andtypesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication.

Moriarty & Santos In Clinical Lipidology: A companion to Braunwald’s Heart DIsease 2015

Phase 3 Study in Patients with HoFH: LDL-C Reduction (Mean % Change) From Baseline to Week

78

3

3

352mg/dL 336mg/dL

Baseline Week 26 Week 56

50.2% reduction

40.1% reduction

Week 78

44.0% reduction 38.4% reduction

(CA) 0mg (ITT)

44.6mg 38.4mg 40.2mg 40.7mg 0mg

Adapted from Cuchel M et al. Lancet 2013; 381:40-46

Adverse Event Category

n of subjects (%)

weeks 0-26

N=29

n of subjects (%)

weeks 26-78

N=23

Any adverse event 27 (93.1) 21 (91.3)

GI Disorders 27 (93.1) 17 (73.9)

Diarrhea 23 (79) 8 (35)

Nausea 18 (62) 7 (30)

Lab abnormalities 15 (51.7) 10 (43.5)

ALT elevation >5 x ULN 4 (13.8) 1 (4.3)

HoFH Phase 3 Study

Treatment Emergent Adverse Events

Adapted from Cuchel M et al. Lancet 2013; 381:40-46

Figure 2

Lomitapide: Hepatic Safety

Cuchel M et al. Lancet 2013; 381:40-46

Antisense Oligonucleotides

Mipomersen

Antisense Therapy1-3

mRNA = messenger RNA.

1. Crooke RM, Graham MJ. Clin Lipidol. 2011;6,675-692.

2. Koller E, et al. Trends Pharmacol Sci. 2000;21:142-148.

3. Visser ME, et al. Eur Heart J. 2012;33:1451-1458.

• Antisense molecules are short, single-stranded, synthetic analogues of natural nucleic acids that are complementary to, and thus bind with, a specific mRNA to prevent disease-related protein synthesis

+

mRNA

mRNA

Protein synthesis Proteins

Antisense Protein synthesis inhibited

Fewer proteins

Raal FJ, Santos RD et al. Lancet. 2010;375:998-1006

39

Pooled Population Homozygous FH

Santos RD et al ATVB 2015 e pub

Incidence of injection site reactions (ISRs) and flu-like symptom (FLS)

events occurring at least once over time.

Santos R D et al. Eur Heart J 2013;eurheartj.eht549

All Subjects

Completers

ISR = 1 in 10 FLS= 1 in 52

Change from baseline in ALT levels and liver fat fraction over time.

Santos R D et al. Eur Heart J 2013;eurheartj.eht549

ALT

Liver Fat

Antibodies against PCSK9

Effect of PCSK9 antibodies in increasing the expression of the LDLR

Percent Reduction from Baseline in Low-Density Lipoprotein (LDL) Cholesterol Levels in the Evolocumab Group, as Compared with the Placebo Group, at

Weeks 12 and 52, According to Background Lipid-Lowering Therapy.

Blom DJ et al. N Engl J Med 2014;370:1809-1819.

N=901

45

Evolocumab Reduces Lp(a) in Heterozygous FH

-35

-30

-25

-20

-15

-10

-5

0

350 mg 420 mg

Lp(a)

46 Raal F et al. Circulation 2012;126:2408-2417

% C

han

ge F

rom

Bas

elin

e

CETP Inhibitors

47

CETP inhibition

Forrester J et al. Circulation. 2005;111:1847-1854

Changes in Cholesterol and Blood Pressure : Anacetrapib

Cannon CP et al. N Engl J Med 2010;363:2406-2415

Ongoing Phase III Trials Anacetrapib Evacetrapib

Name (ID) REVEAL (NCT01252953) ACCELERATE (NCT01687998)

Company Merck (Oxford trial Sponsor) Eli Lilly

Dose 100mg daily 130mg daily

Sample size 30,000 11,000

Inclusion 1) Age ≥50yrs 2) Hx of MI 3) Stroke or cerebr. revasc 4) PAD repair/revasc 5) DM with symptomatic CAD

1) Age ≥18yrs 2) Hx of ACS (30 to 365 days) 3) Cerebrovascular 4) PAD 5) DM with documented CAD

PEP Coronary death, MI, or Coronary Revascularization

CV death, MI, Stroke, Coronary Revascularization, or Hospitalization for UA

Study duration 1) Median ~4 yrs 2) ≥1900 Primary endpoints

1) Median ~2yrs 2) ≥1136 Primary endpoints

• LDL-C is an independent risk factor for atherosclerosis

• There are many proven therapies that reduce LDL-C and prevent CVD

• Statins are the cornerstone of LDL-C lowering

• Other drugs should be added to control LDL-C adequately

Conclusions

51