Management of LDL as a Risk Factor

Raul D. Santos MD, PhD

Heart Institute-InCor

University of Sao Paulo

Brazil

Disclosure

• Consulting for: Merck, Astra Zeneca, ISIS-Genzyme, Novo-Nordisk, BMS, Pfizer, Lilly, Amgem, Aegerion, Sanofi

• Sponsored research: ISIS-Genzyme, GSK, and Roche

• Speakers Bureau: Pfizer, Merck, Astra Zeneca, Abbott, Biolab and Novartis

Management of LDL as

a Risk Factor

• Epidemiological association of

cholesterol and CVD

• Evidence for cholesterol lowering

– Safety and cost effectiveness

• Statins and diabetes onset

• Unmet needs

• The future

Source: The Lancet 2010; 375:959-961 (DOI:10.1016/S0140-6736(10)60364-9)

LDL particles

What is the importance of cholesterol for CVD ?

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

Lancet 2007; 370: 1829-39

Lancet 2007; 370: 1829–39

N=900,000

What is non-HDL cholesterol ?

HDL LDL IDL VLDL CM remnants

apoA-I apoB apoB apoB apoB 48

Cholesterol

Triglycerides

•All lipoproteins

non-HDL

non–HDL-C = Total Cholesterol − HDL-C

Courtesy Roger Blumenthal

N=302,430

Non-HDL-cholesterol, CHD and, Ischemic Stroke

CHD Ischemic Stroke

N=173,312

JAMA 2009;302:1993-2000

4X more

potent

for CHD

vs. Stroke

FUP 2.79 million /persons years

Intervention studies with statins

What’s the evidence?

Lancet 2010.; 376:1670-81

Impact of 40 mg/dl 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%

Re

du

cti

on

in

CH

D E

ve

nts

%

Risk Reduction (%) in CHD Events p/ 39 mg/dl LDL-C Lowering

According to Treatment Length

2nd year >6th year

3rd to 5th years

Adapted from Law MR et al BMJ 2003;326:1423

1st year

-11

-33

-36

-22

+ Importance of reducing

non-HDL-C

Evaluated studies

• 14 with statins (n=100,827) • 7 with fibrates (n=21.647) • 6 with niacin (n=4.445) • 1 with resins (n=3.806) • 1 with diet (n=458) • 1 with ileal bypass (n=838)

TOTAL – 132,021 patient AVERAGE FOLLOW-UP – 4.5 Y

1% non-HDL-C = 1% CHD risk

J Am Coll Cardiol 2009;53:316-322

The ideal cholesterol level?

Is really lower the better?

LDL-C of MI Subjects in The USA: Primary Prevention 2000-2006

LDL

>130 mg/dL 27.9%

100-129 mg/dL 30.6%

< 100 mg/dL 41.5%

Sachedeva A et al. Am Heart J 2009;157:111-7

N=48,093

<70 mg/dL = 12.5%

Re

lative

ris

k o

f C

HD

de

ath

Total Plasma Cholesterol (mg/dl)

0.5

1.0

2.0

MRFIT

272

0.5

116 156 194 233

0.25

Shanghai 0.125

Low Cholesterol – A China Business?

Chen et al. BMJ. 1991;303:276-82. Kannel et al. Am Heart J. 1986 112:825-36.

CTT: Effects on Major Atherosclerotic Events

Pro

po

rtio

nal

red

uct

ion

in

ath

ero

scle

roti

c ev

ent

rate

(9

5%

CI)

0%

5%

10%

15%

20%

25%

30% Statin vs control

(21 trials)

Mean LDL cholesterol difference

between treatment groups (mg/dL)

More vs Less (5 trials)

0 20 40 10 30

Lancet 2010.; 376:1670-81

What is the cost effectiveness of LDL-C lowering?

Who will benefit the most?

Baseline LDL-C and risk reduction

Lancet 2010.; 376:1670-81

Cardiovascular events per 40 mg/dL reduction in LDL-C in 5 years: CTT

Primary

Prevention

Secondary Prevention

Relative risk reduction

20% 20%

Absolute risk reduction

2% 5%

Events avoided per 1,000 (CI 95%)

25 (19-31) 48 (39-57)

NNT 50 20

Mean LDL-C 148 (118-190) mg/dL

Adapted from CTT Lancet 2005;366:1267-78

Does cholesterol lowering cause cancer?

Alsheikh-Ali et al. JACC 2008;52:1141-7

LDL-C Reduction and Cancer Incidence

Lancet 2010.; 376:1670-81

Do Statins Increase the Risk

of Type 2 Diabetes?

Source: The Lancet 2010; 375:735-742 (DOI:10.1016/S0140-6736(09)61965-6)

Statins and The Risk of

Diabetes: Meta-analysis

Relative increment 9% NNH= 255

Meta-analysis of New-Onset Diabetes and First Major

Cardiovascular Events in 5 Large Trials Comparing

Intensive-Dose to Moderate-Dose Statin Therapy

Preiss, D. et al. JAMA 2011;305:2556-2564

NNH=498/ year NNT= 155/year

Risk of new-onset T2DM: baseline fasting glucose > 100 mg/dl, fasting triglycerides>150 mg/dl, BMI >30 kg/m2, and a history of hypertension

Waters DD et al. JACC 2011; 57:1535-45

Do Statins Increase The

Risk of Hemorhagic Stroke?

Randomized Trials Observational Studies

Hackman et al. Circulation 2011 17 Nov e-pub

N=248,391

Do Statins Cause Cognitive

Changes?

FDA: Statins can cause cognitive

changes that are generally reversible

• 333 cases in post-marketing surveys

• HPS- memory loss objectively measured

by TICS questionnaire • 23.4% vs. 24.2 % simvastatin vs. placebo p=0.4

• Dementia

– 0.3% vs. 0.3%

• Other phsyquiatric changes

– 0.7% vs. 0.7%

Lancet 2002;360: 7–22

Statins and severe muscle

damage

Severe muscle disease with

statins: CTT • N=170,000 in 26 trials

• Defined ad CK levels > 10 x ULN

• Simvastatin 80 mg vs. 20-40 mg

– 4/10,000 vs 1/10,000

• Not seen with high dose atorvastatin

• Not associated with LDL-C lowering

Lancet 2010.; 376:1670-81

What are the unmet needs?

% Rates of CHD Patients Attaining LDL-C <70 mg/dL according to gender:LTAP-2

n=2993

Santos RD et al. Am Heart J 2009;158:860-6

637/2053

242/940 242/940

Total

879/2993

Success Faillure

Gender

Women

242/940

Men

637/2053

P=0.0033

% Non-HDL-C Success Rate by Risk Group

Risk group and success determined according to NCEP ATP III guidelines.

6224/9955

1370/1959

3070/5930

1784/2066

Risk Groups

P<0.001 among risk groups.

Santos RD et al. Atherosclerosis 2012; 224:150-3

What is the future?

Present in some cases…

Antisense oligonucleotides: mechanism of action

• Adapted from: Crooke ST, ed. Antisense drug technology: principles, strategies and applications. 2nd ed. Boca Raton, FL: CRC Press, 2007:601

Antisense drug

(oligonucleotide)

Transcription

No disease-associated

protein produced

No

translation

DNA mRNA

Disease-associated

protein produced

Transcription Translation

Traditional

drug

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

Lomitapide: Mode of Action

41

Decreases Secretion into Bloodstream

Apo B-100

MTP

Apo B-48

MT

P

Intestinal Cell

Liver Cell

VLDL

Chylomicron

n

Diet Source

cholesterol

triglyceride

Liver Source

cholesterol

triglyceride

Lomitapide Efficacy in Phase 3 (Completer Population, N=23)

Study Week

Efficacy Phase Safety Phase

Mean

% C

han

ge in

LD

L-C

fro

m B

L (9

5%

CI)

50%

Reduction

44%

Reduction

p<0.001

p<0.001

LDL-C (mg/dL):

352 ± 116 Baseline

199 ± 123 Week 56

168 ± 96 Week 26

Mean Dose: 40 mg

Mean Dose: 45 mg

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

Impact of an PCSK9 mAb

on LDL Receptor Expression

For illustration purposes only

LAPLACE-TIMI 57: Mean Change in LDL-C from Baseline While

Receiving Statin Therapy to Week 12 With AMG 145

Intervention Baseline

LDL-C (mg/dL)

% Change

LDL-C

Attained

LDL-C (mg/dL)

Placebo 124

AMG 145 70 mg Q2W 120 -42%* 73

AMG 145 105 mg Q2W 128 -60%* 54

AMG 145 140 mg Q2W 120 -66%* 45

AMG 280 280 mg Q4W 124 -42%* 69

AMG 145 350 mg Q4W 124 -50%* 60

AMG 145 420 mg Q4W 120 -50%* 58

n = 631

* p < 0.0001 for % change in LDL-C vs placebo Giugliano et al. Lancet 2012; 380: 2007-17

Changes in Apo B, nonHDL-C, and Lp(a) from Baseline

to Week 12 with Alirocumab

% C

han

ge f

rom

Baselin

e t

o W

eek 1

2

1LS mean (SE)

2median (Q1-Q3)

* p < 00001

† p = 0.0022 McKenney et al. J Am Coll Cardiol 2012;59 2344-2353

10

0

-10

-20

-30

-40

-50

-60

-70

Apo B nonHDL-C Lp(a)

-2% -2%

-34%*

-56%*

-63%*

-0%

-13%†

-26%* -29%* -27%*

-48%*

-56%*

Conclusions 1

• There is a clear association between cholesterol levels and the risk of CHD death

• Cholesterol lowering reduces the risk of cardiovascular events and mortality

• The absolute benefit depends on the risk

• Cholesterol reduction does not increase the risk of cancer, hemorrhagic stroke or cognitive dysfunction

Conclusions 2

• Statin use is associated with an increase in the risk of type 2 diabetes – Absolute risk is small

– Greater in those at higher risk of becoming diabetics at baseline

• There is plenty of room for improvement in prevention of subjects at high risk of CVD